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WO2025214467A1 - Amino-substituted heteroaromatic cyclic compound, preparation method therefor and use thereof in medicine - Google Patents

Amino-substituted heteroaromatic cyclic compound, preparation method therefor and use thereof in medicine

Info

Publication number
WO2025214467A1
WO2025214467A1 PCT/CN2025/088477 CN2025088477W WO2025214467A1 WO 2025214467 A1 WO2025214467 A1 WO 2025214467A1 CN 2025088477 W CN2025088477 W CN 2025088477W WO 2025214467 A1 WO2025214467 A1 WO 2025214467A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
cycloalkyl
heterocyclyl
heteroaryl
alkylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/088477
Other languages
French (fr)
Chinese (zh)
Inventor
李心
董怀德
陈一千
白东栋
贺峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2025214467A1 publication Critical patent/WO2025214467A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure belongs to the field of medicine and relates to an amino-substituted heteroaromatic ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a TYK2 inhibitor and/or degrader and its use in the preparation of a medicament for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.
  • general formula (I) an amino-substituted heteroaromatic ring compound represented by general formula (I)
  • a preparation method thereof a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a TYK2 inhibitor and/or degrader and its use in the preparation of a medicament for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.
  • Cytokine signaling plays a key role in controlling the growth, differentiation, function, and communication of immune cells.
  • Receptor-bound Janus kinases JAKs
  • STATs signal transducers and activators of transcription
  • JAK family members including JAK1, JAK2, JAK3, and TYK2, are non-receptor tyrosine protein kinases associated with cytokine receptors. Following stimulation and oligomerization of these receptors, JAK molecules are activated and phosphorylate receptor tyrosine residues, which serve as docking sites for the subsequent recruitment and phosphorylation of STAT proteins. In turn, phosphorylated STAT proteins dimerize, translocate to the nucleus, and activate transcription of genes that mediate cytokine-induced responses. These cytokine-mediated JAK/STAT pathways are tightly regulated, and dysfunctional JAK/STAT activity has been shown to be a hallmark of numerous immune and autoimmune diseases, inflammatory disorders, and cellular transformation.
  • Tyrosine kinase 2 (TYK2), the first member of the JAK family to be identified, is a component of various cytokine pathways, leading to STAT-dependent gene transcription and specific functional responses to cytokines, including the interleukin-12/-23 family (IL-12/IL-23, which share a common p40 subunit), the type I interferon (IFN) family, and the IL-6 and IL-10 families.
  • IL-12/IL-23 which share a common p40 subunit
  • IFN type I interferon
  • IL-6 and IL-10 families TYK2-mediated cytokine signaling plays a key role in the pathogenesis of autoimmune and inflammatory diseases.
  • IL-23 a heterodimer containing p40 and p19 subunits
  • Th17 T helper 17
  • IL-12 composed of p40 and a unique p35 subunit, plays an important role in regulating Th1 development and IFN- ⁇ secretion by these cells.
  • IL-12 and IL-23 play an important role in a variety of inflammatory diseases [such as psoriasis (Ps), lupus, inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA)] (Michele WL T et al., "IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases" Nat Med. 2015, 21: 719–729).
  • Ps psoriasis
  • IBD inflammatory bowel disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • IL-12 and IL-23 subunit, P40, or the shared receptor, IL23R have been found to protect mice from various autoimmune diseases, including psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis (Kyttaris VC et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice," J Immunol. 2010, 184:4605-9).
  • IL-12 and IL-23 have been observed in the lesional skin of psoriasis patients, which then decreases after various psoriasis treatments.
  • monoclonal antibodies that block the IL-12/IL-23 common subunit p40 (Ustekinumab, Briakinumab, etc.) or the IL-23-specific subunit p19 have demonstrated clinical efficacy in the treatment of psoriasis, Crohn's disease, and other conditions.
  • type I IFN family members (IFN- ⁇ , - ⁇ , - ⁇ , - ⁇ , - ⁇ , - ⁇ , etc.), which act through heterodimeric IFN receptors (IFNARs), are important mediators of innate and adaptive immunity. They can also activate multiple components of the immune response and enhance the expression and release of autoantigens, making them key players in the amplification of autoimmune diseases.
  • IFNARs heterodimeric IFN receptors
  • PBMCs peripheral blood mononuclear cells
  • TYK2 inactivated or chemically inhibited in vivo have been found to exhibit disease resistance in experimental autoimmune disease models such as psoriasis, multiple sclerosis, and inflammatory bowel disease.
  • TYK2 active deletion variants such as rs12720356 and rs34536443
  • GWAS Genome-wide association studies
  • the psoriasis area and severity index scores of most patients decreased by more than 75% (PASI 75), and some patients' PASI scores decreased by more than 90% (PASI 90), further demonstrating the effectiveness and potential of the TYK2 target in the treatment of autoimmune diseases.
  • Disclosed patent applications for TYK2 degraders include WO2023076161A1 and others.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:
  • G 1 is selected from N, NR 0 , O, S and CR′;
  • G 2 is N or C
  • G 3 is N or C
  • R 4 , R 5 , R 0 and R 1a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, OR 12 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 01 ;
  • R1 and R2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, OR12 , NR10R11 , C(O) NR10R11 , NR13C (O) R12 , C(O) R12 , C(O) OR12 , OC ( O) R12 , S( O ) rR12 , S(O) rNR10R11 , a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group; and the alkyl group , alkoxy group, alkoxyalkyl group, alkeny
  • R 10 , R 11 , R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , C(O)R 24 , C(O)OR 24 , OC(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycl
  • L 1 , L 3 , L 4 , L 5 and L 6 are the same or different and are each independently selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C( O ), C(O)N( RL ), N(RL)C(O), S(O)r , S( O ) rN ( RL ), N(RL)S(O)r, N( RL ), S( ⁇ NR 23 ), S( ⁇ NR 23 )(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl and heteroaryl; said alkylene, alkenyl, alkynyl, cycloalkyl, heterocycl
  • L 2 is selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, heteroaryl and ring BZ 2 -ring B1; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring B1 and ring B are each independently optionally substituted with one or more R 03 ;
  • Ring B1 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 03 or two R 03 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more R * ;
  • R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, NR 21 R 22 , C(O)NR 21 R 22 , C(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more
  • R 21 , R 22 , R 23 , R 24 and RL are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 30 R 31 , C(O)NR 30 R 31 , NR 33 C(O)R 32 , C(O)R 32 , C(O)OR 32 , OC(O)R 32 , OR 32 , S(O) r R 32 , S(O) r NR 30 R 31 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; said alkyl, alkoxy, alkoxyalkyl,
  • R 30 , R 31 , R 32 and R 33 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group;
  • E is selected from:
  • One of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is a carbon atom and is connected to L 6 , and the others are each independently selected from N, CH and CR q ;
  • R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more R * ;
  • Y1 is N or CR Y1 ;
  • Y2 is CR Y2 R Y4 or C(O);
  • Y3 is N or CR Y3 ;
  • R Y1 , R Y2 , R Y3 and R Y4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group and a heterocyclic group; the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted with one or more R * ;
  • Each r is the same or different and is independently 0, 1 or 2.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof,
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
  • the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof,
  • Z 1 , L 1 to L 6 , R 3 to R 7 and R q are as defined in the general formula (I).
  • the compound represented by the general formula (I), (II), (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V), (V-1) or (V-2) or a pharmaceutically acceptable salt thereof,
  • L 1 to L 6 , R 1a , R 1 to R 7 and R q are as defined in the general formula (I).
  • the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein Z 1 is C(O)NR 1a NR 1 R 2 ; in some embodiments, Z 1 is NR 1a C(O)NR 1 R 2 ; in some embodiments, Z 1 is C(O)NR 1 R 2 ; in some embodiments, Z 1 is C(O)R 2 ; R 1a , R 1 and R 2 are as defined in the general formula (I); in some embodiments, Z 1 is selected from
  • E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2 or 3, s1 is 0, 1, 2, 3 or 4, R q , R 7 , R 8 , Y 1 and Y 2 are as defined in the general formula (I);
  • E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2 or 3, R q and R 7 are as defined in Formula (I); in some embodiments, E is selected from In some embodiments, E is selected from:
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein for In some embodiments, R q , R 7 and s are as defined in the general formula (I).
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein for In some embodiments, R q , R 7 and s are as defined in the general formula (I).
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein for In some embodiments, R q , R 7 and s are as defined in the general formula (I).
  • the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 1a is selected from a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group and OR 12 , and R 12 is as defined in the general formula (I); in some embodiments, R 1a is selected from a hydrogen atom, a hydroxyl group and a C 1-6 alkoxy group; in some embodiments, R 1a is a hydrogen atom.
  • the compounds represented by general formulas (I) to (V) or pharmaceutically acceptable salts thereof wherein R1 and R2 are the same or different and are each independently selected from a hydrogen atom, a C1-6 alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered cycloalkylC1-6 alkyl group, and a 3- to 6-membered heterocyclic group, and the C1-6 alkyl group, the 3- to 6-membered cycloalkyl group, the 3- to 6-membered cycloalkylC1-6 alkyl group, and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R01 ; or R1 , R2 , and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group is optionally substituted by one or more R01 ;
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group, wherein the 3- to 6-membered heterocyclyl group is optionally substituted by one or more R 01 ;
  • R 01 is as defined in the general formula (I);
  • R 1 is C 1-6 alkyl
  • R 2 is C 1-6 alkyl
  • the rings are each independently optionally substituted by one or more selected from halogen, C 1-6 alkyl and ⁇ CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or halogen;
  • R 1 is C 1-6 alkyl
  • R 2 is C 1-6 alkyl
  • R 1 , R 2 and the nitrogen atom to which they are attached together form
  • R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more R 01 ;
  • R 01 is as defined in the general formula (I);
  • R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more ⁇ CR 15 R 16 ;
  • R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;
  • the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 1 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy C 1-6 alkyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 3- to 10-membered cycloalkyl C 1-6 alkyl group and a 3- to 10-membered heterocyclyl C 1-6 alkyl group, and the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkoxy C 1-6 alkyl group, the 3- to 10-membered cycloalkyl group, the 3- to 10-membered heterocyclyl C 1-6 alkyl group
  • the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof wherein R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy C 1-6 alkyl group, OR 12 , NR 10 R 11 , OC(O)R 12 , a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 3- to 10-membered cycloalkyl C 1-6 alkyl group and a 3- to 10-membered heterocyclyl C 1-6 alkyl group, and the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkoxy C 1-6 alkyl group, the 3- to
  • R 2 is a C 1-6 alkyl group or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 alkoxy, hydroxyl, and ⁇ CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;
  • R 2 is C 1-6 alkyl, or R 2 , R 1 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group optionally substituted with one or more R 01 ; In some embodiments, R 2 is C 1-6 alkyl;
  • R2 is selected from Ethyl, In some embodiments, R2 is selected from Ethyl, In some embodiments, R2 is selected from Ethyl, In some embodiments, R2 is selected from In some embodiments,
  • L 1 is a bond or N( RL ); in some embodiments, L 1 is N( RL ), RL is as defined in Formula (I); in some embodiments, L 1 is N( RL ), RL is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, L 1 is a bond or NH; in some embodiments, L 1 is NH.
  • the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof wherein L 2 is selected from a bond, C(O), O, S, C 1-6 alkylene, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl, 5 to 14-membered heteroaryl, ring B-6 to 14-membered aryl, ring B-5 to 14-membered heteroaryl, and
  • the C 1-6 alkylene, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl, 5 to 14-membered heteroaryl and ring B are each independently optionally substituted by one or more R 03 ;
  • L 2 is selected from 6 to 14 membered aryl, 5 to 14 membered heteroaryl, phenyl-ring B and
  • the 6- to 14-membered aryl group, the 5- to 14-membered heteroaryl group, the phenyl group and the ring B are each independently optionally substituted by one or more R 03 ; the ring B and R 03 are as defined in the general formula (I);
  • L2 is In some embodiments, L2 is b is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5 or 6; Ring B, Z 2 and R 03 are as defined in Formula (I);
  • L2 is selected from Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring C is a nitrogen-containing heterocyclyl or heteroaryl; m is 0, 1, 2, 3, 4, 5 or 6; t is an integer from 0 to 16; in some embodiments, L 2 is selected from Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; W is selected from CH, C and N; J1 and J2 are the same or different and are each independently selected from a bond, ( CRaRb ) q , ( CRaRb ) qO , O( CRaRb ) q , NR1 , O and S; Ra and Rb are the same or different and are each independently a hydrogen atom or R03 ; Ri is a hydrogen atom or an alkyl group; Re , Rf and
  • L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is u is 1, 2, 3 or 4; Q and L are the same or different and are each independently selected from a bond, (CR g R h ) q , (CR g R h ) q O, O(CR g R h ) q , NR i , O and S; R g and R h are the same or different and are each independently a hydrogen atom or R 03 , R i is a hydrogen atom or an alkyl group; n is 0, 1, 2 or 3; b is 0, 1, 2 or 3; a is 0, 1 or 2; q is 0, 1 or 2; R 03 is as defined in Formula (I);
  • L2 is selected from In some embodiments, L2 is selected from
  • L2 is selected from It is the connection point with L1 and L3 .
  • the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof wherein Z 2 is a bond or a 3- to 10-membered heterocyclic group, and the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 03 ; in some embodiments, Z 2 is a bond; in some embodiments, Z 2 is a 3- to 10-membered heterocyclic group optionally substituted by one or more R 03 ; in some embodiments, Z 2 is a 3- to 6-membered heterocyclic group optionally substituted by one or more R 03 ; R 03 is as defined in the general formula (I).
  • the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof wherein ring B is selected from a 3- to 10-membered heterocyclic group, a phenyl group, and a 5- to 10-membered heteroaryl group; in some embodiments, ring B is selected from a 3- to 10-membered heterocyclic group, a phenyl group, a 5- or 6-membered heteroaryl group, and a 9- or 10-membered heteroaryl group; in some embodiments, ring B is selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a pyrimidinyl group; in some embodiments, ring B is a pyridyl group; in some embodiments, ring B is In the above embodiment, Ring B is optionally substituted with one or more R 03 ; R 03 is as defined in Formula (I).
  • ring A is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclyl; in some embodiments, ring A is a 3- to 12-membered heterocyclyl; in some embodiments, ring A is a 7- to 12-membered heterocyclyl; in some embodiments, ring A is a 7- to 12-membered bicyclic heterocyclyl; in some embodiments, ring A is a 7-, 8-, or 9-membered bicyclic heterocyclyl; in some embodiments, ring A is selected from In some embodiments, Ring A is selected from The fusion site.
  • Ring C is a 7- to 12-membered nitrogen-containing heterocyclic group; in some embodiments, Ring C is an 8-, 9-, or 10-membered bicyclic nitrogen-containing heterocyclic group.
  • ring E is an aryl or heteroaryl group; in some embodiments, ring E is selected from phenyl, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; in some embodiments, ring E is phenyl or 6-membered heteroaryl; in some embodiments, ring E is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl; in some embodiments, ring E is pyridyl; in some embodiments, ring E is *End is the fusion site.
  • the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof wherein L 6 -L 5 -L 4 -L 3 is selected from C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), 3 to 12-membered heterocyclyl-C 1-6 alkylene and C 1-6 alkylene-3 to 12-membered heterocyclyl, and the 3 to 12-membered heterocyclyl is optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is heterocyclyl-C(O) or heterocyclyl-C 1-6 alkylene, and the heterocyclyl is optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is 3 to 12-membered heterocyclyl-C(O) or 3 to 12-membered heterocyclyl-C 1-6 alkylene
  • L 6 -L 5 -L 4 -L 3 are selected from In some embodiments, L 6 -L 5 -L 4 -L 3 is U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; T is selected from N, CH and CR 03 , W is selected from N, CH and CR 03 , c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3 or 4, and R 03 is as defined in formula (I);
  • L 6 -L 5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 are selected from In some embodiments,
  • U is CH or N
  • V is CH or N
  • U is CH or N
  • V is CH or N
  • c is 1, and/or d is 0 or 1
  • e is 1, and/or f is 1 or 2.
  • v is 0, 1 or 2; in some embodiments, v is 0.
  • T is CH or N
  • W is CH or N
  • Q is selected from a bond, O, CH2O , and CH2CH2O
  • L is selected from a bond, O , CH2O , and CH2CH2O
  • Q is selected from a bond, O, CH2O , and CH2CH2O
  • L is a bond or O
  • Q is a bond or O
  • Q is a bond or O
  • L is a bond or O
  • Q is O, and/or L is O.
  • u is 1 or 2; in some embodiments, u is 1.
  • Q is a bond or O, and/or L is a bond or O, and/or u is 1 or 2; in some embodiments, Q is O, and/or L is O, and/or u is 1.
  • a is 0, 1 or 2; in some embodiments, a is 1.
  • b is 0, 1 or 2; in some embodiments, b is 0.
  • n is 0, 1 or 2; in some embodiments, n is 0.
  • p is 0, 1, or 2; in some embodiments, p is 1.
  • t is 0, 1 or 2; in some embodiments, t is 0.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein for In some embodiments, for In some embodiments, for
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; in some embodiments, R 3 is a hydrogen atom.
  • R 5 is selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R 5 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 5 is a C 1-6 alkyl group; in some embodiments, R 5 is a methyl group.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R6 is selected from hydrogen atom, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; in some embodiments, R6 is a hydrogen atom.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 4 is a hydrogen atom, and/or R 5 is a C 1-6 alkyl group; in some embodiments, R 4 is a hydrogen atom, and/or R 5 is a methyl group.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom, and/or R 4 is a hydrogen atom, and/or R 5 is a C 1-6 alkyl group; in some embodiments, R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom, and/or R 4 is a hydrogen atom, and/or R 5 is a methyl group.
  • each R 02 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 02 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 03 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3-6 membered cycloalkyl, or two R 03 and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group; in some embodiments, each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl, or two R 03 and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group; in some embodiments, each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 1-6
  • each R 04 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 04 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • each R * is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxyC1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R * is the same or different and is independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl.
  • R 10 and R 11 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 10 and R 11 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 10 and R 11 are both hydrogen atoms.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 12 is selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R 12 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 12 is a hydrogen atom; in some embodiments, R 12 is a C 1-6 alkyl group.
  • R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 15 and R 16 are both F.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 21 and R 22 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 21 and R 22 are both hydrogen atoms.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 24 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 24 is a hydrogen atom; in some embodiments, R 24 is a C 1-6 alkyl group.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein r is 2; in some embodiments, r is 1; in some embodiments, r is 0.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 30 and R 31 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 30 and R 31 are both hydrogen atoms.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R 32 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 32 is a C 1-6 alkyl group.
  • the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof wherein R7 is selected from a hydrogen atom, a C1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R7 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R7 is a C1-6 alkyl group; in some embodiments, R7 is a methyl group.
  • the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof wherein Y 1 is N or CH; in some embodiments, Y 1 is N; in some embodiments, Y 1 is CH.
  • the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof wherein Y 2 is CH 2 or C(O); in some embodiments, Y 2 is CH 2 ; in some embodiments, Y 2 is C(O).
  • each R q is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano and 3 to 6 membered cycloalkyl; in some embodiments, each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, each R q is the same or different and is independently selected from halogen; in some embodiments, R q is F.
  • each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl, and/or s is 0, 1 or 2; in some embodiments, each R q is the same or different and is independently halogen, and/or s is 0, 1 or 2.
  • Ra and Rb are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, and a C1-6 haloalkyl group; in some embodiments, Ra and Rb are both hydrogen atoms.
  • R i is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R i is a hydrogen atom.
  • J 1 is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 O, OCH 2 and O
  • J 2 is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 O, OCH 2 and O
  • J 1 is selected from a bond, O, CH 2 and CH 2 CH 2 , and/or J 2 is O or CH 2 O
  • J 1 is CH 2 , and/or J 2 is O or CH 2 O
  • J 1 is CH 2 , and/or J 2 is O or CH 2 O
  • J 1 is CH 2 , and/or J 2 is O.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a C 1-6 alkyl group; Z 1 is C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered hetero
  • E is selected from: s is 0, 1, 2 or 3, R 7 is a hydrogen atom or a C 1-6 alkyl group; R 8 is a hydrogen atom; Y 1 is N or CH; Y 2 is CH 2 or C(O); each R q is the same or different and is independently halogen; L 6 -L 5 -L 4 -L 3 is a 3- to 12-membered heterocyclyl-C(O) or a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, the 3- to 12-membered heterocyclyl group is optionally substituted with one or more R 03 ; L 2 is selected from Q is O, L is O; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is NH.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a methyl group; Z 1 is C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 is a C 1-6 alkyl group, R 2 is a C 1-6 alkyl group, or R 1 , R 2 and the nitrogen atom to which they are connected together form
  • E is selected from: s is 0, 1 or 2, R 7 is a methyl group; R 8 is a hydrogen atom; Y 1 is N or CH; Y 2 is CH 2 or C(O); each R q is the same or different and is independently F; L 6 -L 5 -L 4 -L 3 is L 2 is selected from Q is O, L is O; u is 1 or 2; a is 1; b is 0; n is 0; each R 03 is the same or different and is independently halogen; L 1 is NH.
  • R 7 is a hydrogen atom or a C 1-6 alkyl group; each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 6 -L 5 -L 4 -L 3 is a 3- to 12-membered heterocyclyl-C(O) or a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, and the 3- to 12-membered heterocyclyl group is optionally substituted by one or more R 03 ; L 2 is selected from Q is O, L is O; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is NH.
  • the compound represented by the general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a methyl group; Z 1 is C(O)NR 1 R 2 ; R 1 is a hydrogen atom; and R 2 is selected from
  • each R q is the same or different and is independently halogen, s is 0, 1 or 2; Selected from
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure provides a compound represented by general formula (IA) or a salt thereof,
  • R P is an amino protecting group, preferably PMB;
  • Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).
  • Another aspect of the present disclosure provides a compound represented by general formula (IIA) or a salt thereof,
  • R P is an amino protecting group, preferably PMB;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).
  • Another aspect of the present disclosure provides a compound represented by general formula (IIIA) or a salt thereof,
  • R P is an amino protecting group, preferably PMB;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).
  • Another aspect of the present disclosure provides a compound represented by general formula (IVA), (IV-1A) or (IV-2A) or a salt thereof,
  • R P is an amino protecting group, preferably PMB;
  • Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).
  • Another aspect of the present disclosure provides a compound represented by general formula (V), (V-1A) or (V-2A) or a salt thereof,
  • R P is an amino protecting group, preferably PMB;
  • R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing the compounds represented by the above-mentioned general formulas (IV), (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • the compound represented by the general formula (IV-1A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • the compound represented by the general formula (IV-2) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-2) or its pharmaceutically acceptable salt;
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).
  • Another aspect of the present disclosure relates to a method for preparing the compounds represented by the above-mentioned general formulas (V), (V-1) and (V-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • the compound represented by the general formula (VA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable salt;
  • the compound represented by the general formula (V-1A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;
  • the compound represented by the general formula (V-2A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).
  • compositions comprising a compound of formula (I) to (V) and shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of drugs for inhibiting and/or degrading TYK2.
  • the present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of TYK2 inhibitors and/or degraders.
  • the present disclosure further relates to the use of compounds represented by formula (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.
  • the present disclosure further relates to the use of compounds represented by general formulae (I) to (V) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and/or preventing autoimmune diseases, inflammatory diseases, and cancer; in some embodiments, the use of the compounds is in the preparation of medicaments for treating and/or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia, and asthma.
  • the present disclosure also relates to a method for treating and/or preventing diseases or conditions mediated by or dependent on TYK2, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method for inhibiting and/or degrading TYK2, comprising administering to a patient in need thereof a compound of the aforementioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method for treating and/or preventing autoimmune diseases, inflammatory diseases and cancer, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a compound represented by the above-mentioned general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a compound represented by the aforementioned general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a TYK2 inhibitor and/or degrader.
  • the present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting TYK2 activity and/or degrading TYK2.
  • the present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.
  • the present disclosure further relates to the compounds represented by the above general formulae (I) to (V) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TYK2 activity and/or degrading TYK2.
  • the present disclosure further relates to the compounds of the above-mentioned general formulae (I) to (V) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and/or preventing diseases or conditions mediated by or dependent on TYK2.
  • the present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and/or preventing autoimmune diseases, inflammatory diseases and cancer; in some embodiments, for treating and/or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma.
  • the disease or condition mediated by or dependent on TYK2 is selected from the group consisting of an autoimmune disease, an inflammatory disease, and cancer.
  • the disease or condition mediated or dependent on TYK2 or an autoimmune disease, inflammatory disease and cancer is selected from psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma; in some embodiments it is selected from psoriasis (Ps), lupus, inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulos
  • the active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose.
  • a unit dosage form of a compound or composition of the present disclosure may be in the form of a tablet, capsule, cachet, bottled solution, powder, granules, lozenge, suppository, reconstituted powder, or liquid formulation.
  • suitable unit doses may be in the range of 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.
  • the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.
  • compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation.
  • Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation.
  • excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.
  • Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.
  • Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil.
  • the oil suspension may contain a thickener.
  • Sweeteners and flavoring agents as described above may be added to provide a palatable formulation. These compositions may be preserved by the addition of antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, a mineral oil, or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants.
  • Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion may be injected into the patient's bloodstream by local bolus injection.
  • it is preferred that the solutions and microemulsions be administered in a manner that maintains a constant circulating concentration of the disclosed compound.
  • a continuous intravenous drug delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the present disclosure can be in the form of sterile injection water or oil suspensions for intramuscular and subcutaneous administration.
  • the suspension can be prepared using known techniques with suitable dispersants or wetting agents and suspending agents.
  • Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents.
  • sterile fixed oils can be conveniently used as solvents or suspending media. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the disclosed compounds can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.
  • alkyl refers to a saturated, linear or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a C1-20 alkyl group).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., a C1-10 alkyl group), and preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C1-6 alkyl group).
  • 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
  • the alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C1-10 alkylene), preferably an alkylene group having 1 to 8 carbon atoms (i.e., C1-8 alkylene), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C1-6 alkylene).
  • Non-limiting examples include: -CH2- , -CH(CH3)- , -C( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 ) - , -CH2CH( CH3 ) - , -CH2C ( CH3 ) 2- , -CH2CH2CH2-, -CH2CH2CH2CH2- , etc.
  • Alkylene groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen , alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkenyl).
  • the alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., C2-6 alkenyl).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.
  • the alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of a D atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • alkenylene refers to a divalent alkenyl group, wherein alkenyl is as defined above.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkynyl).
  • the alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., C2-6 alkynyl).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.
  • Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • alkynylene refers to a divalent alkynyl group wherein alkynyl is as defined above.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, propylthio, and butylthio.
  • Alkylthio can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered cycloalkyl group) or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered
  • Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spiroalkyl refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl).
  • the spiroalkyl is preferably a spiroalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), more preferably a spiroalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl).
  • the spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 6-membered/3-member
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl).
  • the fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-member
  • connection point can be at any position; wait.
  • bridged cycloalkyl refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl).
  • the bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl).
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl.
  • bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.
  • Non-limiting examples include:
  • connection point can be at any position.
  • the cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl).
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group), or a heterocyclic group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclic group), or a heterocyclic group having 7 to 12 ring atoms (i.e., a 7- to 12-membered heterocyclic group); further preferably, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group), or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membere
  • Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.
  • the polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.
  • Nonrogen-containing heterocyclic group refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms in the ring, wherein the heterocyclic group is as defined above. Preferably, it is a 3- to 10-membered nitrogen-containing heterocyclic group, more preferably a 4- to 7-membered nitrogen-containing heterocyclic group, and most preferably a 5- or 6-membered nitrogen-containing heterocyclic group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl).
  • the spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms.
  • a spiro heterocyclic radical i.e., a 6 to 14 yuan spiro heterocyclic radical
  • a spiro heterocyclic radical i.e., a 7 to 10 yuan spiro heterocyclic radical
  • the spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S-, or -S-S-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
  • the fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical).
  • the fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yu
  • bridged heterocyclic group refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group).
  • nitrogen may be optionally oxidized, i.e., to form nitrogen oxides
  • the sulfur may be optionally oxidized, i.e., to form sulfox
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group).
  • heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups.
  • Non-limiting examples include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated ⁇ electron system, which has 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 6 to 20-membered aromatic group).
  • the aryl group is preferably an aromatic group having 6 to 14 ring atoms (i.e., 6 to 14-membered aromatic group), more preferably an aromatic group having 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group).
  • the monocyclic aromatic group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • the aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated ⁇ electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S- or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered heteroaryl).
  • the heteroaryl group is preferably a heteroaryl group having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl group), more preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and most preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).
  • the monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like.
  • the polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • the polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • the heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.
  • cycloalkyloxy refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to an -O-heterocyclyl group wherein heterocyclyl is as defined above.
  • aryloxy refers to an -O-aryl group in which aryl is as defined above.
  • heteroaryloxy refers to an -O-heteroaryl group, wherein heteroaryl is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.
  • alkoxyalkyl refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • TBS refers to tert-butyldimethylsilyl.
  • acetyl refers to C(O) CH3 .
  • amino protecting group refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), and the like.
  • the disclosed compounds may exist in specific stereoisomeric forms.
  • stereoisomer refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers).
  • the substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques.
  • An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer.
  • separation of enantiomers and diastereomers is typically accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.
  • the compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation about a single bond, where the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation barrier to allow separation of individual conformers.
  • certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses.
  • isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as, respectively, 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete.
  • Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.
  • a position is specifically designated as deuterium, D
  • the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 15% deuterium incorporation).
  • Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e.,
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and includes both situations where the event or circumstance occurs and where it does not occur.
  • C 1-6 alkyl optionally substituted with halogen or cyano includes both situations where the alkyl is substituted with halogen or cyano and situations where the alkyl is not substituted with halogen or cyano.
  • substitution means that one or more hydrogen atoms, preferably 1, 2 or 3, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).
  • a “pharmaceutical composition” refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
  • the method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).
  • the method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).
  • the method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).
  • the present invention discloses a method for preparing the compounds represented by general formula (IV-1), (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, comprising the following steps:
  • the compound represented by the general formula (IV-1A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • the compound represented by the general formula (IV-2A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).
  • the present invention discloses a method for preparing the compounds represented by general formula (V), (V-1) and (V-2) or pharmaceutically acceptable salts thereof, comprising the following steps:
  • the compound represented by the general formula (V-1A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;
  • the compound represented by the general formula (V-2A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;
  • R P is an amino protecting group, preferably PMB;
  • R 4 is a hydrogen atom;
  • R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).
  • the reagents providing acidic conditions in the above synthesis scheme include but are not limited to hydrogen chloride, hydrogen chloride in 1,4-dioxane, hydrochloric acid in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf; preferably trifluoroacetic acid.
  • the reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.
  • HPLC High performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • the aqueous phase was adjusted to pH 5 with 1 M hydrochloric acid, and extracted with dichloromethane (50 mL ⁇ 3).
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1b (2.9 g).
  • the product was used directly in the next reaction without purification.
  • the crude compound 1h (83 mg, 85.1 ⁇ mol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at 110°C for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to give the title compound 1 (a mixture of a pair of enantiomers, 10 mg, yield: 13.7%).
  • the crude compound 2d (255 mg, 1.72 mmol) was dissolved in methanol (1 mL) and acetic acid (0.3 mL). Zinc powder (1.1 g, 17 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 16 hours. Methanol was added to dilute the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 2e (200 mg). The product was used directly in the next reaction without purification.
  • Example 2 The synthetic route of Example 1 was used, and the second step raw material 1-aminopyrrolidine hydrochloride was replaced by compound 2e to obtain the title compound 2 (8 mg, yield: 25.1%) (a mixture of a pair of enantiomers).
  • the crude compound 4b (37 g, 303.1 mmol) was dissolved in methanol (600 mL) and acetic acid (75 mL). Zinc powder (1.4 g, 21.4 mmol) was added in batches under ice bath. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. Methanol (500 mL) was added to the residue to dissolve it and then filtered. The filtrate was concentrated under reduced pressure. 1.5 L of 1.25 M sodium hydroxide aqueous solution and 650 mL of 1,4-dioxane were added. After stirring and dissolving, the mixture was cooled to 0 °C and di-tert-butyl dicarbonate was added.
  • Example 2 The synthetic route of Example 1 was adopted, and the second step raw material 1-aminopyrrolidine hydrochloride was replaced with compound 4c to obtain the title compound 4 (a mixture of a pair of enantiomers, 4 mg, yield: 6.5%).
  • reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL/min) to give the title compound 5 (a pair of diastereoisomer mixture, 4 mg, yield: 16%).
  • preparative HPLC Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL/min
  • 1,2-Bis(trimethylsilyloxy)cyclobutene 6a 100 g, 433.9 mmol, Jiangsu Aikon
  • benzyl alcohol 46.9 g, 433.9 mmol
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent C to give the title compound 6b (racemic compound, 43.8 g, yield: 57.3%).
  • Test Example 1 TYK2 JH2 and JAK1 JH2 in vitro enzyme binding assay
  • This experiment uses fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effects of compounds on TYK2 JH2 and JAK1 JH2 pseudokinases.
  • TR-FRET fluorescence resonance energy transfer
  • TYK2 JH2 or JAK1 JH2 pseudokinases are simultaneously bound to the fluorescently labeled Tracer and the Tb antibody.
  • the Tb antibody acts as a fluorescence donor, generating 495nm fluorescence under the influence of excitation light of a certain wavelength.
  • Tracer acting as a fluorescence acceptor, can only receive 495nm fluorescence when it is sufficiently close to the Tb antibody, thereby generating 520nm fluorescence, i.e., the fluorescence resonance energy transfer signal.
  • the TR-FRET signal decreases due to reduced Tracer binding.
  • the 520nm/495nm signal ratio can reflect the inhibitory activity of the compound binding to the pseudokinase.
  • Microplate reader Envision 2105 (Perkin Elmer)
  • Constant temperature incubator CIMO, SPX-60BS-II
  • Thermo MATRIX multichannel pipette Thermo Fisher, 2-125 ⁇ L
  • Ultra-low temperature freezer Haier ultralow temperature freezer
  • the disclosed compounds have a significant inhibitory effect on TYK2-JH2 pseudokinase.
  • Test Example 2 Inhibition of IFN ⁇ -induced STAT1 protein phosphorylation in HeLa cells by the disclosed compounds
  • the AlphaLISA method was used to detect the inhibitory effect of the disclosed compounds on IFN ⁇ -induced STAT1 protein phosphorylation in HeLa cells.
  • the specific content is as follows:
  • HeLa cells were purchased from the American Type Culture Collection (ATCC) and cultured in MEM medium (10% FBS) at 37° C. in a 5% carbon dioxide incubator, and passaged 2-3 times a week.
  • ATCC American Type Culture Collection
  • MEM medium 10% FBS
  • Test compounds were dissolved in DMSO to 0.5 mM.
  • the initial concentration of the compound was 0.5 mM, diluted 3 times, and 10 concentration gradients were performed.
  • lysis solution Prepare lysis solution according to the AlphaLISA SureFire Ultra STAT1 pY701 kit instructions. Aspirate the cell culture supernatant and add 50 ⁇ L of lysis solution to each well. Incubate cells at room temperature with shaking for 15 minutes.
  • the disclosed compounds have a good inhibitory effect on IFN ⁇ -induced STAT1 protein phosphorylation in HeLa cells.
  • Test Example 3 Experiment on the inhibition of IFN ⁇ -induced IP10 production in human whole blood by the disclosed compounds
  • the supernatant was collected: the cell plate was removed from the 37-degree incubator, centrifuged at 2000rpm/min for 5 minutes, 80ul of supernatant was taken out of each well and transferred to a new 96-well round-bottom plate, sealed with tin foil, and stored in a -80-degree refrigerator for testing.
  • the IP10 in the supernatant was detected by ELISA using the human IP-10/CXCL10 ELISA kit from Xinbosheng Bio.
  • Y aX + b, R squared > 0.99.
  • Y represents the OD450 value
  • X represents the IP10 concentration. Calculate the IP10 concentration corresponding to each OD450 value. The final concentration is 100X (pg/ml).
  • IFN-a-stimulated wells treated with DMSO serve as positive controls, while unstimulated wells treated with DMSO serve as negative controls.
  • the inhibition rate is: (positive control well - test compound) / (positive control well - negative control well) * 100%.
  • Graphpad software was used to draw an inhibition curve based on the compound concentration points and the corresponding inhibition rate, and the compound concentration at which the inhibition rate was 50%, i.e., the IC 50 value, was calculated.
  • the disclosed compounds have significant inhibitory activity on IFN ⁇ -induced IP10 production in human whole blood.
  • Test Example 4 Degradation activity of the disclosed compounds on TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.
  • TYK2 is localized in the cytoplasm and participates in the signaling of multiple cytokines.
  • OCI-LY3 cells are a human diffuse large B-cell lymphoma cell line that expresses high levels of TYK2, which is involved in the signaling of cytokines such as IL-10.
  • the degradation rate of TYK2 in compound-treated cells was measured using ultrasensitive electrochemiluminescence (Meso Scale Discovery, MSD) to assess the compound's activity against intracellular TYK2.
  • Cells were suspended at a density of 5E5/mL in RPMI 1640 medium (Mei Lun PWL015; containing 20% FBS, Gibco 10091-14; containing 55 ⁇ M mercaptoethanol, Gibco 31350010) and plated into 96-well cell culture plates (Corning, 3599) at a volume of 196 ⁇ L per well.
  • the cells were incubated at 37°C in a 5% CO2 incubator. Afterwards, 4 ⁇ L of cell culture medium containing a 4-fold serial dilution of the compound was added to the experimental wells, or 4 ⁇ L of culture medium containing DMSO (final concentration 0.1%) was added to the positive and negative control wells.
  • the cell culture plates were shaken at 300 rpm for 5 minutes to mix thoroughly and incubated in a 37°C, 5% CO2 incubator for 24 hours. After incubation, the plates were centrifuged at 400 g for 5 minutes, and the supernatant was discarded to obtain a cell pellet. 45 ⁇ L of 1x lysis buffer (revvity, ALSU-LB-100ML) was added to each well, shaken at room temperature for 5 minutes, and then sonicated for 5 minutes. Finally, the plates were centrifuged at 2000 g for 5 minutes, and the supernatant was collected as the cell lysate sample.
  • 1x lysis buffer (revvity, ALSU-LB-100ML)
  • MSD 96-well plates (MSD, L15XA-6) were coated overnight at 4°C with 50 ⁇ L of 1 ⁇ g/mL TYK2 antibody (Santa Cruz, sc-5271) in PBS buffer added to each well.
  • the coating solution was discarded and 150 ⁇ L of phosphate-buffered saline (PBS) containing 5% BSA was added to each well for blocking for 1 hour.
  • PBS + 0.05% Tween 20 25 ⁇ L of cell lysate sample or TYK2 standard (BPS Bioscience, 100400) was added to each well and incubated at 500 rpm for 1.5 hours. The sample was discarded and the plate was washed three times.
  • the disclosed compounds have significant degradation activity against TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.
  • Test Example 5 ELISA experiment on the effects of the disclosed compounds on pSTAT3 in human T lymphocytes induced by IFN ⁇
  • Cryopreserved human PBMCs were revived in RPMI 1640 complete growth medium containing 10% inactivated FBS.
  • T cells were isolated from the PBMCs using a T cell isolation kit and cultured overnight. Overnight cultured T cells were seeded into 96-well plates at 1 ⁇ 10 5 /well. Cells were treated with serial dilutions of the compound and incubated in a 37°C & 5% CO 2 incubator for 1 hour. IFN ⁇ was added at a final concentration of 200 ng/mL and incubated in a 37°C & 5% CO 2 incubator for 30 minutes. The treated cells were then lysed, and the level of cellular phosphorylated STAT3 was measured using an ELISA kit according to the manufacturer's instructions.
  • Inhibition data were calculated by comparing 0% inhibition with IFN ⁇ /DMSO control wells and 100% inhibition with non-stimulated control wells. Dose-response curves were then generated to determine the concentration required to inhibit the cellular response by 50% (IC 50 ), which was determined by nonlinear regression analysis using GraphPad Prism.
  • the compounds disclosed herein have an inhibitory effect on TYK2-mediated and IFN ⁇ -induced STAT3 phosphorylation in human T lymphocytes.
  • Test Example 6 Inhibitory effect of the disclosed compounds on IL-12/IL-18-induced IFN- ⁇ production in human PBMC cells
  • Fresh PBMC cells were centrifuged (300g/min, 10min), the supernatant was discarded, and fresh culture medium was added to resuspend the cell pellet and counted.
  • a cell suspension with a cell density of 6.66E5/ml was prepared and mixed. 150ul of the cell suspension was added to each well of a 96-well round-bottom plate. The cells were placed in a 37-degree incubator.
  • the compound was prepared with DMSO to a 20mM stock solution, and then diluted 10-fold in a 96-well round-bottom plate to a first concentration of 2mM. The compound was then diluted 4-fold with DMSO in sequence, for a total of 9 concentration points.
  • the DMSO blank wells were used as blank controls.
  • the DMSO solution of the compound obtained above was further diluted 25-fold: 6ul of the DMSO compound solution was added to 144ul of fresh culture medium and shaken on a plate shaker for 10 minutes to mix. 25ul/well was added to the cell plate, repeated up and down, with a final DMSO concentration of 0.5%, and incubated in a 37-degree incubator for 30 minutes. Dilute the IL-12 stock solution (200 ⁇ g/ml) 12,500-fold and the IL-18 stock solution (100 ⁇ g/ml) 1250-fold, and mix them in a 1:1 volume ratio. Add 25 ⁇ l per well to the cells, for a final concentration of 1 ng/ml for IL-12 and 5 ng/ml for IL-18.
  • IL-12/IL-18-stimulated wells treated with DMSO served as positive controls, while unstimulated wells treated with DMSO served as negative controls.
  • the inhibition rate was calculated as: (positive control well - test compound) / (positive control well - negative control well) * 100%. Inhibition curves were plotted using GraphPad software based on the compound concentrations and the corresponding inhibition rates. The compound concentration that achieved 50% inhibition ( IC50 ) was calculated.
  • the disclosed compounds have good inhibitory activity against IFN- ⁇ induced by IL-12/IL-18.

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Abstract

The present disclosure relates to an amino-substituted heteroaromatic cyclic compound, a preparation method therefor, and the use thereof in medicine. Specifically, the present disclosure relates to an amino-substituted heteroaromatic cyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, the use thereof as a therapeutic agent, particularly as a TYK2 inhibitor and/or a degradation agent, and the use thereof in the preparation of a drug for treating and/or preventing TYK2-mediated or -dependent diseases or disorders.

Description

氨基取代的杂芳环类化合物、其制备方法及其在医药上的应用Amino-substituted heteroaromatic ring compounds, preparation methods thereof and their applications in medicine 技术领域Technical Field

本公开属于医药领域，涉及一种通式(I)所示的氨基取代的杂芳环类化合物、其制备方法、含有该化合物的药物组合物以及其作为治疗剂的用途，特别是作为TYK2抑制剂和/或降解剂的用途和在制备用于治疗和/或预防由TYK2介导的或依赖性的疾病或病症的药物中的用途。The present disclosure belongs to the field of medicine and relates to an amino-substituted heteroaromatic ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a TYK2 inhibitor and/or degrader and its use in the preparation of a medicament for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.

背景技术Background Art

细胞因子信号传导在控制免疫细胞的生长、分化、功能和交流中起关键作用。受体结合的Janus激酶(JAKs)以及信号转导和转录激活因子(STATs)的作用介导了多种细胞因子信号转导途径。Cytokine signaling plays a key role in controlling the growth, differentiation, function, and communication of immune cells. Receptor-bound Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) mediate multiple cytokine signaling pathways.

JAK家族成员，包括JAK1、JAK2、JAK3和TYK2，是细胞因子受体相关的非受体酪氨酸蛋白激酶，在刺激和寡聚这些受体后，JAK分子被激活并使受体酪氨酸残基磷酸化以充当停靠位点，以用于随后的STAT蛋白募集和磷酸化。反过来，磷酸化的STAT蛋白则二聚化，转运至细胞核并激活介导细胞因子诱导的应答的基因的转录。这些细胞因子介导的JAK/STAT通路受到严格调控，功能异常的JAK/STAT活性已被证明是许多免疫和自身免疫性疾病，炎性疾病以及细胞转化的标志。JAK family members, including JAK1, JAK2, JAK3, and TYK2, are non-receptor tyrosine protein kinases associated with cytokine receptors. Following stimulation and oligomerization of these receptors, JAK molecules are activated and phosphorylate receptor tyrosine residues, which serve as docking sites for the subsequent recruitment and phosphorylation of STAT proteins. In turn, phosphorylated STAT proteins dimerize, translocate to the nucleus, and activate transcription of genes that mediate cytokine-induced responses. These cytokine-mediated JAK/STAT pathways are tightly regulated, and dysfunctional JAK/STAT activity has been shown to be a hallmark of numerous immune and autoimmune diseases, inflammatory disorders, and cellular transformation.

酪氨酸激酶2(TYK2)是JAK家族中第一个被鉴定的成员，各种细胞因子途径的组成部分，导致STAT依赖的基因转录和细胞因子的特定功能响应，包括白介素12/-23家族(IL-12/IL-23，具有共同的p40亚基)，I型干扰素(IFN)家族以及IL-6和IL-10家族。TYK2介导的细胞因子信号传导在自身免疫性疾病和炎性疾病的发病机制中起着关键作用。具体而言，IL-23(含有p40和p19亚基的异二聚体)对于T辅助细胞17(Th17)的分化和增殖至关重要，这些T辅助细胞是几种自身免疫性疾病的关键参与者。由p40和独特的p35亚基组成的IL-12在调节Th1发育和这些细胞的IFN-γ分泌中起着重要的作用。通过介导Th1/Th17反应，IL-12和IL-23在多种炎性疾病[如银屑病(Ps)、狼疮、炎症性肠病(IBD)、多发性硬化症(MS)、类风湿性关节炎(RA)]中起重要作用等(Michele WL T et al.,“IL-12and IL-23cytokines:from discovery to targeted therapies for immune-mediated inflammatory diseases”Nat Med.2015,21:719–729)。例如，在小鼠模型中，发现IL-12和IL-23的共同亚基P40或共有受体IL23R阻断或缺失可保护小鼠免受各种自身免疫性疾病(银屑病、狼疮、炎症性肠病、多发性硬化症、类风湿性关节炎等)的侵害(Kyttaris VC et al.,“Cutting edge:IL-23receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice”J Immunol.2010,184:4605-9)。在人类疾病中，银屑病患者的病变皮肤中观察到高水平的IL-12和IL-23，然后在银屑病的各种治疗后水平下降。此外，已证明阻断IL-12/IL-23共同亚基p40(Ustekinumab，Briakinumab等)或IL-23特异性亚基p19(Tildrakizumab，Risankizumab等)的单克隆抗体在治疗银屑病方面具有临床疗效，克罗恩氏病等。同时，通过异二聚体IFN受体(IFNAR)发挥作用的I型IFN家族成员(IFN-α、-β、-ε、-κ、-ω等)是先天免疫和适应性免疫的重要介质，同时也能激活免疫应答中的多种元件及增强自身抗原表达和释放，而成为自身免疫疾病扩增的关键参与者。I型IFN在系统性红斑狼疮(SLE)发病机理中的重要性已通过实验证实，狼疮易感NZB小鼠模型中，IFNAR的缺失很大程度上减轻了疾病严重程度及疾病致死率。在人类SLE患者中，在很多患者中发现了血清IFNα水平升高以及I型IFN调控基因在外周血单核细胞(PBMC)和受影响器官中的表达水平升高。此外，其他一些研究也报道I型干扰素的激活与SLE的疾病程度密切相关。Tyrosine kinase 2 (TYK2), the first member of the JAK family to be identified, is a component of various cytokine pathways, leading to STAT-dependent gene transcription and specific functional responses to cytokines, including the interleukin-12/-23 family (IL-12/IL-23, which share a common p40 subunit), the type I interferon (IFN) family, and the IL-6 and IL-10 families. TYK2-mediated cytokine signaling plays a key role in the pathogenesis of autoimmune and inflammatory diseases. Specifically, IL-23 (a heterodimer containing p40 and p19 subunits) is essential for the differentiation and proliferation of T helper 17 (Th17) cells, which are key players in several autoimmune diseases. IL-12, composed of p40 and a unique p35 subunit, plays an important role in regulating Th1 development and IFN-γ secretion by these cells. By mediating Th1/Th17 responses, IL-12 and IL-23 play an important role in a variety of inflammatory diseases [such as psoriasis (Ps), lupus, inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA)] (Michele WL T et al., "IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases" Nat Med. 2015, 21: 719–729). For example, in mouse models, blocking or deleting the common IL-12 and IL-23 subunit, P40, or the shared receptor, IL23R, has been found to protect mice from various autoimmune diseases, including psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis (Kyttaris VC et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice," J Immunol. 2010, 184:4605-9). In humans, high levels of IL-12 and IL-23 have been observed in the lesional skin of psoriasis patients, which then decreases after various psoriasis treatments. Furthermore, monoclonal antibodies that block the IL-12/IL-23 common subunit p40 (Ustekinumab, Briakinumab, etc.) or the IL-23-specific subunit p19 (Tildrakizumab, Risankizumab, etc.) have demonstrated clinical efficacy in the treatment of psoriasis, Crohn's disease, and other conditions. Furthermore, type I IFN family members (IFN-α, -β, -ε, -κ, -ω, etc.), which act through heterodimeric IFN receptors (IFNARs), are important mediators of innate and adaptive immunity. They can also activate multiple components of the immune response and enhance the expression and release of autoantigens, making them key players in the amplification of autoimmune diseases. The importance of type I IFNs in the pathogenesis of systemic lupus erythematosus (SLE) has been experimentally confirmed. In the lupus-prone NZB mouse model, IFNAR deficiency significantly reduced disease severity and mortality. In human SLE patients, elevated serum IFNα levels and increased expression of type I IFN-regulated genes in peripheral blood mononuclear cells (PBMCs) and affected organs have been found in many patients. Furthermore, other studies have also reported that activation of type I IFNs is closely associated with the severity of SLE disease.

多项研究证据表明TYK2在上述自身免疫性疾病发病机理中的重要性。例如，发现体内TYK2失活或受化学抑制的啮齿动物在银屑病，多发性硬化症和炎症性肠病等实验性自身免疫疾病模型中表现出抗病力。人群研究发现，在墨西哥Mestizo人群中，携带TYK2活性缺失变体(如rs12720356和rs34536443)的儿童和成年人SLE发生减少。此外，在北欧，英国和中国汉族人群中，TYK2 SNP突变也报道与SLE相关。全基因组关联研究(GWAS)发现TYK2的几种活性缺失变体与抵抗炎症性疾病显著相关，包括多发性硬化症、银屑病、克罗恩病、狼疮和类风湿性关节炎，进一步表明TYK2在广泛的自身免疫疾病中具有重要作用。Evidence from multiple studies indicates the importance of TYK2 in the pathogenesis of the above-mentioned autoimmune diseases. For example, rodents in which TYK2 is inactivated or chemically inhibited in vivo have been found to exhibit disease resistance in experimental autoimmune disease models such as psoriasis, multiple sclerosis, and inflammatory bowel disease. Population studies have found that in the Mexican Mestizo population, children and adults carrying TYK2 active deletion variants (such as rs12720356 and rs34536443) have a reduced incidence of SLE. In addition, TYK2 SNP mutations have also been reported to be associated with SLE in Nordic, British, and Han Chinese populations. Genome-wide association studies (GWAS) have found that several active deletion variants of TYK2 are significantly associated with resistance to inflammatory diseases, including multiple sclerosis, psoriasis, Crohn's disease, lupus, and rheumatoid arthritis, further indicating that TYK2 plays an important role in a wide range of autoimmune diseases.

由此可见，开发抑制TYK2介导的细胞因子信号传导途径作用的药物针对人类自身免疫性疾病有潜在的治疗益处。实际上，已显示出高度选择性的变构TYK2抑制剂BMS986165可有效阻断IL-12/IL-23和I型IFN信号通路，从而在多种实验性自身免疫疾病模型(银屑病、SLE和IBD)中显示出显著药效。此外，2期临床试验结果报道，该药物在中度至重度斑块状银屑病患者中达到疗效主要终点，且有良好的风险效益比。在服用BMS986165 12周后，多数患者的银屑病面积和严重指数评分下降超过75％(PASI 75)，有些患者PASI评分下降超过90％(PASI 90)，进一步说明了TYK2这一靶点在自身免疫性疾病治疗领域的有效性及潜力。This shows that the development of drugs that inhibit the effects of TYK2-mediated cytokine signaling pathways has potential therapeutic benefits for human autoimmune diseases. In fact, the highly selective allosteric TYK2 inhibitor BMS986165 has been shown to effectively block the IL-12/IL-23 and type I IFN signaling pathways, thereby demonstrating significant efficacy in a variety of experimental autoimmune disease models (psoriasis, SLE, and IBD). In addition, the results of a Phase 2 clinical trial reported that the drug achieved the primary efficacy endpoint in patients with moderate to severe plaque psoriasis and had a good risk-benefit ratio. After taking BMS986165 for 12 weeks, the psoriasis area and severity index scores of most patients decreased by more than 75% (PASI 75), and some patients' PASI scores decreased by more than 90% (PASI 90), further demonstrating the effectiveness and potential of the TYK2 target in the treatment of autoimmune diseases.

公开的TYK2降解剂的专利申请包括WO2023076161A1等。Disclosed patent applications for TYK2 degraders include WO2023076161A1 and others.

发明内容Summary of the Invention

本公开的目的是提供一种通式(I)所示的化合物，或其可药用的盐：
The purpose of the present disclosure is to provide a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:

其中：in:

G1选自N、NR0、O、S和CR’；G 1 is selected from N, NR 0 , O, S and CR′;

G2为N或C；G 2 is N or C;

G3为N或C；G 3 is N or C;

Z1选自C(O)NR1R2、C(O)NR1aOR2、C(O)NR1aNR1R2、NR1aC(O)NR1R2、C(O)C(O)NR1R2、C(O)R2、C(＝NR1a)NR1R2、S(O)rR2、S(＝NR1a)R2和S(＝NR1a)(O)R2；Z 1 is selected from C(O)NR 1 R 2 , C(O)NR 1a OR 2 , C(O)NR 1a NR 1 R 2 , NR 1a C(O)NR 1 R 2 , C(O)C(O)NR 1 R 2 , C(O)R 2 , C(=NR 1a )NR 1 R 2 , S(O) r R 2 , S(=NR 1a )R 2 and S(=NR 1a )(O)R 2 ;

R4、R5、R0和R1a相同或不同，且各自独立地选自氢原子、烷基、烷氧基、羟基、OR12、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；R 4 , R 5 , R 0 and R 1a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, OR 12 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 01 ;

R1和R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、OR12、NR10R11、C(O)NR10R11、NR13C(O)R12、C(O)R12、C(O)OR12、OC(O)R12、S(O)rR12、S(O)rNR10R11、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；或R1、R2及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R01所取代； R1 and R2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, OR12 , NR10R11 , C(O) NR10R11 , NR13C (O) R12 , C(O) R12 , C(O) OR12 , OC ( O) R12 , S( O ) rR12 , S(O) rNR10R11 , a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group; and the alkyl group , alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group are each independently optionally substituted with one or more R01 ; or R1 , R 2 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R 01 ;

R10、R11、R12和R13相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR21R22、C(O)NR21R22、NR23C(O)R24、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rNR21R22、OR24、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；R 10 , R 11 , R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , C(O)R 24 , C(O)OR 24 , OC(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 01 ;

或R10、R11及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R01所取代；or R 10 , R 11 and the nitrogen atom to which they are attached together form a heterocyclic group, and the heterocyclic group is optionally substituted by one or more R 01 ;

R3、R6和R’相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烯基、炔基、氰基、硝基、NR21R22、C(O)NR21R22、C(O)R24、C(O)OR24、S(O)rR24、S(O)rNR21R22、OR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；R 3 , R 6 and R 'are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O) OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(＝NR 23 )(O)R 24 , P(O)R 21 R 22 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally replaced by one or more R 02 replaced;

L1、L3、L4、L5和L6相同或不同，且各自独立地选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、C(O)-杂环基、杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、亚烷基、烯基、炔基、环烷基、杂环基、亚烷基-杂环基、杂环基-亚烷基、杂环基-杂环基、芳基和杂芳基；所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；L 1 , L 3 , L 4 , L 5 and L 6 are the same or different and are each independently selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C( O ), C(O)N( RL ), N(RL)C(O), S(O)r , S( O ) rN ( RL ), N(RL)S(O)r, N( RL ), S(═NR 23 ), S(═NR 23 )(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl and heteroaryl; said alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R 03 ;

L2选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、C(O)-杂环基、杂环基-C(O)、亚烷基、烯基、炔基、环烷基、杂环基、亚烷基-杂环基、杂环基-亚烷基、杂环基-杂环基、芳基、杂芳基和环B-Z2-环B1；所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环B1和环B各自独立地任选被一个或多个R03所取代；L 2 is selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, heteroaryl and ring BZ 2 -ring B1; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring B1 and ring B are each independently optionally substituted with one or more R 03 ;

环B1选自环烷基、杂环基、芳基和杂芳基；Ring B1 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

环B选自环烷基、杂环基、芳基和杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Z2选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、亚烷基、N(RL)、S(O)r、S(＝NR23)、S(＝NR23)(O)、环烷基、杂环基、芳基和杂芳基；所述亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代； Z2 is selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), alkylene, N( RL ), S(O) r , S(= NR23 ), S(= NR23 )(O), cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R03 ;

各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR21R22、C(O)NR21R22、NR23C(O)R24、NR23C(O)NR21R22、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、S(O)rNR21R22、NR23S(O)rR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、OR24、＝CR15R16、＝NR23、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；Each of R 01 , R 02 , R 03 and R 04 is the same or different and is each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , NR 23 C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , OC(O)R 24 , S(O) r R 24 , S(O) r OR 24 , S(O) r NR 21 R 22 , NR 23 S(O) r R 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(═NR 23 )(O)R 24 , P(O)R 21 R 22 , OR 24 , ═CR 15 R 16 , ═NR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R * ;

或两个R03及与其相连的原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；or two R 03 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more R * ;

R15和R16相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR21R22、C(O)NR21R22、C(O)R24、S(O)rR24、S(O)rNR21R22、OR24、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；或R15、R16及与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基和杂环基各自独立地任选被一个或多个R*所取代；R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, NR 21 R 22 , C(O)NR 21 R 22 , C(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R * ; or R 15 , R 16 and the carbon atom to which they are attached together form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more R * ;

R21、R22、R23、R24和RL相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR30R31、C(O)NR30R31、NR33C(O)R32、C(O)R32、C(O)OR32、OC(O)R32、OR32、S(O)rR32、S(O)rNR30R31、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；R 21 , R 22 , R 23 , R 24 and RL are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 30 R 31 , C(O)NR 30 R 31 , NR 33 C(O)R 32 , C(O)R 32 , C(O)OR 32 , OC(O)R 32 , OR 32 , S(O) r R 32 , S(O) r NR 30 R 31 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted with one or more R * ;

R30、R31、R32和R33相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；R 30 , R 31 , R 32 and R 33 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group;

E选自：
E is selected from:

为单键或者双键； is a single bond or a double bond;

Q1、Q2、Q3、Q4和Q5中的一者为碳原子且与L6连接，其它各自独立地选自N、CH和CRq；One of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is a carbon atom and is connected to L 6 , and the others are each independently selected from N, CH and CR q ;

各个Rq相同或不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR21R22、C(O)NR21R22、C(O)R24、C(O)OR24、S(O)rR24、S(O)rNR21R22、OR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；each R q is the same or different and is independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(＝NR 23 )(O)R 24 , P(O)R 21 R 22 , cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 04 ;

或两个Rq及与其相连的碳原子一起形成环烷基或杂环基，所述环烷基和杂环基各自独立地任选被一个或多个R04所取代；or two R q together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted with one or more R 04 ;

R7和R8相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基和杂环基，所述烷基、烷氧基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more R * ;

Y1为N或CRY1； Y1 is N or CR Y1 ;

Y2为CRY2RY4或C(O)； Y2 is CR Y2 R Y4 or C(O);

Y3为N或CRY3； Y3 is N or CR Y3 ;

RY1、RY2、RY3和RY4相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、环烷基和杂环基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；R Y1 , R Y2 , R Y3 and R Y4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group and a heterocyclic group; the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted with one or more R * ;

或，RY2、RY4及与其相连的碳原子一起形成环烷基或杂环基；所述的环烷基和杂环基各自独立地任选被一个或多个R*所取代；Or, RY2 , RY4 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * ;

各个R*相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、烷硫基、氨基、-NH烷基、-N(烷基)2、-亚烷基-氨基、-亚烷基-NH烷基、-亚烷基-N(烷基)2、酰胺基、硝基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基；each R * is the same or different and is independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, alkylthio, amino, -NHalkyl, -N(alkyl) 2 , -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl) 2 , amido, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

各个r相同或不同，且各自独立地为0、1或2。Each r is the same or different and is independently 0, 1 or 2.

在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐，
In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof,

其中，E、L1至L6、Z1和R3至R6如通式(I)中所定义。wherein E, L1 to L6 , Z1 and R3 to R6 are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐，
In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

其中，E、L1至L6、Z1和R3至R6如通式(I)中所定义。wherein E, L1 to L6 , Z1 and R3 to R6 are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)、(II)所示的化合物或其可药用的盐，其为通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，
In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof,

其中，s为0、1、2或3；Where s is 0, 1, 2 or 3;

Z1、L1至L6、R3至R7和Rq如通式(I)中所定义。Z 1 , L 1 to L 6 , R 3 to R 7 and R q are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)、(II)、(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其为通式(V)、(V-1)或(V-2)所示的化合物或其可药用的盐，

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V), (V-1) or (V-2) or a pharmaceutically acceptable salt thereof,

其中，s为0、1、2或3；Where s is 0, 1, 2 or 3;

L1至L6、R1a、R1至R7和Rq如通式(I)中所定义。L 1 to L 6 , R 1a , R 1 to R 7 and R q are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中Z1为C(O)NR1aNR1R2；在一些实施方案中，Z1为NR1aC(O)NR1R2；在一些实施方案中，Z1为C(O)NR1R2；在一些实施方案中，Z1为C(O)R2；R1a、R1和R2如通式(I)中所定义；在一些实施方案中，Z1选自 In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein Z 1 is C(O)NR 1a NR 1 R 2 ; in some embodiments, Z 1 is NR 1a C(O)NR 1 R 2 ; in some embodiments, Z 1 is C(O)NR 1 R 2 ; in some embodiments, Z 1 is C(O)R 2 ; R 1a , R 1 and R 2 are as defined in the general formula (I); in some embodiments, Z 1 is selected from

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中E选自： 在一些实施方案中，E选自： 在一些实施方案中，E选自： 在一些实施方案中，E选自： s为0、1、2或3，s1为0、1、2、3或4，Rq、R7、R8、Y1和Y2如通式(I)中所定义；In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2 or 3, s1 is 0, 1, 2, 3 or 4, R q , R 7 , R 8 , Y 1 and Y 2 are as defined in the general formula (I);

在一些实施方案中，E选自：在一些实施方案中，E选自： 在一些实施方案中，E选自： s为0、1、2或3，Rq和R7如通式(I)中所定义；在一些实施方案中，E选自 在一些实施方案中，E选自 In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2 or 3, R q and R 7 are as defined in Formula (I); in some embodiments, E is selected from In some embodiments, E is selected from

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中为在一些实施方案中为在一些实施方案中为Rq、R7和s如通式(I)中所定义。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, In some embodiments, R q , R 7 and s are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中为在一些实施方案中为在一些实施方案中为Rq、R7和s如通式(I)中所定义。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, In some embodiments, R q , R 7 and s are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中为在一些实施方案中为在一些实施方案中为Rq、R7和s如通式(I)中所定义。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, In some embodiments, R q , R 7 and s are as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R1a选自氢原子、羟基、C1-6烷基、C1-6烷氧基、3至6元环烷基和OR12，R12如通式(I)中所定义；在一些实施方案中，R1a选自氢原子、羟基和C1-6烷氧基；在一些实施方案中，R1a为氢原子。In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 1a is selected from a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group and OR 12 , and R 12 is as defined in the general formula (I); in some embodiments, R 1a is selected from a hydrogen atom, a hydroxyl group and a C 1-6 alkoxy group; in some embodiments, R 1a is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R1和R2相同或不同，且各自独立地选自氢原子、C1-6烷基、3至6元环烷基、3至6元环烷基C1-6烷基和3至6元杂环基，所述C1-6烷基、3至6元环烷基、3至6元环烷基C1-6烷基和3至6元杂环基各自独立地任选被一个或多个R01所取代；或R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；In some embodiments of the present disclosure, the compounds represented by general formulas (I) to (V) or pharmaceutically acceptable salts thereof, wherein R1 and R2 are the same or different and are each independently selected from a hydrogen atom, a C1-6 alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered cycloalkylC1-6 alkyl group, and a 3- to 6-membered heterocyclic group, and the C1-6 alkyl group, the 3- to 6-membered cycloalkyl group, the 3- to 6-membered cycloalkylC1-6 alkyl group, and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R01 ; or R1 , R2 , and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group is optionally substituted by one or more R01 ;

在一些实施方案中，R1为氢原子或C1-6烷基，R2选自氢原子、C1-6烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被一个或多个R01所取代，或R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；R01如通式(I)中所定义；In some embodiments, R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group, wherein the 3- to 6-membered heterocyclyl group is optionally substituted by one or more R 01 ; R 01 is as defined in the general formula (I);

在一些实施方案中，R1为C1-6烷基，R2为C1-6烷基，或R1、R2及与其相连的氮原子一起形成环该环各自独立地任选被选自卤素、C1-6烷基和＝CR15R16中的一个或多个所取代，R15和R16相同或不同，且各自独立地为氢原子或卤素；In some embodiments, R 1 is C 1-6 alkyl, R 2 is C 1-6 alkyl, or R 1 , R 2 and the nitrogen atom to which they are attached together form a ring The rings are each independently optionally substituted by one or more selected from halogen, C 1-6 alkyl and ═CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or halogen;

在一些实施方案中，R1为C1-6烷基，R2为C1-6烷基，或R1、R2及与其相连的氮原子一起形成 In some embodiments, R 1 is C 1-6 alkyl, R 2 is C 1-6 alkyl, or R 1 , R 2 and the nitrogen atom to which they are attached together form

在一些实施方案中，R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；R01如通式(I)中所定义；In some embodiments, R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more R 01 ; R 01 is as defined in the general formula (I);

在一些实施方案中，R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个＝CR15R16所取代；R15和R16相同或不同，且各自独立地为氢原子或卤素；In some embodiments, R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more ═CR 15 R 16 ; R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

在一些实施方案中，R1、R2及与其相连的氮原子一起形成其各自独立地任选被选自卤素、C1-6烷基和＝CR15R16中的一个或多个所取代，R15和R16相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R1、R2及与其相连的氮原子一起形成 In some embodiments, R 1 , R 2 and the nitrogen atom to which they are attached together form They are each independently optionally substituted by one or more selected from halogen, C 1-6 alkyl and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 1 , R 2 and the nitrogen atom to which they are attached together form

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R1选自氢原子、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基、C1-6羟烷基、C1-6烷氧基C1-6烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基C1-6烷基和3至10元杂环基C1-6烷基，所述C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基C1-6烷基和3至10元杂环基C1-6烷基各自独立地任选被一个或多个R01所取代；R01如通式(I)中所定义；在一些实施方案中，R1选自氢原子、C1-6烷基、3至6元环烷基和3至6元环烷基C1-6烷基；在一些实施方案中，R1为氢原子或C1-6烷基；在一些实施方案中，R1选自氢原子、甲基和乙基；在一些实施方案中，R1为氢原子；在一些实施方案中，R1为氢原子或C1-6烷基；在一些实施方案中，R1为乙基。In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 1 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy C 1-6 alkyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 3- to 10-membered cycloalkyl C 1-6 alkyl group and a 3- to 10-membered heterocyclyl C 1-6 alkyl group, and the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkoxy C 1-6 alkyl group, the 3- to 10-membered cycloalkyl group, the 3- to 10-membered heterocyclyl group, the 3- to 10-membered cycloalkyl C 1-6 alkyl group and the 3- to 10-membered heterocyclyl C 1-6 alkyl group are each independently optionally substituted by one or more R 01 ; R 01 is as defined in the general formula (I); in some embodiments, R In some embodiments, R 1 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered cycloalkyl C 1-6 alkyl group; in some embodiments, R 1 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 1 is selected from the group consisting of a hydrogen atom, a methyl group, and an ethyl group; in some embodiments, R 1 is a hydrogen atom; in some embodiments, R 1 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 1 is an ethyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R2选自氢原子、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基、C1-6羟烷基、C1-6烷氧基C1-6烷基、OR12、NR10R11、OC(O)R12、3至10元环烷基、3至10元杂环基、3至10元环烷基C1-6烷基和3至10元杂环基C1-6烷基，所述C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基C1-6烷基和3至10元杂环基C1-6烷基各自独立地任选被一个或多个R01所取代，或R2、R1及与其相连的氮原子一起形成任选被一个或多个R01取代的3至6元杂环基；R01、R10、R11和R12如通式(I)中所定义；In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy C 1-6 alkyl group, OR 12 , NR 10 R 11 , OC(O)R 12 , a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 3- to 10-membered cycloalkyl C 1-6 alkyl group and a 3- to 10-membered heterocyclyl C 1-6 alkyl group, and the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkoxy C 1-6 alkyl group, the 3- to 10-membered cycloalkyl group, the 3- to 10-membered heterocyclyl group, the 3- to 10-membered cycloalkyl C 1-6 alkyl group and the 3- to 10-membered heterocyclyl C 1-6 alkyl group are each independently optionally replaced by one or more R 01 , or R 2 , R 1 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group optionally substituted by one or more R 01 ; R 01 , R 10 , R 11 and R 12 are as defined in the general formula (I);

在一些实施方案中，R2选自氢原子、C1-6烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6烷氧基、羟基和＝CR15R16中的一个或多个所取代，R15和R16相同或不同，且各自独立地为氢原子或卤素，或R2、R1及与其相连的氮原子一起形成任选被一个或多个R01取代的3至6元杂环基；In some embodiments, R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted by one or more selected from an oxo group, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a hydroxyl group, and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen, or R 2 , R 1 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group optionally substituted by one or more R 01 ;

在一些实施方案中，R2为C1-6烷基或3至6元杂环基，所述3至6元杂环基任选被选自卤素、C1-6烷氧基、羟基和＝CR15R16中的一个或多个所取代，R15和R16相同或不同，且各自独立地为氢原子或卤素；In some embodiments, R 2 is a C 1-6 alkyl group or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 alkoxy, hydroxyl, and ═CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

在一些实施方案中，R2为C1-6烷基，或R2、R1及与其相连的氮原子一起形成任选被一个或多个R01取代的3至6元杂环基；在一些实施方案中，R2为C1-6烷基；In some embodiments, R 2 is C 1-6 alkyl, or R 2 , R 1 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group optionally substituted with one or more R 01 ; In some embodiments, R 2 is C 1-6 alkyl;

在一些实施方案中，R2选自乙基、 在一些实施方案中，R2选自乙基、 在一些实施方案中，R2选自 乙基、在一些实施方案中，R2选自 在一些实施方案中为 In some embodiments, R2 is selected from Ethyl, In some embodiments, R2 is selected from Ethyl, In some embodiments, R2 is selected from Ethyl, In some embodiments, R2 is selected from In some embodiments,

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L1选自键、O、S、O-C1-6亚烷基、C1-6亚烷基-O、C(O)、C(O)-C1-6亚烷基、C1-6亚烷基-C(O)、C(O)-3至12元杂环基、3至12元杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、N(RL)、S(＝NR23)、S(＝NR23)(O)、C1-6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至10元芳基和5至14元杂芳基；所述的C1- 6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至10元芳基和5至14元杂芳基各自独立地任选被一个或多个R03所取代，RL和R03如通式(I)中所定义；In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 1 is selected from a bond, O, S, OC 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C( O ), C(O)N( RL ), N(RL)C(O), N( RL ), S(＝NR 23 ), S(＝NR 23 )(O), C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl; the C 1-6 alkylene , C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl are each independently optionally substituted with one or more R 03 , RL and R 03 are as defined in the general formula (I);

在一些实施方案中，L1为键或N(RL)；在一些实施方案中，L1为N(RL)，RL如通式(I)中所定义；在一些实施方案中，L1为N(RL)，RL为氢原子或C1-6烷基；在一些实施方案中，L1为键或NH；在一些实施方案中，L1为NH。In some embodiments, L 1 is a bond or N( RL ); in some embodiments, L 1 is N( RL ), RL is as defined in Formula (I); in some embodiments, L 1 is N( RL ), RL is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, L 1 is a bond or NH; in some embodiments, L 1 is NH.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L2选自键、C(O)、O、S、C1-6亚烷基、3至12元环烷基、3至12元杂环基、6至14元芳基、5至14元杂芳基、环B-6至14元芳基、环B-5至14元杂芳基和所述C1-6亚烷基、3至12元杂环基、6至14元芳基、5至14元杂芳基和环B各自独立地任选被一个或多个R03所取代；In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 2 is selected from a bond, C(O), O, S, C 1-6 alkylene, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl, 5 to 14-membered heteroaryl, ring B-6 to 14-membered aryl, ring B-5 to 14-membered heteroaryl, and The C 1-6 alkylene, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl, 5 to 14-membered heteroaryl and ring B are each independently optionally substituted by one or more R 03 ;

在一些实施方案中，L2选自6至14元芳基、5至14元杂芳基、苯基-环B和所述6至14元芳基、5至14元杂芳基、苯基和环B各自独立地任选被一个或多个R03所取代；环B和R03如通式(I)中所定义；In some embodiments, L 2 is selected from 6 to 14 membered aryl, 5 to 14 membered heteroaryl, phenyl-ring B and The 6- to 14-membered aryl group, the 5- to 14-membered heteroaryl group, the phenyl group and the ring B are each independently optionally substituted by one or more R 03 ; the ring B and R 03 are as defined in the general formula (I);

在一些实施方案中，L2为在一些实施方案中，L2为b为0、1、2或3；n为0、1、2、3、4、5或6；环B、Z2和R03如通式(I)中所定义；In some embodiments, L2 is In some embodiments, L2 is b is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5 or 6; Ring B, Z 2 and R 03 are as defined in Formula (I);

在一些实施方案中，L2选自 环A选自环烷基、杂环基、芳基和杂芳基；环C为含氮杂环基或杂芳基；m为0、1、2、3、4、5或6；t为0至16的整数；在一些实施方案中，L2选自 环A选自环烷基、杂环基、芳基和杂芳基；环E选自环烷基、杂环基、芳基和杂芳基；W为选自CH、C和N；J1和J2相同或不同，且各自独立地选自键、(CRaRb)q、(CRaRb)qO、O(CRaRb)q、NRi、O和S；Ra和Rb相同或不同，且各自独立地为氢原子或R03；Ri为氢原子或烷基；Re、Rf及与其相连的碳原子一起形成环烷基或杂环基，Rj和Rk为氢原子或R03，或Rj、Rk及与其相连的碳原子一起形成环烷基或杂环基，Re和Rf为氢原子或R03，L2连接至所述形成的环上或与J1或J2连接；m为0、1、2、3、4、5或6；q为0、1或2；b为0、1、2或3；n为0、1、2、3或4；环B和R03如通式(I)中所定义；In some embodiments, L2 is selected from Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring C is a nitrogen-containing heterocyclyl or heteroaryl; m is 0, 1, 2, 3, 4, 5 or 6; t is an integer from 0 to 16; in some embodiments, L 2 is selected from Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; W is selected from CH, C and N; J1 and J2 are the same or different and are each independently selected from a bond, ( CRaRb ) q , ( CRaRb ) qO , O( CRaRb ) q , NR1 , O and S; Ra and Rb are the same or different and are each independently a hydrogen atom or R03 ; Ri is a hydrogen atom or an alkyl group; Re , Rf and the carbon atom to which they are attached together form a cycloalkyl or heterocyclyl group, Rj and Rk are hydrogen atoms or R03 , or Rj , Rk and the carbon atom to which they are attached together form a cycloalkyl or heterocyclyl group, Re and Rf are hydrogen atoms or R03 , and L2 is connected to the formed ring or to J1 or J 2 connected; m is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1 or 2; b is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; Ring B and R 03 are as defined in Formula (I);

在一些实施方案中，L2选自 在一些实施方案中，L2选自 在一些实施方案中，L2为u为1、2、3或4；Q和L相同或不同，且各自独立地选自键、(CRgRh)q、(CRgRh)qO、O(CRgRh)q、NRi、O和S；Rg和Rh相同或不同，且各自独立地为氢原子或R03，Ri为氢原子或烷基；n为0、1、2或3；b为0、1、2或3；a为0、1或2；q为0、1或2；R03如通式(I)中所定义；In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is u is 1, 2, 3 or 4; Q and L are the same or different and are each independently selected from a bond, (CR g R h ) q , (CR g R h ) q O, O(CR g R h ) q , NR i , O and S; R g and R h are the same or different and are each independently a hydrogen atom or R 03 , R i is a hydrogen atom or an alkyl group; n is 0, 1, 2 or 3; b is 0, 1, 2 or 3; a is 0, 1 or 2; q is 0, 1 or 2; R 03 is as defined in Formula (I);

在一些实施方案中，L2选自 在一些实施方案中，L2选自 In some embodiments, L2 is selected from In some embodiments, L2 is selected from

在一些实施方案中，L2选自 为与L1和L3的连接点。In some embodiments, L2 is selected from It is the connection point with L1 and L3 .

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中环B1为 In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein ring B1 is

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中Z2为键或3至10元杂环基，所述3至10元杂环基任选被一个或多个R03所取代；在一些实施方案中，Z2为键；在一些实施方案中，Z2为任选被一个或多个R03所取代的3至10元杂环基；在一些实施方案中，Z2为任选被一个或多个R03所取代的3至6元杂环基；R03如通式(I)中所定义。In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein Z 2 is a bond or a 3- to 10-membered heterocyclic group, and the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 03 ; in some embodiments, Z 2 is a bond; in some embodiments, Z 2 is a 3- to 10-membered heterocyclic group optionally substituted by one or more R 03 ; in some embodiments, Z 2 is a 3- to 6-membered heterocyclic group optionally substituted by one or more R 03 ; R 03 is as defined in the general formula (I).

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中环B选自3至10元杂环基、苯基和5至10元杂芳基；在一些实施方案中，环B选自3至10元杂环基、苯基、5或6元杂芳基和9或10元杂芳基；在一些实施方案中，环B选自苯基、吡啶基、吡嗪基、哒嗪基和嘧啶基；在一些实施方案中，环B为吡啶基；在一些实施方案中，环B为上述实施方案中，环B任选地被一个或多个R03所取代；R03如通式(I)中所定义。In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein ring B is selected from a 3- to 10-membered heterocyclic group, a phenyl group, and a 5- to 10-membered heteroaryl group; in some embodiments, ring B is selected from a 3- to 10-membered heterocyclic group, a phenyl group, a 5- or 6-membered heteroaryl group, and a 9- or 10-membered heteroaryl group; in some embodiments, ring B is selected from a phenyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a pyrimidinyl group; in some embodiments, ring B is a pyridyl group; in some embodiments, ring B is In the above embodiment, Ring B is optionally substituted with one or more R 03 ; R 03 is as defined in Formula (I).

在本公开一些实施方案中，环A为3至12元环烷基或3至12元杂环基；在一些实施方案中，环A为3至12元杂环基；在一些实施方案中，环A为7至12元杂环基；在一些实施方案中，环A为7至12元双环杂环基；在一些实施方案中，环A为7、8或9元双环杂环基；在一些实施方案中，环A选自 在一些实施方案中，环A选自 为稠合位点。In some embodiments of the present disclosure, ring A is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclyl; in some embodiments, ring A is a 3- to 12-membered heterocyclyl; in some embodiments, ring A is a 7- to 12-membered heterocyclyl; in some embodiments, ring A is a 7- to 12-membered bicyclic heterocyclyl; in some embodiments, ring A is a 7-, 8-, or 9-membered bicyclic heterocyclyl; in some embodiments, ring A is selected from In some embodiments, Ring A is selected from The fusion site.

在本公开一些实施方案中，环C为7至12元含氮杂环基；在一些实施方案中，环C为8、9或10元双环含氮杂环基。In some embodiments of the present disclosure, Ring C is a 7- to 12-membered nitrogen-containing heterocyclic group; in some embodiments, Ring C is an 8-, 9-, or 10-membered bicyclic nitrogen-containing heterocyclic group.

在本公开一些实施方案中，环E为芳基或杂芳基；在一些实施方案中，环E选自苯基、5或6元杂芳基、3至8元环烷基和3至8元杂环基；在一些实施方案中，环E为苯基或6元杂芳基；在一些实施方案中，环E选自苯基、吡啶基、吡嗪基、哒嗪基和嘧啶基；在一些实施方案中，环E为吡啶基；在一些实施方案中，环E为*端为稠合位点。In some embodiments of the present disclosure, ring E is an aryl or heteroaryl group; in some embodiments, ring E is selected from phenyl, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; in some embodiments, ring E is phenyl or 6-membered heteroaryl; in some embodiments, ring E is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl; in some embodiments, ring E is pyridyl; in some embodiments, ring E is *End is the fusion site.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L3选自键、O、S、O-C1-6亚烷基、C1-6亚烷基-O、C(O)、C(O)-C1-6亚烷基、C1-6亚烷基-C(O)、C(O)-3至12元杂环基、3至12元杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、C1- 6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、C1-6亚烷基-3至12元杂环基、3至12元杂环基-C1-6亚烷基、3至12元杂环基-3至12元杂环基、6至10元芳基和5至14元杂芳基；所述的C1-6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至14元芳基和5至14元杂芳基各自独立地任选被一个或多个R03所取代，r、RL和R03如通式(I)中所定义；在一些实施方案中，L3选自键、C1-6亚烷基和3至12元杂环基，所述3至12元杂环基任选被一个或多个R03所取代；R03如通式(I)中所定义；在一些实施方案中，L3为键或C1-6亚烷基；在一些实施方案中，L3为键或(CH2)p，p为0、1、2、3或4；在一些实施方案中，L3为键。In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 3 is selected from a bond, O, S, OC 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), C (O)N(RL), N( RL )C(O), S(O) r , S( O ) rN (RL), N( RL )S(O) r , N( RL ), S(＝NR 23 ), S(＝NR 23 )(O), C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12 -membered cycloalkyl, 3 to 12-membered heterocyclyl, C 1-6 alkylene-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C 1-6 alkylene, 3 to 12-membered heterocyclyl-3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl; the C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl and 5 to 14-membered heteroaryl are each independently optionally substituted with one or more R 03 , r, RL and R 03 are as defined in the general formula (I); in some embodiments, L 3 is selected from a bond, C 1-6 alkylene and 3 to 12-membered heterocyclyl, the 3 to 12-membered heterocyclyl is optionally substituted with one or more R 03 ; R 03 is as defined in the general formula (I); in some embodiments, L 3 is a bond or C 1-6 alkylene; in some embodiments, L 3 is a bond or (CH 2 ) p , p is 0, 1, 2, 3 or 4; in some embodiments, L 3 is a bond.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L4选自键、O、S、O-C1-6亚烷基、C1-6亚烷基-O、C(O)、C(O)-C1-6亚烷基、C1-6亚烷基-C(O)、C(O)-3至12元杂环基、3至12元杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、C1- 6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、C1-6亚烷基-3至12元杂环基、3至12元杂环基-C1-6亚烷基、3至12元杂环基-3至12元杂环基、6至10元芳基和5至14元杂芳基；所述的C1-6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至14元芳基和5至14元杂芳基各自独立地任选被一个或多个R03所取代，r、RL和R03如通式(I)中所定义；在一些实施方案中，L4选自键、C1-6亚烷基、C(O)和3至12元杂环基，所述3至12元杂环基任选被一个或多个R03所取代；R03如通式(I)中所定义；在一些实施方案中，L4选自C(O)、3至12元杂环基-C(O)、C(O)N(RL)和C1-6亚烷基，所述3至12元杂环基任选被一个或多个R03所取代；RL和R03如通式(I)中所定义；在一些实施方案中，L4为C1-6亚烷基或C(O)；在一些实施方案中，L4为(CH2)p或C(O)，p为0、1、2、3或4；在一些实施方案中，L4为C(O)；在一些实施方案中，L4为或C(O)；在一些实施方案中，L4为 In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 4 is selected from a bond, O, S, OC 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), C (O)N(RL), N( RL )C(O), S(O) r , S( O ) rN (RL), N( RL )S(O) r , N( RL ), S(＝NR 23 ), S(＝NR 23 )(O), C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12 -membered cycloalkyl, 3 to 12-membered heterocyclyl, C 1-6 alkylene-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C 1-6 alkylene, 3 to 12-membered heterocyclyl-3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl; the C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl and 5 to 14-membered heteroaryl are each independently optionally substituted with one or more R 03 , R, RL and R 03 are as defined in the general formula (I); in some embodiments, L 4 is selected from a bond, C 1-6 alkylene, C (O) and 3 to 12-membered heterocyclyl, the 3 to 12-membered heterocyclyl is optionally substituted with one or more R 03 ; R 03 is as defined in the general formula (I); in some embodiments, L 4 is selected from C(O), 3 to 12 membered heterocyclyl-C(O), C(O)N( RL ) and C 1-6 alkylene, wherein the 3 to 12 membered heterocyclyl is optionally substituted with one or more R 03 ; RL and R 03 are as defined in the general formula (I); in some embodiments, L 4 is C 1-6 alkylene or C(O); in some embodiments, L 4 is (CH 2 ) p or C(O), p is 0, 1, 2, 3 or 4; in some embodiments, L 4 is C(O); in some embodiments, L 4 is Or C(O); In some embodiments, L 4 is

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L5选自键、O、S、O-C1-6亚烷基、C1-6亚烷基-O、C(O)、C(O)-C1-6亚烷基、C1-6亚烷基-C(O)、C(O)-3至12元杂环基、3至12元杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、C1- 6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、C1-6亚烷基-3至12元杂环基、3至12元杂环基-C1-6亚烷基、3至12元杂环基-3至12元杂环基、6至10元芳基和5至14元杂芳基；所述的C1-6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至14元芳基和5至14元杂芳基各自独立地任选被一个或多个R03所取代，r、RL和R03如通式(I)中所定义；在一些实施方案中，L5为3至12元杂环基，所述3至12元杂环基任选被一个或多个R03所取代；在一些实施方案中，L5为3至12元杂环基；在一些实施方案中，L5为U选自N、CH和CR03，V选自N、CH和CR03；c为0、1或2；d为0、1或2；e为0、1或2；f为1或2；v为0、1、2、3或4；R03如通式(I)中所定义；在一些实施方案中，L5为 In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 5 is selected from a bond, O, S, OC 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), C (O)N(RL), N( RL )C(O), S(O) r , S( O ) rN (RL), N( RL )S(O) r , N( RL ), S(＝NR 23 ), S(＝NR 23 )(O), C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12 -membered cycloalkyl, 3 to 12-membered heterocyclyl, C 1-6 alkylene-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C 1-6 alkylene, 3 to 12-membered heterocyclyl-3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl; the C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl and 5 to 14-membered heteroaryl are each independently optionally substituted with one or more R 03 , r, RL and R 03 are as defined in the general formula (I); in some embodiments, L 5 is a 3 to 12-membered heterocyclyl, the 3 to 12-membered heterocyclyl is optionally substituted with one or more R 03 ; in some embodiments, L 5 is a 3 to 12-membered heterocyclyl; in some embodiments, L 5 is U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4; R 03 is as defined in formula (I); in some embodiments, L 5 is

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L6选自键、O、S、O-C1-6亚烷基、C1-6亚烷基-O、C(O)、C(O)-C1-6亚烷基、C1-6亚烷基-C(O)、C(O)-3至12元杂环基、3至12元杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、C1- 6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、C1-6亚烷基-3至12元杂环基、3至12元杂环基-C1-6亚烷基、3至12元杂环基-3至12元杂环基、6至10元芳基和5至14元杂芳基；所述的C1-6亚烷基、C2-6烯基、C2-6炔基、3至12元环烷基、3至12元杂环基、6至14元芳基和5至14元杂芳基各自独立地任选被一个或多个R03所取代，r、RL和R03如通式(I)中所定义；在一些实施方案中，L6选自键、C1-6亚烷基和3至12元杂环基，所述3至12元杂环基任选被一个或多个R03所取代；R03如通式(I)中所定义；在一些实施方案中，L6为键。In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 6 is selected from a bond, O, S, OC 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), C (O)N(RL), N( RL )C(O), S(O) r , S( O ) rN (RL), N( RL )S(O) r , N( RL ), S(＝NR 23 ), S(＝NR 23 )(O), C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12 -membered cycloalkyl, 3 to 12-membered heterocyclyl, C 1-6 alkylene-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C 1-6 alkylene, 3 to 12-membered heterocyclyl-3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl; the C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 14-membered aryl and 5 to 14-membered heteroaryl are each independently optionally substituted by one or more R 03 , r, RL and R 03 are as defined in the general formula (I); in some embodiments, L 6 is selected from a bond, C 1-6 alkylene and 3 to 12-membered heterocyclyl, the 3 to 12-membered heterocyclyl is optionally substituted by one or more R 03 ; R 03 is as defined in the general formula (I); in some embodiments, L 6 is a bond.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中L6-L5-L4-L3选自C(O)-3至12元杂环基、3至12元杂环基-C(O)、3至12元杂环基-C1-6亚烷基和C1-6亚烷基-3至12元杂环基，所述3至12元杂环基任选被一个或多个R03所取代；在一些实施方案中，L6-L5-L4-L3为杂环基-C(O)或杂环基-C1-6亚烷基，所述杂环基任选被一个或多个R03所取代；在一些实施方案中，L6-L5-L4-L3为3至12元杂环基-C(O)或3至12元杂环基-C1-6亚烷基，所述3至12元杂环基任选被一个或多个R03所取代；在一些实施方案中，L6-L5-L4-L3为3至12元杂环基-C(O)，所述3至12元杂环基任选被一个或多个R03所取代，R03如通式(I)中所定义；In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 6 -L 5 -L 4 -L 3 is selected from C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), 3 to 12-membered heterocyclyl-C 1-6 alkylene and C 1-6 alkylene-3 to 12-membered heterocyclyl, and the 3 to 12-membered heterocyclyl is optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is heterocyclyl-C(O) or heterocyclyl-C 1-6 alkylene, and the heterocyclyl is optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is 3 to 12-membered heterocyclyl-C(O) or 3 to 12-membered heterocyclyl-C 1-6 alkylene, and the 3 to 12-membered heterocyclyl is optionally substituted with one or more R In some embodiments, L 6 -L 5 -L 4 -L 3 is a 3- to 12-membered heterocyclyl-C(O), which is optionally substituted with one or more R 03 , wherein R 03 is as defined in the general formula (I);

在一些实施方案中，L6-L5-L4-L3选自 在一些实施方案中，L6-L5-L4-L3为 U选自N、CH和CR03，V选自N、CH和CR03；T选自N、CH和CR03，W选自N、CH和CR03，c为0、1或2；d为0、1或2；e为0、1或2；f为1或2；v为0、1、2、3或4，p为0、1、2、3或4；x为0、1、2、3或4，R03如通式(I)中所定义；In some embodiments, L 6 -L 5 -L 4 -L 3 are selected from In some embodiments, L 6 -L 5 -L 4 -L 3 is U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; T is selected from N, CH and CR 03 , W is selected from N, CH and CR 03 , c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3 or 4, and R 03 is as defined in formula (I);

在一些实施方案中，L6-L5-L4-L3为在一些实施方案中，L6-L5-L4-L3为在一些实施方案中，L6-L5-L4-L3选自 在一些实施方案中为 In some embodiments, L 6 -L 5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 are selected from In some embodiments,

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中选自 In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein Selected from

在一些实施方案中，选自 In some embodiments, Selected from

在一些实施方案中，为 In some embodiments, for

在本公开一些实施方案中，U为CH或N，和/或V为CH或N。In some embodiments of the present disclosure, U is CH or N, and/or V is CH or N.

在本公开一些实施方案中，U为CH或N，和/或V为CH或N，和c为1，和/或d为0或1，和/或e为1，和/或f为1或2。In some embodiments of the present disclosure, U is CH or N, and/or V is CH or N, and c is 1, and/or d is 0 or 1, and/or e is 1, and/or f is 1 or 2.

在本公开一些实施方案中，v为0、1或2；在一些实施方案中，v为0。In some embodiments of the present disclosure, v is 0, 1 or 2; in some embodiments, v is 0.

在本公开一些实施方案中，T为CH或N，和/或W为CH或N。In some embodiments of the present disclosure, T is CH or N, and/or W is CH or N.

在本公开一些实施方案中，Q选自键、O、CH2O和CH2CH2O，和/或L选自键、O、CH2O和CH2CH2O；在一些实施方案中，Q选自键、O、CH2O和CH2CH2O，和/或L为键或O；在一些实施方案中，Q为键或O，和/或L为键或O；在一些实施方案中，Q为O，和/或L为O。In some embodiments of the present disclosure, Q is selected from a bond, O, CH2O , and CH2CH2O , and/or L is selected from a bond, O , CH2O , and CH2CH2O ; in some embodiments, Q is selected from a bond, O, CH2O , and CH2CH2O , and/or L is a bond or O ; in some embodiments, Q is a bond or O , and/or L is a bond or O; in some embodiments, Q is O, and/or L is O.

在本公开一些实施方案中，u为1或2；在一些实施方案中，u为1。In some embodiments of the present disclosure, u is 1 or 2; in some embodiments, u is 1.

在本公开一些实施方案中，Q为键或O，和/或L为键或O，和/或u为1或2；在一些实施方案中，Q为O，和/或L为O，和/或u为1。In some embodiments of the present disclosure, Q is a bond or O, and/or L is a bond or O, and/or u is 1 or 2; in some embodiments, Q is O, and/or L is O, and/or u is 1.

在本公开一些实施方案中，a为0、1或2；在一些实施方案中，a为1。In some embodiments of the present disclosure, a is 0, 1 or 2; in some embodiments, a is 1.

在本公开一些实施方案中，b为0、1或2；在一些实施方案中，b为0。In some embodiments of the present disclosure, b is 0, 1 or 2; in some embodiments, b is 0.

在本公开一些实施方案中，n为0、1或2；在一些实施方案中，n为0。In some embodiments of the present disclosure, n is 0, 1 or 2; in some embodiments, n is 0.

在本公开一些实施方案中，p为0、1或2；在一些实施方案中，p为1。In some embodiments of the present disclosure, p is 0, 1, or 2; in some embodiments, p is 1.

在本公开一些实施方案中，t为0、1或2；在一些实施方案中，t为0。In some embodiments of the present disclosure, t is 0, 1 or 2; in some embodiments, t is 0.

在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中为在一些实施方案中，为在一些实施方案中，为 In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, for In some embodiments, for

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和C1-6卤代烷氧基；在一些实施方案中，R3为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; in some embodiments, R 3 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R4为氢原子或C1-6烷基；在一些实施方案中，R4为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 4 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 4 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R5选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R5为氢原子或C1-6烷基；在一些实施方案中，R5为C1-6烷基；在一些实施方案中，R5为甲基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 5 is selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R 5 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 5 is a C 1-6 alkyl group; in some embodiments, R 5 is a methyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R6选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和C1-6卤代烷氧基；在一些实施方案中，R6为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R6 is selected from hydrogen atom, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; in some embodiments, R6 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R3为氢原子，和/或R6为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R4为氢原子，和/或R5为C1-6烷基；在一些实施方案中，R4为氢原子，和/或R5为甲基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 4 is a hydrogen atom, and/or R 5 is a C 1-6 alkyl group; in some embodiments, R 4 is a hydrogen atom, and/or R 5 is a methyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R3为氢原子，和/或R6为氢原子，和/或R4为氢原子，和/或R5为C1-6烷基；在一些实施方案中，R3为氢原子，和/或R6为氢原子，和/或R4为氢原子，和/或R5为甲基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom, and/or R 4 is a hydrogen atom, and/or R 5 is a C 1-6 alkyl group; in some embodiments, R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom, and/or R 4 is a hydrogen atom, and/or R 5 is a methyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中RL为氢原子或C1-6烷基；在一些实施方案中，RL为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein RL is a hydrogen atom or a C1-6 alkyl group; in some embodiments, RL is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个R01相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基烷基、3至6元环烷基和＝CR15R16，R15和R16如通式(I)中所定义；在一些实施方案中，各个R01相同或不同，且各自独立地选自氧代基、卤素、C1-6烷基、C1-6烷氧基、羟基、3至6元环烷基和＝CR15R16，R15和R16相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；在一些实施方案中，各个R01相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基、羟基和＝CR15R16，R15和R16相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，各个R01相同或不同，且各自独立地选自氧代基、F、甲基、甲氧基、羟基、环丙基、在一些实施方案中，各个R01相同或不同，且各自独立地选自F、甲基、甲氧基和在一些实施方案中，各个R01相同或不同，且各自独立地为＝CR15R16；R15和R16如通式(I)中所定义；在一些实施方案中，各个R01相同或不同，且各自独立地为＝CR15R16；R15和R16相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R01为 In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 01 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyalkyl, 3-6 membered cycloalkyl and =CR 15 R 16 , R 15 and R 16 are as defined in the general formula (I); in some embodiments, each R 01 is the same or different and is independently selected from oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, 3-6 membered cycloalkyl and =CR 15 R 16 , R 15 and R 16 are the same or different and are independently selected from hydrogen atom, halogen and C 1-6 alkyl; in some embodiments, each R 01 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, each R 01 is the same or different and is each independently selected from oxo, F, methyl, methoxy, hydroxyl, cyclopropyl, In some embodiments, each R 01 is the same or different and is independently selected from F, methyl, methoxy and In some embodiments, each R 01 is the same or different and is independently ═CR 15 R 16 ; R 15 and R 16 are as defined in Formula (I); in some embodiments, each R 01 is the same or different and is independently ═CR 15 R 16 ; R 15 and R 16 are the same or different and are independently hydrogen or halogen; in some embodiments, R 01 is

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个R02相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R02相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 02 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 02 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个R03相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基，或两个R03及与其相连的的碳原子一起形成环烷基或杂环基；在一些实施方案中，各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基，或两个R03及与其相连的的碳原子一起形成环烷基或杂环基；在一些实施方案中，各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，各个R03相同或不同，且各自独立地为卤素；在一些实施方案中，R03为F。In some embodiments of the present disclosure, the compounds represented by the general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 03 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3-6 membered cycloalkyl, or two R 03 and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group; in some embodiments, each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl, or two R 03 and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group; in some embodiments, each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, each R 03 is the same or different and is independently halogen; in some embodiments, R 03 is F.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个R04相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R04相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 04 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 04 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个R*相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R*相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R * is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxyC1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R * is the same or different and is independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R10和R11相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R10和R11相同或不同，且各自独立地为氢原子或甲基；在一些实施方案中，R10和R11均为氢原子。In some embodiments of the present disclosure, in the compounds represented by general formulae (I) to (V) or pharmaceutically acceptable salts thereof, R 10 and R 11 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 10 and R 11 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 10 and R 11 are both hydrogen atoms.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R12选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R12为氢原子或C1-6烷基；在一些实施方案中，R12为氢原子；在一些实施方案中，R12为C1-6烷基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 12 is selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R 12 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 12 is a hydrogen atom; in some embodiments, R 12 is a C 1-6 alkyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R15和R16相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；在一些实施方案中，R15和R16相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R15和R16相同或不同，且各自独立地为氢原子或F；在一些实施方案中，R15和R16均为F。In some embodiments of the present disclosure, in the compounds represented by general formulae (I) to (V) or pharmaceutically acceptable salts thereof, R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 15 and R 16 are both F.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R21和R22相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R21和R22均为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 21 and R 22 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 21 and R 22 are both hydrogen atoms.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R23为氢原子或C1-6烷基；在一些实施方案中，R23为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 23 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 23 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R24为氢原子或C1-6烷基；在一些实施方案中，R24为氢原子；在一些实施方案中，R24为C1-6烷基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 24 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 24 is a hydrogen atom; in some embodiments, R 24 is a C 1-6 alkyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中r为2；在一些实施方案中，r为1；在一些实施方案中，r为0。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein r is 2; in some embodiments, r is 1; in some embodiments, r is 0.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R30和R31相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R30和R31均为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 30 and R 31 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 30 and R 31 are both hydrogen atoms.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R32为氢原子或C1-6烷基；在一些实施方案中，R32为C1-6烷基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 32 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 32 is a C 1-6 alkyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R33为氢原子或C1-6烷基；在一些实施方案中，R33为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 33 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 33 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R7选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R7为氢原子或C1-6烷基；在一些实施方案中，R7为C1-6烷基；在一些实施方案中，R7为甲基。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R7 is selected from a hydrogen atom, a C1-6 alkyl group and a 3- to 6-membered cycloalkyl group; in some embodiments, R7 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R7 is a C1-6 alkyl group; in some embodiments, R7 is a methyl group.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中R8为氢原子或C1-6烷基；在一些实施方案中，R8为氢原子。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 8 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 8 is a hydrogen atom.

在本公开一些实施方案中，所述的通式(I)至(III)所示的化合物或其可药用的盐，其中Y1为N或CH；在一些实施方案中，Y1为N；在一些实施方案中，Y1为CH。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein Y 1 is N or CH; in some embodiments, Y 1 is N; in some embodiments, Y 1 is CH.

在本公开一些实施方案中，所述的通式(I)至(III)所示的化合物或其可药用的盐，其中Y2为CH2或C(O)；在一些实施方案中，Y2为CH2；在一些实施方案中，Y2为C(O)。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein Y 2 is CH 2 or C(O); in some embodiments, Y 2 is CH 2 ; in some embodiments, Y 2 is C(O).

在本公开一些实施方案中，所述的通式(I)至(III)所示的化合物或其可药用的盐，其中Y3为N或CH；在一些实施方案中，Y3为CH。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein Y 3 is N or CH; in some embodiments, Y 3 is CH.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个Rq相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基、氰基和3至6元环烷基；在一些实施方案中，各个Rq相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，各个Rq相同或不同，且各自独立地为卤素；在一些实施方案中，Rq为F。In some embodiments of the present disclosure, the compounds represented by general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R q is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano and 3 to 6 membered cycloalkyl; in some embodiments, each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, each R q is the same or different and is independently selected from halogen; in some embodiments, R q is F.

在本公开一些实施方案中，所述的通式(I)至(V)所示的化合物或其可药用的盐，其中各个Rq相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基，和/或s为0、1或2；在一些实施方案中，各个Rq相同或不同，且各自独立地为卤素，和/或s为0、1或2。In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl, and/or s is 0, 1 or 2; in some embodiments, each R q is the same or different and is independently halogen, and/or s is 0, 1 or 2.

在本公开一些实施方案中，Ra和Rb相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，Ra和Rb均为氢原子。In some embodiments of the present disclosure, Ra and Rb are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, and a C1-6 haloalkyl group; in some embodiments, Ra and Rb are both hydrogen atoms.

在本公开一些实施方案中，Ri为氢原子或C1-6烷基；在一些实施方案中，Ri为氢原子。In some embodiments of the present disclosure, R i is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R i is a hydrogen atom.

在本公开一些实施方案中，J1选自键、CH2、CH2CH2、CH2O、OCH2和O，和/或J2选自键、CH2、CH2CH2、CH2O、OCH2和O；在一些实施方案中，J1选自键、O、CH2和CH2CH2，和/或J2为O或CH2O；在一些实施方案中，J1为CH2，和/或J2为O或CH2O；在一些实施方案中，J1为CH2，和/或J2为O。In some embodiments of the present disclosure, J 1 is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 O, OCH 2 and O, and/or J 2 is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 O, OCH 2 and O; in some embodiments, J 1 is selected from a bond, O, CH 2 and CH 2 CH 2 , and/or J 2 is O or CH 2 O; in some embodiments, J 1 is CH 2 , and/or J 2 is O or CH 2 O; in some embodiments, J 1 is CH 2 , and/or J 2 is O.

在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中R3为氢原子，R6为氢原子，R4为氢原子，R5为C1-6烷基；Z1为C(O)NR1aNR1R2，R1a为氢原子，R1为氢原子或C1-6烷基，R2选自氢原子、C1-6烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被一个或多个R01所取代，或R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；各个R01相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基、羟基和＝CR15R16，R15和R16相同或不同，且各自独立地为氢原子或卤素；In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a C 1-6 alkyl group; Z 1 is C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 01 ; each R 01 is the same or different and is independently selected from halogen, C 1-6 alkyl group, C 1-6 alkoxy group, hydroxyl group, and =CR 15 R 16 , R R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

E选自： s为0、1、2或3，R7为氢原子或C1-6烷基；R8为氢原子；Y1为N或CH；Y2为CH2或C(O)；各个Rq相同或不同，且各自独立地为卤素；L6-L5-L4-L3为3至12元杂环基-C(O)或3至12元杂环基-C1-6亚烷基，所述3至12元杂环基任选被一个或多个R03所取代；L2选自 Q为O，L为O；u为1或2；a为0、1或2；b为0、1或2；n为0、1或2；各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；L1为NH。E is selected from: s is 0, 1, 2 or 3, R 7 is a hydrogen atom or a C 1-6 alkyl group; R 8 is a hydrogen atom; Y 1 is N or CH; Y 2 is CH 2 or C(O); each R q is the same or different and is independently halogen; L 6 -L 5 -L 4 -L 3 is a 3- to 12-membered heterocyclyl-C(O) or a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, the 3- to 12-membered heterocyclyl group is optionally substituted with one or more R 03 ; L 2 is selected from Q is O, L is O; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is NH.

在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中R3为氢原子，R6为氢原子，R4为氢原子，R5为甲基；Z1为C(O)NR1aNR1R2，R1a为氢原子，R1为C1-6烷基，R2为C1-6烷基，或R1、R2及与其相连的氮原子一起形成 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a methyl group; Z 1 is C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 is a C 1-6 alkyl group, R 2 is a C 1-6 alkyl group, or R 1 , R 2 and the nitrogen atom to which they are connected together form

E选自： s为0、1或2，R7为甲基；R8为氢原子；Y1为N或CH；Y2为CH2或C(O)；各个Rq相同或不同，且各自独立地为F；L6-L5-L4-L3为L2选自 Q为O，L为O；u为1或2；a为1；b为0；n为0；各个R03相同或不同，且各自独立地为卤素；L1为NH。E is selected from: s is 0, 1 or 2, R 7 is a methyl group; R 8 is a hydrogen atom; Y 1 is N or CH; Y 2 is CH 2 or C(O); each R q is the same or different and is independently F; L 6 -L 5 -L 4 -L 3 is L 2 is selected from Q is O, L is O; u is 1 or 2; a is 1; b is 0; n is 0; each R 03 is the same or different and is independently halogen; L 1 is NH.

在本公开一些实施方案中，所述的通式(V)、(V-1)、(V-2)所示的化合物或其可药用的盐，其中R3为氢原子，R6为氢原子，R4为氢原子，R5为C1-6烷基；R1a为氢原子，R1为氢原子或C1-6烷基，R2选自氢原子、C1-6烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被一个或多个R01所取代，或R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；各个R01相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基、羟基和＝CR15R16，R15和R16相同或不同，且各自独立地为氢原子或卤素；In some embodiments of the present disclosure, the compound represented by the general formula (V), (V-1), or (V-2), or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a C 1-6 alkyl group; R 1a is a hydrogen atom, R 1 is a hydrogen atom or a C 1-6 alkyl group, and R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 01 ; each R 01 is the same or different and is independently selected from halogen, C 1-6 alkyl group, C 1-6 alkoxy group, hydroxyl group, and =CR 15 R 16 , and R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

s为0、1、2或3，R7为氢原子或C1-6烷基；各个Rq相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；L6-L5-L4-L3为3至12元杂环基-C(O)或3至12元杂环基-C1-6亚烷基，所述3至12元杂环基任选被一个或多个R03所取代；L2选自 Q为O，L为O；u为1或2；a为0、1或2；b为0、1或2；n为0、1或2；各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；L1为NH。s is 0, 1, 2 or 3, R 7 is a hydrogen atom or a C 1-6 alkyl group; each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 6 -L 5 -L 4 -L 3 is a 3- to 12-membered heterocyclyl-C(O) or a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, and the 3- to 12-membered heterocyclyl group is optionally substituted by one or more R 03 ; L 2 is selected from Q is O, L is O; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is NH.

在本公开一些实施方案中，所述的通式(V)、(V-1)、(V-2)所示的化合物或其可药用的盐，其中R3为氢原子，R6为氢原子，R4为氢原子，R5为C1-6烷基；R1a为氢原子，R1为C1-6烷基，R2为C1-6烷基，或R1、R2及与其相连的氮原子一起形成s为0、1、2或3，R7为甲基；各个Rq相同或不同，且各自独立地为卤素；L6-L5-L4-L3为L2为b为0、1或2；n为0、1或2；各个R03相同或不同，且各自独立地为卤素；L1为NH。In some embodiments of the present disclosure, the compound represented by the general formula (V), (V-1), or (V-2), or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a C 1-6 alkyl group; R 1a is a hydrogen atom, R 1 is a C 1-6 alkyl group, and R 2 is a C 1-6 alkyl group, or R 1 , R 2 , and the nitrogen atom to which they are connected together form s is 0, 1, 2 or 3, R 7 is methyl; each R q is the same or different and is independently halogen; L 6 -L 5 -L 4 -L 3 is L2 is b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different and is independently halogen; L 1 is NH.

在本公开一些实施方案中，所述的通式(IV)、(IV-1)、(IV-2)所示的化合物或其可药用的盐，其中R3为氢原子，R6为氢原子，R4为氢原子，R5为甲基；Z1为C(O)NR1R2；R1为氢原子；R2选自 In some embodiments of the present disclosure, the compound represented by the general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, and R 5 is a methyl group; Z 1 is C(O)NR 1 R 2 ; R 1 is a hydrogen atom; and R 2 is selected from

为为为R7为甲基；各个Rq相同或不同，且各自独立地为卤素，s为0、1或2；选自 for for for R 7 is methyl; each R q is the same or different and is independently halogen, s is 0, 1 or 2; Selected from

表A本公开的典型化合物包括但不限于：



Table A Typical compounds of the present disclosure include, but are not limited to:



本公开另一方面提供一种通式(IA)所示的化合物或其盐，
Another aspect of the present disclosure provides a compound represented by general formula (IA) or a salt thereof,

其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB;

Z1、G1、G2、G3、L1至L6、E、R3、R5和R6如通式(I)中所定义。Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).

本公开另一方面提供一种通式(IIA)所示的化合物或其盐，
Another aspect of the present disclosure provides a compound represented by general formula (IIA) or a salt thereof,

其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB;

Z1、E、L1至L6、R3、R5和R6如通式(II)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).

本公开另一方面提供一种通式(IIIA)所示的化合物或其盐，
Another aspect of the present disclosure provides a compound represented by general formula (IIIA) or a salt thereof,

其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB;

Z1、E、L1至L6、R3、R5和R6如通式(III)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).

本公开另一方面提供一种通式(IVA)、(IV-1A)或(IV-2A)所示的化合物或其盐，
Another aspect of the present disclosure provides a compound represented by general formula (IVA), (IV-1A) or (IV-2A) or a salt thereof,

其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB;

Z1、R3、R5、R6、L1至L6、R7、Rq和s如通式(IV)、(IV-1)或(IV-2)中所定义。Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).

本公开另一方面提供一种通式(V)、(V-1A)或(V-2A)所示的化合物或其盐，

Another aspect of the present disclosure provides a compound represented by general formula (V), (V-1A) or (V-2A) or a salt thereof,

其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB;

R1a、R1、R2、R3、R5、R6、L1至L6、R7、Rq和s如通式(V)、(V-1)或(V-2)中所定义。R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).

表B本公开的典型中间体化合物或其盐包括但不限于：



Table B Typical intermediate compounds or salts thereof disclosed herein include but are not limited to:



本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其盐发生脱保护反应得到通式(I)所示的化合物或其可药用的盐；The compound represented by the general formula (IA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、G1、G2、G3、L1至L6、E、R3、R5和R6如通式(I)中所定义。Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).

本公开另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIA)所示的化合物或其盐发生脱保护反应得到通式(II)所示的化合物或其可药用的盐；The compound represented by general formula (IIA) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、E、L1至L6、R3、R5和R6如通式(II)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).

本公开另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIIA)所示的化合物或其盐发生脱保护反应得到通式(III)所示的化合物或其可药用的盐；The compound represented by general formula (IIIA) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、E、L1至L6、R3、R5和R6如通式(III)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).

本公开另一方面涉及一种制备上述通式(IV)、(IV-1)和(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：
Another aspect of the present disclosure relates to a method for preparing the compounds represented by the above-mentioned general formulas (IV), (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

通式(IVA)所示的化合物或其盐发生脱保护反应得到通式(IV)所示的化合物或其可药用的盐；
The compound represented by general formula (IVA) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

通式(IV-1A)所示的化合物或其盐发生脱保护反应得到通式(IV-1)所示的化合物或其可药用的盐；
The compound represented by the general formula (IV-1A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

通式(IV-2)所示的化合物或其盐发生脱保护反应得到通式(IV-2)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-2) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-2) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、R3、R5、R6、L1至L6、R7、Rq和s如通式(IV)、(IV-1)或(IV-2)中所定义。Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).

本公开另一方面涉及一种制备上述通式(V)、(V-1)和(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
Another aspect of the present disclosure relates to a method for preparing the compounds represented by the above-mentioned general formulas (V), (V-1) and (V-2) or pharmaceutically acceptable salts thereof, the method comprising:

通式(VA)所示的化合物或其盐发生脱保护反应得到通式(V)所示的化合物或其可药用的盐；
The compound represented by the general formula (VA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable salt;

通式(V-1A)所示的化合物或其盐发生脱保护反应得到通式(V-1)所示的化合物或其可药用的盐；
The compound represented by the general formula (V-1A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;

通式(V-2A)所示的化合物或其盐发生脱保护反应得到通式(V-2)所示的化合物或其可药用的盐；The compound represented by the general formula (V-2A) or a salt thereof undergoes a deprotection reaction to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

R1a、R1、R2、R3、R5、R6、L1至L6、R7、Rq和s如通式(V)、(V-1)或(V-2)中所定义。R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).

本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)至(V)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (V) and shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本公开进一步涉及通式(I)至(V)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于抑制和/或降解TYK2的药物中的用途。The present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of drugs for inhibiting and/or degrading TYK2.

本公开进一步涉及通式(I)至(V)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备TYK2抑制剂和/或降解剂的药物中的用途。The present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of TYK2 inhibitors and/or degraders.

本公开进一步涉及通式(I)至(V)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于治疗和/或预防由TYK2介导的或依赖性的疾病或病症的药物中的用途。The present disclosure further relates to the use of compounds represented by formula (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.

本公开进一步涉及通式(I)至(V)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于治疗和/或预防自身免疫性疾病、炎性疾病和癌症的药物中的用途；在一些实施方案中，其为在制备用于治疗和/或预防银屑病、狼疮、炎症性肠病、多发性硬化症、类风湿性关节炎、克罗恩病、斑块状银屑病、银屑病性关节炎、掌跖脓疱病、干燥综合征、溃疡性结肠炎、斑秃、化脓性汗腺炎、免疫紊乱、后葡萄膜炎、全葡萄膜炎、皮肌炎、瘢痕性脱发和哮喘的药物中的用途。The present disclosure further relates to the use of compounds represented by general formulae (I) to (V) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and/or preventing autoimmune diseases, inflammatory diseases, and cancer; in some embodiments, the use of the compounds is in the preparation of medicaments for treating and/or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia, and asthma.

本公开还涉及一种治疗和/或预防由TYK2介导的或依赖性的疾病或病症的方法，其包括给予所需患者上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method for treating and/or preventing diseases or conditions mediated by or dependent on TYK2, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本公开还涉及一种抑制和/或降解TYK2的方法，其包括给予所需患者上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method for inhibiting and/or degrading TYK2, comprising administering to a patient in need thereof a compound of the aforementioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本公开还涉及一种治疗和/或预防自身免疫性疾病、炎性疾病和癌症的方法，其包括给予所需患者上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method for treating and/or preventing autoimmune diseases, inflammatory diseases and cancer, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本公开进一步涉及一种上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作药物。The present disclosure further relates to a compound represented by the above-mentioned general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

本公开进一步涉及一种上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作TYK2抑制剂和/或降解剂。The present disclosure further relates to a compound represented by the aforementioned general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a TYK2 inhibitor and/or degrader.

本公开进一步涉及一种上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作抑制TYK2活性和/或降解TYK2的药物。The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting TYK2 activity and/or degrading TYK2.

本公开进一步涉及一种上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作治疗和/或预防由TYK2介导的或依赖性的疾病或病症的药物。The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and/or preventing diseases or conditions mediated by or dependent on TYK2.

本公开进一步涉及上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于抑制TYK2活性和/或降解TYK2。The present disclosure further relates to the compounds represented by the above general formulae (I) to (V) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TYK2 activity and/or degrading TYK2.

本公开进一步涉及上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防由TYK2介导的或依赖性的疾病或病症。The present disclosure further relates to the compounds of the above-mentioned general formulae (I) to (V) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and/or preventing diseases or conditions mediated by or dependent on TYK2.

本公开进一步涉及一种上述通式(I)至(V)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防自身免疫性疾病、炎性疾病和癌症；在一些实施方案中用于治疗和/或预防银屑病、狼疮、炎症性肠病、多发性硬化症、类风湿性关节炎、克罗恩病、斑块状银屑病、银屑病性关节炎、掌跖脓疱病、干燥综合征、溃疡性结肠炎、斑秃、化脓性汗腺炎、免疫紊乱、后葡萄膜炎、全葡萄膜炎、皮肌炎、瘢痕性脱发和哮喘。The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and/or preventing autoimmune diseases, inflammatory diseases and cancer; in some embodiments, for treating and/or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma.

在本公开一些实施方案中，由TYK2介导的或依赖性的疾病或病症选自自身免疫性疾病、炎性疾病和癌症。In some embodiments of the present disclosure, the disease or condition mediated by or dependent on TYK2 is selected from the group consisting of an autoimmune disease, an inflammatory disease, and cancer.

在本公开一些实施方案中，由TYK2介导的或依赖性的疾病或病症或自身免疫性疾病、炎性疾病和癌症选自银屑病、狼疮、炎症性肠病、多发性硬化症、类风湿性关节炎、克罗恩病、斑块状银屑病、银屑病性关节炎、掌跖脓疱病、干燥综合征、溃疡性结肠炎、斑秃、化脓性汗腺炎、免疫紊乱、后葡萄膜炎、全葡萄膜炎、皮肌炎、瘢痕性脱发和哮喘；在一些实施方案中其选自银屑病(Psoriasis,Ps)、狼疮、炎症性肠病(Inflammatory bowel disease,IBD)、多发性硬化症(Multiple sclerosis,MS)、类风湿性关节炎(Rheumatoid arthritis,RA)、克罗恩病(Crohn's Disease)、斑块状银屑病(Plaque Psoriasis)、掌跖脓疱病(Palmoplantar Pustulosis)、干燥综合征(Syndrome)、系统性红斑狼疮(Systemic Lupus Erythematosus)、银屑病性关节炎(Psoriatic Arthritis)、溃疡性结肠炎(Ulcerative Colitis)、毛发扁平苔藓(Lichen Planopilaris)、斑秃(Alopecia Areata)、化脓性汗腺炎(Hidradenitis Suppurativa)、泛发性脓疱型银屑病(Generalized Pustular Psoriasis)、红皮病型银屑病(Erythrodermic Psoriasis)、免疫紊乱、后葡萄膜炎、全葡萄膜炎、皮肌炎(Dermatomyositis)、炎症性表皮内源性皮肤病(Inflammatory Epidermal Genodermatoses)、盘状和/或亚急性皮肤型红斑狼疮(Active Discoid and/or Subacute Cutaneous Lupus Erythematosus(DLE/SCLE))、狼疮性肾炎、瘢痕性脱发、非节段性白癜风、成人活动性系统性红斑狼疮、特应性皮炎(atopic dermatitis)、后葡萄膜炎非感染性葡萄膜炎(Uveitis Posterior Non-Infectious Uveitis)、中度非感染性全葡萄膜炎(Intermediate Noninfectious Panuveitis)、哮喘、呼吸窘迫综合征、细菌性肺炎、全身性炎症反应综合征、T-细胞急性淋巴细胞白血病、新型冠状病毒肺炎(COVID-19)和神经炎症疾病(Neuroinflammation Disorders)。In some embodiments of the present disclosure, the disease or condition mediated or dependent on TYK2 or an autoimmune disease, inflammatory disease and cancer is selected from psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma; in some embodiments it is selected from psoriasis (Ps), lupus, inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma; Syndrome, Systemic Lupus Erythematosus, Psoriatic Arthritis, Ulcerative Colitis, Lichen Planopilaris, Alopecia Areata, Hidradenitis Suppurativa, Generalized Pustular Psoriasis, Erythrodermic Psoriasis, Immune Disorders, Posterior Uveitis, Panuveitis, Dermatomyositis, Inflammatory Epidermal Genodermatoses, Active Discoid and/or Subacute Cutaneous Lupus Erythematosus Erythematosus (DLE/SCLE), lupus nephritis, scarring alopecia, non-segmental vitiligo, active systemic lupus erythematosus in adults, atopic dermatitis, posterior uveitis (non-infectious uveitis), intermediate non-infectious panuveitis, asthma, respiratory distress syndrome, bacterial pneumonia, systemic inflammatory response syndrome, T-cell acute lymphoblastic leukemia, novel coronavirus pneumonia (COVID-19), and neuroinflammation disorders.

可将活性化合物制成适合于通过任何适当途径给药的形式，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be in the form of a tablet, capsule, cachet, bottled solution, powder, granules, lozenge, suppository, reconstituted powder, or liquid formulation.

作为一般性指导，合适的单位剂量可以是0.1～1000mg。As a general guide, suitable unit doses may be in the range of 0.1 to 1000 mg.

本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation. Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents as described above may be added to provide a palatable formulation. These compositions may be preserved by the addition of antioxidants.

本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion may be injected into the patient's bloodstream by local bolus injection. Alternatively, it is preferred that the solutions and microemulsions be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspensions for intramuscular and subcutaneous administration. The suspension can be prepared using known techniques with suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspending media. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

术语说明Terminology

除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless otherwise stated, the terms used in the specification and claims have the following meanings.

术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-10烷基)，优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkyl" refers to a saturated, linear or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a C1-20 alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., a C1-10 alkyl group), and preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C1-6 alkyl group). 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, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至10个碳原子的亚烷基(即C1- 10亚烷基)，优选具有1至8个碳原子的亚烷基(即C1-8亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C1-10 alkylene), preferably an alkylene group having 1 to 8 carbon atoms (i.e., C1-8 alkylene), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C1-6 alkylene). Non-limiting examples include: -CH2- , -CH(CH3)- , -C( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 ) - , -CH2CH( CH3 ) - , -CH2C ( CH3 ) 2- , -CH2CH2CH2-, -CH2CH2CH2CH2- , etc. Alkylene groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen , alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkenyl). The alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., C2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of a D atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“亚烯基”指二价烯基，其中烯基如上所定义。The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above.

术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkynyl). The alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“亚炔基”指二价炔基，其中炔基如上所定义。The term "alkynylene" refers to a divalent alkynyl group wherein alkynyl is as defined above.

术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

术语“烷硫基”指-S-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲硫基、乙硫基、丙硫基和丁硫基等。烷硫基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, propylthio, and butylthio. Alkylthio can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环系统(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)或3至10个环原子的环烷基(即3至10元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)、4至7个环原子的环烷基(即4至7元环烷基)或5或6个环原子的环烷基(即5或6元环烷基)；最优选具有5或6个环原子的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered cycloalkyl group) or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group); and most preferably a cycloalkyl group having 5 or 6 ring atoms.

所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl is preferably a spiroalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), more preferably a spiroalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered monospirocycloalkyl group. Non-limiting examples include:

其连接点可在任意位置； Its connection point can be at any position;

等。 wait.

术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include:

其连接点可在任意位置；等。 Its connection point can be at any position; wait.

术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环系统，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

其连接点可在任意位置。 Its connection point can be at any position.

环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环系统(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)或3至10个环原子的杂环基(即3至10元杂环基)或7至12个环原子的杂环基(即7至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)、4至7个环原子的杂环基(即4至7元杂环基)或5或6个环原子的杂环基(即5或6元杂环基)；最优选具有5或6个环原子的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group), or a heterocyclic group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclic group), or a heterocyclic group having 7 to 12 ring atoms (i.e., a 7- to 12-membered heterocyclic group); further preferably, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group), or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); and most preferably, a heterocyclic group having 5 or 6 ring atoms.

所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、四氢呋喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、氮杂环丁烷基、吗啉基、硫代吗啉基和高哌嗪基等。Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

“含氮杂环基”指杂环基环内至少含有一个(例如1、2、3或4个)氮原子，杂环基如上所定义。优选为3至10元含氮杂环基，更优选为4至7元含氮杂环基，最优选为5或6元含氮杂环基。"Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms in the ring, wherein the heterocyclic group is as defined above. Preferably, it is a 3- to 10-membered nitrogen-containing heterocyclic group, more preferably a 4- to 7-membered nitrogen-containing heterocyclic group, and most preferably a 5- or 6-membered nitrogen-containing heterocyclic group.

术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan monospiro heterocyclic radical. Non-limiting examples include:

等。 wait.

术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S-, or -S-S-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

等。 wait.

术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

等。 wait.

杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环系统(即多环芳基)，其具有6至20个(例如6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即6至20元芳基)。所述芳基优选具有6至14个环原子的芳基(即6至14元芳基)，更优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括：The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 6 to 20-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 14 ring atoms (i.e., 6 to 14-membered aromatic group), more preferably an aromatic group having 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

等。 wait.

芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环系统(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元杂芳基)。所述杂芳基优选具有5至14个环原子的杂芳基(即5至14元杂芳基)，更优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，最优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -O-O-, -O-S- or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl group), more preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and most preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).

所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

等。 wait.

杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

术语“杂环基氧基”指-O-杂环基，其中杂环基如上所定义。The term "heterocyclyloxy" refers to an -O-heterocyclyl group wherein heterocyclyl is as defined above.

术语“芳基氧基”指-O-芳基，其中芳基如上所定义。The term "aryloxy" refers to an -O-aryl group in which aryl is as defined above.

术语“杂芳基氧基”指-O-杂芳基，其中杂芳基如上所定义。The term "heteroaryloxy" refers to an -O-heteroaryl group, wherein heteroaryl is as defined above.

术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基、烷基如上所定义。The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基、烷基如上所定义。The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基、烷基如上所定义。The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

术语“杂芳基烷基”指烷基被一个或多个杂芳基取代，其中杂芳基、烷基如上所定义。The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

术语“羟烷氧基”指烷氧基被一个或多个羟基取代，其中烷氧基如上所定义。The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

术语“烷氧基烷基”指烷基被一个或多个烷氧基取代，其中烷基和烷氧基如上所定义；优选为-烷基-烷氧基；包括但不限于甲氧基甲基、乙氧基甲基、甲氧基乙基。The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“羟基”指-OH。The term "hydroxy" refers to -OH.

术语“氨基”指-NH2。The term "amino" refers to -NH2 .

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“硝基”指-NO2。The term "nitro" refers to -NO2 .

术语“氧代”或“氧代基”指“＝O”。The term "oxo" or "oxo" refers to "=0".

术语“羰基”指C＝O。The term "carbonyl" refers to C=O.

TBS指叔丁基二甲基硅基。TBS refers to tert-butyldimethylsilyl.

术语“酰胺基”指-CONH2。The term "amido" refers to -CONH2 .

术语“乙酰基”指C(O)CH3。The term "acetyl" refers to C(O) CH3 .

术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基(PMB)等。The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), and the like.

本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

本公开的化合物可包含其所有方式的旋转异构体和构象上受限的状态。还包括阻转异构体，术语“阻转异构体”为由于围绕单键的旋转受阻而产生的立体异构体，其中归因于立体应变或其他促成因素的能量差异形成足够高的旋转壁垒以允许个别构象异构体分离。例如，某些本公开化合物可以以阻转异构体的混合物的形式(如等比例混合物、富集一种阻转异构体的混合物等)或经纯化的一种阻转异构体的形式存在。The compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation about a single bond, where the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation barrier to allow separation of individual conformers. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer.

本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:

如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as, respectively, 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.

相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

当一个位置被特别地指定为氘D时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即至少15％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘(即至少15％的氘掺入)、至少2000倍的丰度的氘(即至少30％的氘掺入)、至少3000倍的丰度的氘(即至少45％的氘掺入)、至少3340倍的丰度的氘(即至少50.1％的氘掺入)、至少3500倍的丰度的氘(即至少52.5％的氘掺入)、至少4000倍的丰度的氘(即至少60％的氘掺入)、至少4500倍的丰度的氘(即至少67.5％的氘掺入)、至少5000倍的丰度的氘(即至少75％的氘掺入)、至少5500倍的丰度的氘(即至少82.5％的氘掺入)、至少6000倍的丰度的氘(即至少90％的氘掺入)、至少6333.3倍的丰度的氘(即至少95％的氘掺入)、至少6466.7倍的丰度的氘(即至少97％的氘掺入)、至少6600倍的丰度的氘(即至少99％的氘掺入)、至少6633.3倍的丰度的氘(即至少99.5％的氘掺入)或更高丰度的氘。When a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 15% deuterium incorporation). Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 50 ...0% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in de deuterium is incorporated at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (i.e., at least 99.5% deuterium incorporation), or more.

“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的C1- 6烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素或氰基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and includes both situations where the event or circumstance occurs and where it does not occur. For example, "C 1-6 alkyl optionally substituted with halogen or cyano" includes both situations where the alkyl is substituted with halogen or cyano and situations where the alkyl is not substituted with halogen or cyano.

“取代”或“取代的”指基团中的一个或多个氢原子，优选1、2或3个，更优选1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。"Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1, 2 or 3, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

本公开化合物的合成方法Synthesis method of the disclosed compound

为了完成本公开的目的，本公开采用如下技术方案：In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

方案一Option 1

本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

通式(IA)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(I)所示的化合物或其可药用的盐；The compound represented by general formula (IA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、G1、G2、G3、L1至L6、E、R3、R5和R6如通式(I)中所定义。Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in the general formula (I).

方案二Option 2

本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

通式(IIA)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(II)所示的化合物或其可药用的盐；The compound represented by general formula (IIA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、E、L1至L6、R3、R5和R6如通式(II)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (II).

方案三Option 3

本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

通式(IIIA)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(III)所示的化合物或其可药用的盐；The compound represented by general formula (IIIA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、E、L1至L6、R3、R5和R6如通式(III)中所定义。Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in the general formula (III).

方案四Option 4

本公开通式(IV-1)、(IV-1)和(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The present invention discloses a method for preparing the compounds represented by general formula (IV-1), (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, comprising the following steps:

通式(IVA)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(IV)所示的化合物或其可药用的盐；
The compound represented by general formula (IVA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

通式(IV-1A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(IV-1)所示的化合物或其可药用的盐；
The compound represented by the general formula (IV-1A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

通式(IV-2A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(IV-2)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-2A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

Z1、R3、R5、R6、L1至L6、R7、Rq和s如通式(IV)、(IV-1)或(IV-2)中所定义。Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (IV), (IV-1) or (IV-2).

方案五Plan 5

本公开通式(V)、(V-1)和(V-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The present invention discloses a method for preparing the compounds represented by general formula (V), (V-1) and (V-2) or pharmaceutically acceptable salts thereof, comprising the following steps:

通式(VA)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(V)所示的化合物或其可药用的盐；
The compound represented by general formula (VA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (V) or its pharmaceutically acceptable salt;

通式(V-1A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(V-1)所示的化合物或其可药用的盐；
The compound represented by the general formula (V-1A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;

通式(V-2A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(V-2)所示的化合物或其可药用的盐；The compound represented by the general formula (V-2A) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;

其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

R1a、R1、R2、R3、R5、R6、L1至L6、R7、Rq和s如通式(V)、(V-1)或(V-2)中所定义。R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in the general formula (V), (V-1) or (V-2).

以上合成方案中提供酸性条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸的1,4-二氧六环溶液、三氟醋酸、甲酸、乙酸、盐酸、浓硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me3SiCl和TMSOTf；优选为三氟醋酸。The reagents providing acidic conditions in the above synthesis scheme include but are not limited to hydrogen chloride, hydrogen chloride in 1,4-dioxane, hydrochloric acid in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf; preferably trifluoroacetic acid.

上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

具体实施方式DETAILED DESCRIPTION

以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

实施例Example

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 <-6 > (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d <6> ), deuterated chloroform (CDCl <3> ), or deuterated methanol (CD <3> OD), with tetramethylsilane (TMS) as the internal standard.

MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).

waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).

本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

微波反应使用CEM Discover-S 908860型微波反应器。Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.

实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.

实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, and C: petroleum ether/ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

实施例1Example 1

5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)-N-(吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺1
5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)-N-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 1

第一步first step

5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸1b5-Chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 1b

将5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯1a(5g，13.3mmol，采用专利申请“WO2020055636A1”中说明书第14页Preparation 3公开的方法制备而得)溶于水(40mL)和四氢呋喃(80mL)，加入一水合氢氧化锂(2.23g，53.1mmol)，30℃反应48小时，反应液减压浓缩，加入水稀释，用乙酸乙酯(50mL×1)萃取，水相用1M盐酸调节pH至5，二氯甲烷萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩即得到粗品标题化合物1b(2.9g)，产品不经纯化直接用于下一步反应。5-Chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester 1a (5 g, 13.3 mmol, prepared by the method disclosed in Preparation 3 on page 14 of the specification of patent application "WO2020055636A1") was dissolved in water (40 mL) and tetrahydrofuran (80 mL), and lithium hydroxide monohydrate (2.23 g, 53.1 mmol) was added. The mixture was reacted at 30°C for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (50 mL×1). The aqueous phase was adjusted to pH 5 with 1 M hydrochloric acid, and extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1b (2.9 g). The product was used directly in the next reaction without purification.

MS m/z(ESI):345[M-1]。MS m/z(ESI):345[M-1].

第二步Step 2

5-氯-7-((4-甲氧基苄基)(甲基)氨基)-N-(吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺1c5-Chloro-7-((4-methoxybenzyl)(methyl)amino)-N-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 1c

将粗品化合物1b(450mg，1.3mmol)，1-氨基吡咯烷盐酸盐(238.6mg，1.9mmol，上海毕得)溶于N,N-二甲基乙酰胺(20mL)，加入N,N-二异丙基乙胺(503mg，3.89mmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(740.1mg，1.94mmol)，搅拌反应1小时，反应液中加入水，用乙酸乙酯萃取(15mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1c(300mg，产率：55.7％)。The crude compound 1b (450 mg, 1.3 mmol) and 1-aminopyrrolidine hydrochloride (238.6 mg, 1.9 mmol, Shanghai Bid) were dissolved in N,N-dimethylacetamide (20 mL), and N,N-diisopropylethylamine (503 mg, 3.89 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) (740.1 mg, 1.94 mmol) were added. The reaction was stirred for 1 hour, and water was added to the reaction solution. The mixture was extracted with ethyl acetate (15 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1c (300 mg, yield: 55.7%).

MS m/z(ESI):415.2[M+1]。MS m/z(ESI):415.2[M+1].

第三步Step 3

3-((7-((4-甲氧基苄基)(甲基)氨基)-3-(吡咯烷-1-基氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-2-氧代-2H-[1,2'-联吡啶]-5'-羧酸甲酯1e3-((7-((4-methoxybenzyl)(methyl)amino)-3-(pyrrolidin-1-ylaminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylic acid methyl ester 1e

将化合物1c(213mg，513μmol)，3-氨基-2-氧代-2H-[1,2'-联吡啶]-5'-羧酸甲酯1d(140mg，570.8μmol，采用专利申请“WO2023076161”中说明书第507页Example1.8公开的方法制备而得)溶于1,4-二氧六环(5mL)，加入醋酸钯(25.6mg，114.1μmol)，2,2’-双(二苯基膦)-1,1’-联萘(71.1mg，106.7μmol)，碳酸铯(558mg，1.7mmol)，110℃搅拌反应1小时，反应液冷却至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1e(200mg，产率：56.1％)。Compound 1c (213 mg, 513 μmol) and methyl 3-amino-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylate 1d (140 mg, 570.8 μmol, prepared by the method disclosed in Example 1.8 on page 507 of the specification of patent application "WO2023076161") were dissolved in 1,4-dioxane (5 mL), and palladium acetate (25.6 mg, 114.1 μmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (71.1 mg, 106.7 μmol), and cesium carbonate (558 mg, 1.7 mmol) were added. The mixture was stirred at 110°C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1e (200 mg, yield: 56.1%).

MS m/z(ESI):624.2[M+1]。MS m/z(ESI):624.2[M+1].

第四步Step 4

3-((7-((4-甲氧基苄基)(甲基)氨基)-3-(吡咯烷-1-基氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-2-氧代-2H-[1,2'-联吡啶]-5'-羧酸1f3-((7-((4-methoxybenzyl)(methyl)amino)-3-(pyrrolidin-1-ylaminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylic acid 1f

将化合物1e(240mg，384.8μmol)溶于水(2mL)和四氢呋喃(10mL)，加入一水合氢氧化锂(80.7mg，1.9mmol)，搅拌反应16小时，反应液减压浓缩，加入水稀释，用1M盐酸调节pH至5，析出固体，过滤，滤饼干燥后即得到粗品标题化合物1f(200mg)，产品不经纯化直接用于下一步反应。Compound 1e (240 mg, 384.8 μmol) was dissolved in water (2 mL) and tetrahydrofuran (10 mL), and lithium hydroxide monohydrate (80.7 mg, 1.9 mmol) was added. The mixture was stirred and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 5 with 1 M hydrochloric acid. The precipitated solid was filtered and the filter cake was dried to obtain the crude title compound 1f (200 mg). The product was used directly in the next reaction without purification.

MS m/z(ESI):608.1[M-1]。MS m/z(ESI):608.1[M-1].

第五步Step 5

5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-((4-甲氧基苄基)(甲基)氨基)-N-(吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺1h5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridinyl]-3-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 1h

将粗品化合物1f(52mg，82.3μmol)，3-(3-甲基-2-氧代-4-(2,7-二氮杂螺[3.5]壬-7-基)-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮-2,2,2三氟乙酸盐1g(55.1mg，110.8μmol，采用专利申请“WO2023076161”中说明书第546页Example 1.31公开的方法制备而得)溶于N,N-二甲基乙酰胺(2mL)，加入N,N-二异丙基乙胺(55.1mg，426.5μmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(48.6mg，127.9μmol)，搅拌反应2小时，反应液中加入水，用二氯甲烷萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩即得到粗品标题化合物1h(一对对映异构体混合物，83mg)，产品不经纯化直接用于下一步反应。MS m/z(ESI):975.5[M+1]。The crude compound 1f (52 mg, 82.3 μmol) and 1 g of 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione-2,2,2-trifluoroacetate (55.1 mg, 110.8 μmol, prepared by the method disclosed in Example 1.31 on page 546 of the specification of patent application "WO2023076161") were dissolved in N,N-dimethylacetamide (2 mL) and added. N,N-Diisopropylethylamine (55.1 mg, 426.5 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (48.6 mg, 127.9 μmol) were added and stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1h (a mixture of a pair of enantiomers, 83 mg). The product was used directly in the next reaction without purification. MS m/z (ESI): 975.5 [M+1].

第六步Step 6

5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)-N-(吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺15-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)-N-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 1

将粗品化合物1h(83mg，85.1μmol)溶于二氯甲烷(2mL)，加入三氟醋酸(2mL)，110℃反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物1(一对对映异构体混合物，10mg，产率：13.7％)。The crude compound 1h (83 mg, 85.1 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at 110°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to give the title compound 1 (a mixture of a pair of enantiomers, 10 mg, yield: 13.7%).

MS m/z(ESI):855.6[M+1]。MS m/z(ESI):855.6[M+1].

1H NMR(500MHz,CDCl3):δ8.92(s,1H),8.47(dd,1H),8.46(s,1H),8.42(s,1H),8.25-8.20(m,1H),8.14(dd,1H),8.10(s,1H),8.05(s,1H),7.69(dd,1H),7.03(d,1H),6.87(d,1H),6.62(s,1H),6.43(t,1H),6.30(d,1H),5.49(s,1H),5.26-5.21(m,1H),4.23(s,1H),4.16(s,1H),4.12(s,1H),4.05(s,1H),3.79(s,3H),3.18(d,2H),3.12(d,3H),3.07(d,2H),2.97(d,1H),2.89-2.83(m,1H),2.81-2.72(m,2H),2.28-2.21(m,2H),2.07(d,4H),2.00(p,4H)。 1 H NMR (500MHz, CDCl 3 ): δ8.92(s,1H),8.47(dd,1H),8.46(s,1H),8.42(s,1H),8.25-8.20(m,1H),8.14(dd,1H),8.10(s,1H),8.0 5(s,1H),7.69(dd,1H),7.03(d,1H),6.87(d,1H),6.62(s,1H),6.43(t,1H),6.30(d,1H),5.49(s,1H),5.26 -5.21(m,1H),4.23(s,1H),4.16(s,1H),4.12(s,1H),4.05(s,1H),3.79(s,3H),3.18(d,2H),3.12(d,3H),3 .07(d,2H),2.97(d,1H),2.89-2.83(m,1H),2.81-2.72(m,2H),2.28-2.21(m,2H),2.07(d,4H),2.00(p,4H).

实施例2Example 2

N-(3-(二氟亚甲基)吡咯烷-1-基)-5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺2
N-(3-(difluoromethylene)pyrrolidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2

第一步first step

3-(二氟亚甲基)吡咯烷-1-甲酸叔丁酯2btert-Butyl 3-(difluoromethylene)pyrrolidine-1-carboxylate 2b

将3-氧代吡咯烷-1-甲酸叔丁酯2a(3.94g，21.3mmol，上海毕得)溶于N,N-二甲基甲酰胺(5mL)，加入2,2-二氟-2-(三苯基膦酰基)乙酸乙酯(18.94g，53.2mmol，上海乐研)，80℃搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物2b(500mg，产率：10.7％)。Tert-butyl 3-oxopyrrolidine-1-carboxylate 2a (3.94 g, 21.3 mmol, Shanghai Bidex) was dissolved in N,N-dimethylformamide (5 mL), and ethyl 2,2-difluoro-2-(triphenylphosphonyl)acetate (18.94 g, 53.2 mmol, Shanghai Leyan) was added. The reaction was stirred at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2b (500 mg, yield: 10.7%).

MS m/z(ESI):163.9[M-55]。MS m/z(ESI):163.9[M-55].

第二步Step 2

3-(二氟亚甲基)吡咯烷盐酸盐2c3-(Difluoromethylene)pyrrolidine hydrochloride 2c

将化合物2b(500mg，2.28mmol)溶于4M氯化氢的1,4-二氧六环溶液(20mL)，搅拌反应5小时，反应液减压浓缩即得粗品标题化合物2c(350mg)，产物不经纯化，直接用于下步反应。Compound 2b (500 mg, 2.28 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (20 mL) and stirred for 5 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 2c (350 mg), which was used directly in the next step without purification.

第三步Step 3

3-(二氟亚甲基)-1-亚硝基吡咯烷2d3-(Difluoromethylene)-1-nitrosopyrrolidine 2d

将粗品化合物2c(350mg，2.9mmol)溶于四氢呋喃(5mL)中，加入亚硝酸叔丁酯(787.8mg，7.6mmol)，搅拌反应5小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物2d(430mg，产率：98％)。The crude compound 2c (350 mg, 2.9 mmol) was dissolved in tetrahydrofuran (5 mL), and tert-butyl nitrite (787.8 mg, 7.6 mmol) was added. The reaction was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 2d (430 mg, yield: 98%).

MS m/z(ESI):149.1[M+1]。MS m/z(ESI):149.1[M+1].

第四步Step 4

3-(二氟亚甲基)吡咯烷-1-胺2e3-(Difluoromethylene)pyrrolidin-1-amine 2e

将粗品化合物2d(255mg，1.72mmol)溶于甲醇(1mL)和乙酸(0.3mL)，冰浴下加入锌粉(1.1g，17mmol)，恢复室温搅拌反应16小时，反应液中加入甲醇稀释，过滤，滤液减压浓缩即得到粗品标题化合物2e(200mg)，产品不经纯化直接用于下一步反应。The crude compound 2d (255 mg, 1.72 mmol) was dissolved in methanol (1 mL) and acetic acid (0.3 mL). Zinc powder (1.1 g, 17 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 16 hours. Methanol was added to dilute the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 2e (200 mg). The product was used directly in the next reaction without purification.

MS m/z(ESI)：135.0[M+1]。MS m/z(ESI):135.0[M+1].

第五步Step 5

N-(3-(二氟亚甲基)吡咯烷-1-基)-5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺2N-(3-(difluoromethylene)pyrrolidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2

采用实施例1的合成路线，将第二步原料1-氨基吡咯烷盐酸盐替换为化合物2e得到标题化合物2(8mg，产率：25.1％)(一对对映异构体混合物)。The synthetic route of Example 1 was used, and the second step raw material 1-aminopyrrolidine hydrochloride was replaced by compound 2e to obtain the title compound 2 (8 mg, yield: 25.1%) (a mixture of a pair of enantiomers).

MS m/z(ESI):903.2[M+1]。MS m/z(ESI):903.2[M+1].

1H NMR(500MHz,DMSO-d6):δ11.09(br,1H),9.07(s,1H),8.91(s,1H),8.69(s,1H),8.41(d,1H),8.31-8.29(m,1H),8.24(s,1H),8.00(d,1H),7.97-7.94(m,1H),7.66(d,1H),6.97-6.94(m,2H),6.89-6.85(m,2H),6.43(t,1H),6.23(s,1H),5.37-5.32(m,2H),4.29-4.27(m,1H),4.19-4.16(m,1H),3.89-3.86(m,4H),3.64(s,4H),3.13-3.10(m,2H),3.05-3.03(m,1H),2.95-2.92(m,3H),2.03-1.91(m,4H),1.48-1.45(m,1H),1.24-1.18(m,4H),0.08-0.07(m,1H)。 1 H NMR (500MHz, DMSO-d 6 ): δ11.09(br,1H),9.07(s,1H),8.91(s,1H),8.69(s,1H),8.41(d,1H),8.31-8.29(m,1H),8.24(s,1H),8.00 (d,1H),7.97-7.94(m,1H),7.66(d,1H),6.97-6.94(m,2H),6.89-6.85(m,2H),6.43(t,1H),6.23(s,1H),5.37 -5.32(m,2H),4.29-4.27(m,1H),4.19-4.16(m,1H),3.89-3.86(m,4H),3.64(s,4H),3.13-3.10(m,2H),3.05 -3.03(m,1H),2.95-2.92(m,3H),2.03-1.91(m,4H),1.48-1.45(m,1H),1.24-1.18(m,4H),0.08-0.07(m,1H).

实施例3Example 3

5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-1H-[1,2'-联吡啶]-3-基)氨基)-N',N'-二乙基-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰肼3
5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-1H-[1,2'-bipyridyl]-3-yl)amino)-N',N'-diethyl-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid hydrazide 3

采用实施例1的合成路线，将第二步原料1-氨基吡咯烷盐酸盐替换为1,1-二乙基肼2,2,2-三氟乙酸盐(采用文献“Chemical Communications,2021,vol.57,#91,p.12187-12190”公开的S9a的方法制备而得)得到标题化合物3(30mg，产率：68.2％)(一对对映异构体混合物)。Using the synthetic route of Example 1, the second-step raw material 1-aminopyrrolidine hydrochloride was replaced with 1,1-diethylhydrazine 2,2,2-trifluoroacetate (prepared using the S9a method disclosed in the document "Chemical Communications, 2021, vol. 57, #91, p. 12187-12190") to obtain the title compound 3 (30 mg, yield: 68.2%) (a mixture of a pair of enantiomers).

MS m/z(ESI):857.4[M+1]。MS m/z(ESI):857.4[M+1].

1H NMR(500MHz,CDCl3):δ8.92(s,1H),8.48(s,1H),8.41(dt,1H),8.23(d,1H),8.16-8.11(m,1H),8.08(d,2H),7.68(dd,1H),7.03(s,1H),6.96-6.94(m,1H),6.62(s,1H),6.46(t,1H),6.31(d,1H),5.50(d,1H),5.39-5.35(m,1H),5.22(dd,1H),4.23(s,1H),4.16(s,1H),4.12(s,1H),4.05(s,1H),3.79(s,3H),3.18(d,2H),3.12(d,3H),2.93(q,4H),2.83-2.73(m,3H),2.27-2.22(m,2H),2.03(s,4H),1.67(d,1H),1.24(t,6H)。 1 H NMR (500MHz, CDCl 3 ): δ8.92(s,1H),8.48(s,1H),8.41(dt,1H),8.23(d,1H),8.16-8.11(m,1H),8.08(d,2H),7.68(dd,1 H),7.03(s,1H),6.96-6.94(m,1H),6.62(s,1H),6.46(t,1H),6.31(d,1H),5.50(d,1H),5.39-5.35(m ,1H),5.22(dd,1H),4.23(s,1H),4.16(s,1H),4.12(s,1H),4.05(s,1H),3.79(s,3H),3.18(d,2H),3. 12(d,3H),2.93(q,4H),2.83-2.73(m,3H),2.27-2.22(m,2H),2.03(s,4H),1.67(d,1H),1.24(t,6H).

实施例4Example 4

N-(3,3-二氟氮杂环丁烷-1-基)-5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺4
N-(3,3-difluoroazetidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 4

第一步first step

3,3-二氟-1-亚硝基氮杂环丁烷4b3,3-Difluoro-1-nitrosoazetidine 4b

将化合物3,3-二氟氮杂环丁烷盐酸盐4a(30g，231.6mmol)溶于四氢呋喃(600mL)，0℃下加入亚硝酸叔丁酯(67.5g，654.6mmol)，搅拌反应4小时，反应液减压浓缩即得到粗品标题化合物4b(28.1g)，产品不经纯化直接用于下一步反应。MS m/z(ESI)：122.9[M+1]。Compound 3,3-difluoroazetidine hydrochloride 4a (30 g, 231.6 mmol) was dissolved in tetrahydrofuran (600 mL). Tert-butyl nitrite (67.5 g, 654.6 mmol) was added at 0°C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 4b (28.1 g). The product was used directly in the next step without purification. MS m/z (ESI): 122.9 [M+1].

第二步Step 2

3,3-二氟氮杂环丁烷-1-胺盐酸盐4c3,3-Difluoroazetidine-1-amine hydrochloride 4c

将粗品化合物4b(37g，303.1mmol)溶于甲醇(600mL)和乙酸(75mL)，冰浴下分批加入锌粉(1.4g，21.4mmol)，恢复室温搅拌反应0.5小时，反应液过滤，滤液减压浓缩，残余物中加入甲醇(500mL)溶解后过滤，滤液减压浓缩，加入1.25M氢氧化钠水溶液1.5L和650mL 1,4-二氧六环，搅拌溶解后降温到0℃加入二碳酸二叔丁酯(21mL)，搅拌反应30分钟，加入二氯甲烷(500mL)并分液，水相用二氯甲烷萃取(300mL×2)后用1M盐酸调节至pH～1，所得水溶液减压浓缩，残余物加入甲醇(450mL)溶解后过滤，滤液减压浓缩，残余物用约500mL的四氢呋喃和二氯甲烷(V:V＝1:1)打浆，过滤，滤饼干燥后即得到粗品标题化合物4c(16g)，产品不经纯化直接用于下一步反应。The crude compound 4b (37 g, 303.1 mmol) was dissolved in methanol (600 mL) and acetic acid (75 mL). Zinc powder (1.4 g, 21.4 mmol) was added in batches under ice bath. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. Methanol (500 mL) was added to the residue to dissolve it and then filtered. The filtrate was concentrated under reduced pressure. 1.5 L of 1.25 M sodium hydroxide aqueous solution and 650 mL of 1,4-dioxane were added. After stirring and dissolving, the mixture was cooled to 0 °C and di-tert-butyl dicarbonate was added. Ester (21 mL) was stirred for 30 minutes, dichloromethane (500 mL) was added and the layers were separated. The aqueous phase was extracted with dichloromethane (300 mL × 2) and then adjusted to pH ~ 1 with 1 M hydrochloric acid. The resulting aqueous solution was concentrated under reduced pressure, and the residue was dissolved in methanol (450 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with about 500 mL of tetrahydrofuran and dichloromethane (V:V = 1:1), filtered, and the filter cake was dried to obtain the crude title compound 4c (16 g). The product was used directly in the next reaction without purification.

MS m/z(ESI)：109.0[M+1]。MS m/z(ESI):109.0[M+1].

第三步Step 3

N-(3,3-二氟氮杂环丁烷-1-基)-5-((5'-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺4N-(3,3-difluoroazetidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 4

采用实施例1的合成路线，将第二步原料1-氨基吡咯烷盐酸盐替换为化合物4c得到标题化合物4(一对对映异构体混合物，4mg，产率：6.5％)。The synthetic route of Example 1 was adopted, and the second step raw material 1-aminopyrrolidine hydrochloride was replaced with compound 4c to obtain the title compound 4 (a mixture of a pair of enantiomers, 4 mg, yield: 6.5%).

MS m/z(ESI):877.4[M+1]。MS m/z(ESI):877.4[M+1].

1H NMR(500MHz,CDCl3):δ8.90(s,2H),8.37(s,1H),8.32(d,1H),8.21(d,1H),8.13-8.10(m,3H),7.69(d,1H),7.05-6.84(m,2H),6.60-6.54(m,2H),6.30(d,1H),5.50(s,1H),5.36-5.33(m,1H),5.20(dd,1H),4.44(t,4H),4.21-4.02(m,4H),3.76(s,3H),3.16-3.14(m,2H),3.10(d,3H),2.96-2.93(m,1H),2.86-2.72(m,3H),2.22(t,2H),2.03-2.00(m,3H)。 1 H NMR (500MHz, CDCl 3 ): δ8.90(s,2H),8.37(s,1H),8.32(d,1H),8.21(d,1H),8.13-8.10(m,3H),7.69(d, 1H),7.05-6.84(m,2H),6.60-6.54(m,2H),6.30(d,1H),5.50(s,1H),5.36-5.33(m, 1H),5.20(dd,1H),4.44(t,4H),4.21-4.02(m,4H),3.76(s,3H),3.16-3.14(m,2H), 3.10(d,3H),2.96-2.93(m,1H),2.86-2.72(m,3H),2.22(t,2H),2.03-2.00(m,3H).

实施例5Example 5

5-((2-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-7-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺5

5-((2-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 5

第一步first step

(1S,2S)-2-(二苄基氨基)环丁烷-1-醇5b-1(1S,2S)-2-(Dibenzylamino)cyclobutane-1-ol 5b-1

(1R,2R)-2-(二苄基氨基)环丁烷-1-醇5b-2(1R,2R)-2-(Dibenzylamino)cyclobutane-1-ol 5b-2

化合物rac-(1R,2R)-2-(二茉氨基)环丁烷-1-醇5a(440g，1645mmol，采用专利申请“WO20200231594A1”中说明书第108页Example-18公开的方法制备而得)经手性柱拆分(Waters SFC 150，色谱柱：40*250mm,10μm；流动相A：超临界二氧化碳，流动相B：乙醇(含0.1％7.0mol/L氨甲醇溶液)，梯度配比：A:B＝85:15，流速：145mL/min)得到标题化合物5b-1(238.2g，产率：54.1％)和5b-2(239.3g，产率：54.3％)。Compound rac-(1R,2R)-2-(diamino)cyclobutane-1-ol 5a (440 g, 1645 mmol, prepared by the method disclosed in Example-18 on page 108 of the specification of patent application "WO20200231594A1") was separated by chiral column (Waters SFC 150, chromatographic column: 40*250mm,10μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% 7.0mol/L ammonia methanol solution), gradient ratio: A:B=85:15, flow rate: 145mL/min) to obtain the title compounds 5b-1 (238.2g, yield: 54.1%) and 5b-2 (239.3g, yield: 54.3%).

单一构型化合物(较短保留时间)：5b-1(238.2g)。Single configuration compound (shorter retention time): 5b-1 (238.2 g).

MS m/z(ESI):268.2[M+1]。MS m/z(ESI):268.2[M+1].

手性HPLC分析：保留时间1.698分钟，纯度：99％(色谱柱:100*3mm,3μm；流动相A：超临界二氧化碳，流动相B：乙醇(含0.1％二乙胺)，梯度配比：A:B＝85:15，流速：1.5mL/min)。Chiral HPLC analysis: retention time 1.698 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5mL/min).

单一构型化合物(较长保留时间)：5b-2(239.3g)。Single configuration compound (longer retention time): 5b-2 (239.3 g).

MS m/z(ESI):268.2[M+1]。MS m/z(ESI):268.2[M+1].

手性HPLC分析：保留时间2.452分钟，纯度：99％(色谱柱:100*3mm,3μm；流动相A：超临界二氧化碳，流动相B：乙醇(含0.1％二乙胺)，梯度配比：A:B＝85:15，流速：1.5mL/min)。Chiral HPLC analysis: retention time 2.452 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5mL/min).

第二步Step 2

(1R,2R)-N,N-二苄基-2-甲氧基环丁烷-1-胺5c(1R,2R)-N,N-Dibenzyl-2-methoxycyclobutane-1-amine 5c

将化合物5b-2(205g，766.7mmol)溶于四氢呋喃(2500mL)中，0℃下加入叔丁醇钾(112.8g，1mol)，加毕搅拌反应30分钟，加入碘甲烷(131g，922.9mmol)，搅拌反应4小时，反应液倒入冰水，用乙酸乙酯萃取(500mL×3)，合并有机相，用水，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5c(192.4g，产率：89.1％)。Compound 5b-2 (205 g, 766.7 mmol) was dissolved in tetrahydrofuran (2500 mL), and potassium tert-butoxide (112.8 g, 1 mol) was added at 0°C. The mixture was stirred and reacted for 30 minutes. Iodomethane (131 g, 922.9 mmol) was added and stirred and reacted for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (500 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 5c (192.4 g, yield: 89.1%).

MS m/z(ESI):282.2[M+1]。MS m/z(ESI):282.2[M+1].

第三步Step 3

(1R,2R)-2-甲氧基环丁烷-1-胺盐酸盐5d(1R,2R)-2-Methoxycyclobutane-1-amine hydrochloride 5d

将化合物5c(192g，682.3mmol)溶于甲醇(2000mL)，加入10％钯碳加氢催化剂(湿)(76.8g)，氢气置换，搅拌反应16小时，反应液过滤，冰浴下滤液中加入4M氯化氢的1,4-二氧六环溶液(260mL)，搅拌反应30小时，反应液减压浓缩即得粗品标题化合物5d(98g)，产物不经纯化，直接用于下步反应。Compound 5c (192 g, 682.3 mmol) was dissolved in methanol (2000 mL), and 10% palladium-carbon hydrogenation catalyst (wet) (76.8 g) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The reaction solution was filtered, and a 4 M hydrogen chloride solution in 1,4-dioxane (260 mL) was added to the filtrate under ice bath. The mixture was stirred for 30 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5d (98 g). The product was used directly in the next step without purification.

第四步Step 4

3-溴-6-(羟甲基)吡啶-2(1H)-酮5f3-Bromo-6-(hydroxymethyl)pyridin-2(1H)-one 5f

将5-溴-6-氧代-1,6-二氢吡啶-2-羧酸甲酯5e(5g，20.32mmol，上海毕得)溶于四氢呋喃(50mL)，冰浴下加入2M硼氢化锂的四氢呋喃溶液(12mL)，自然恢复室温搅拌反应16小时，反应液用饱和氯化铵溶液淬灭，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5f(3.6g，产率：86.8％)。Methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate 5e (5 g, 20.32 mmol, Shanghai Bidex) was dissolved in tetrahydrofuran (50 mL). A 2M solution of lithium borohydride in tetrahydrofuran (12 mL) was added under ice-cooling. The mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 5f (3.6 g, yield: 86.8%).

MS m/z(ESI):203.9[M+1]。MS m/z(ESI):203.9[M+1].

第五步Step 5

3-溴-6-(氯甲基)吡啶-2(1H)-酮5g3-Bromo-6-(chloromethyl)pyridin-2(1H)-one 5g

将化合物5f(2.5g，12.25mmol)溶于二氯甲烷(40mL)，冰浴下加入氯化亚砜(5.83g，49mmol)和几滴N,N-二甲基甲酰胺，恢复室温搅拌反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物5g(2.7g，产率：99％)。Compound 5f (2.5 g, 12.25 mmol) was dissolved in dichloromethane (40 mL). Thionyl chloride (5.83 g, 49 mmol) and a few drops of N,N-dimethylformamide were added under ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent C to give the title compound 5g (2.7 g, yield: 99%).

MS m/z(ESI):221.9[M+1]。MS m/z(ESI):221.9[M+1].

第六步Step 6

3-溴-6-(((2-羟乙基)氨基)甲基)吡啶-2(1H)-酮5h3-Bromo-6-(((2-hydroxyethyl)amino)methyl)pyridin-2(1H)-one 5h

将化合物5g(200mg，899.01μmol)溶于N,N-二甲基乙酰胺(20mL)，加入乙醇胺(164.74mg，2.7mmol)，搅拌反应16小时，反应液减压浓缩即得到粗品标题化合物5h(222mg)，产品不经纯化直接用于下一步反应。Compound 5g (200 mg, 899.01 μmol) was dissolved in N,N-dimethylacetamide (20 mL), and ethanolamine (164.74 mg, 2.7 mmol) was added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 5h (222 mg). The product was used directly in the next reaction without purification.

MS m/z(ESI):247.1[M+1]。MS m/z(ESI):247.1[M+1].

第七步Step 7

((5-溴-6-氧代-1,6-二氢吡啶-2-基)甲基)(2-羟乙基)氨基甲酸叔丁酯5itert-Butyl ((5-bromo-6-oxo-1,6-dihydropyridin-2-yl)methyl)(2-hydroxyethyl)carbamate 5i

将粗品化合物5h(222mg，898.46μmol)溶于二氯甲烷(20mL)，加入三乙胺(272.2mg，2.7mmol)，二碳酸二叔丁酯(588.2mg，2.7mmol)，搅拌反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5i(300mg，产率：96.1％)。The crude compound 5h (222 mg, 898.46 μmol) was dissolved in dichloromethane (20 mL), and triethylamine (272.2 mg, 2.7 mmol) and di-tert-butyl dicarbonate (588.2 mg, 2.7 mmol) were added. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 5i (300 mg, yield: 96.1%).

MS m/z(ESI):347.2[M+1]。MS m/z(ESI):347.2[M+1].

第八步Step 8

7-溴-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸叔丁酯5jtert-Butyl 7-bromo-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate 5j

将化合物5i(300mg，864μmol)溶于四氢呋喃(10mL)，加入三苯基膦(226.6mg，864.04μmol)，偶氮二甲酸二异丙酯(174.7mg，864.04μmol)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5j(80mg，产率：28％)。Compound 5i (300 mg, 864 μmol) was dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (226.6 mg, 864.04 μmol) and diisopropyl azodicarboxylate (174.7 mg, 864.04 μmol) were added. The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 5j (80 mg, yield: 28%).

MS m/z(ESI):329.2[M+1]。MS m/z(ESI):329.2[M+1].

第九步Step 9

5-氨基-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯5k5-amino-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester 5k

将化合物1a(0.5g，1.39mmol)溶于7M氨甲醇溶液(10mL)，封管120℃搅拌反应16小时，反应液降至室温后减压浓缩，残余物中加入甲醇，过滤，滤饼用乙酸乙酯洗涤，干燥后即得粗品标题化合物5k(100mg)，产物不经纯化，直接用于下步反应。Compound 1a (0.5 g, 1.39 mmol) was dissolved in 7 M ammonia methanol solution (10 mL), sealed and stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Methanol was added to the residue, filtered, and the filter cake was washed with ethyl acetate and dried to give the crude title compound 5k (100 mg). The product was used directly in the next step without purification.

MS m/z(ESI):356.2[M+1]。MS m/z(ESI):356.2[M+1].

第十步Step 10

7-((3-(乙氧羰基)-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-5-基)氨基)-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸叔丁酯5ltert-Butyl 7-((3-(ethoxycarbonyl)-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate

将化合物5k(72.8mg，205μmol)溶于1,4-二氧六环(5mL)，加入化合物5j(67.5mg，205μmol)，三(二亚苄基丙酮)二钯(37.5mg，41μmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(23.7mg，41μmol)，碳酸铯(133.6mg，410μmol)，氮气置换，100℃反应4小时。反应液降减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5l(90mg，产率：72.7％)。Compound 5k (72.8 mg, 205 μmol) was dissolved in 1,4-dioxane (5 mL), and compound 5j (67.5 mg, 205 μmol), tris(dibenzylideneacetone)dipalladium (37.5 mg, 41 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.7 mg, 41 μmol), and cesium carbonate (133.6 mg, 410 μmol) were added. The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 5l (90 mg, 72.7% yield).

MS m/z(ESI):604.5[M+1]。MS m/z(ESI):604.5[M+1].

第十一步Step 11

5-((2-(叔丁氧基羰基)-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-7-基)氨基)-7-((4-5-((2-(tert-Butoxycarbonyl)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)-7-((4-

甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸5mMethoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5m

将化合物5l(90mg，149μmol)溶于甲醇(2mL)，水(2mL)和四氢呋喃(2mL)，加入一水合氢氧化锂(62.6mg，1.5mmol)，60℃反应4小时，反应液降至室温后加入水稀释，用1M盐酸调节pH至3-4，用乙酸乙酯萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，即得到标题化合物5m(80mg)，产品不经纯化直接用于下一步反应。Compound 5l (90 mg, 149 μmol) was dissolved in methanol (2 mL), water (2 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (62.6 mg, 1.5 mmol) was added. The reaction was carried out at 60°C for 4 hours. After the reaction solution was cooled to room temperature, it was diluted with water and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5m (80 mg). The product was used directly in the next reaction without purification.

MS m/z(ESI):576.5[M+1]。MS m/z(ESI):576.5[M+1].

第十二步Step 12

7-((7-((4-甲氧基苄基)(甲基)氨基)-3-(((1R,2R)-2-甲氧基环丁基)氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸叔丁酯5ntert-Butyl 7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate

将化合物5m(80mg，139μmol)，化合物5d(42mg，305μmol)溶于N,N-二甲基甲酰胺(3mL)，加入N,N-二异丙基乙胺(53.8mg，416.9μmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(68.6mg，180.6μmol)，搅拌反应14小时，反应液中加入水，用乙酸乙酯萃取(10mL×3)，合并有机相，用水，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5n(35mg，产率：38.2％)。Compound 5m (80 mg, 139 μmol) and compound 5d (42 mg, 305 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (53.8 mg, 416.9 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) (68.6 mg, 180.6 μmol) were added. The reaction mixture was stirred for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 5n (35 mg, yield: 38.2%).

MS m/z(ESI):659.6[M+1]。MS m/z(ESI):659.6[M+1].

第十三步Step 13

N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)-5-((6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-7-基)氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺盐酸盐5oN-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride 5o

将化合物5n(20mg，30.3μmol)溶于二氯甲烷(5mL)，加入4M氯化氢的1,4-二氧六环溶液(1mL)，搅拌反应2小时，反应液减压浓缩即得粗品标题化合物5o(13mg)，产物不经纯化，直接用于下步反应。Compound 5n (20 mg, 30.3 μmol) was dissolved in dichloromethane (5 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5o (13 mg). The product was used directly in the next step without purification.

MS m/z(ESI):439.2[M+1]。MS m/z(ESI):439.2[M+1].

第十四步Step 14

5-((2-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-6-氧代-1,3,4,6-四氢-2H-吡啶并[1,2-a]吡嗪-7-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺55-((2-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 5

将化合物5o(13mg，27.4μmol)，化合物1g(13.6mg，27.4μmol)，N,N-二异丙基乙胺(19.2mg，148.3μmol)溶于二氯甲烷(1mL)，冰浴下加入三光气(2.8mg，9.6μmol)的二氯甲烷溶液(0.5mL)，搅拌反应14小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈32％-45％，流速：30mL/min)得到标题化合物5(一对非对映异构体混合物，4mg，产率：16％)。Compound 5o (13 mg, 27.4 μmol), compound 1g (13.6 mg, 27.4 μmol), and N,N-diisopropylethylamine (19.2 mg, 148.3 μmol) were dissolved in dichloromethane (1 mL). A dichloromethane solution (0.5 mL) of triphosgene (2.8 mg, 9.6 μmol) was added under ice bath and stirred for 14 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL/min) to give the title compound 5 (a pair of diastereoisomer mixture, 4 mg, yield: 16%).

MS m/z(ESI):848.5[M+1]。MS m/z(ESI):848.5[M+1].

1H NMR(500MHz,CDCl3):δ8.42-8.31(m,2H),7.98(d,1H),7.02(s,1H),6.90(d,1H),6.61(d,1H),6.26(d,2H),5.48(s,1H),5.37(d,1H),5.21(d,1H),4.61-4.56(m,1H),4.52(s,1H),4.43(t,1H),3.90-3.70(m,6H),3.39(s,3H),3.11(d,3H),2.74(s,5H),2.24(t,2H),2.03(s,4H),1.28(d,8H),0.91(d,2H)。 1 H NMR (500MHz, CDCl 3 ): δ8.42-8.31(m,2H),7.98(d,1H),7.02(s,1H),6.90(d,1H),6.61(d, 1H),6.26(d,2H),5.48(s,1H),5.37(d,1H),5.21(d,1H),4.61-4.56(m, 1H),4.52(s,1H),4.43(t,1H),3.90-3.70(m,6H),3.39(s,3H),3.11(d ,3H),2.74(s,5H),2.24(t,2H),2.03(s,4H),1.28(d,8H),0.91(d,2H).

实施例6Example 6

5-(((2aS,8aR)-7-(4-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬-2-基)哌啶-1-羰基)-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺6

5-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidine-1-carbonyl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6

第一步first step

2-(苄氧基)环丁烷-1-酮6b2-(Benzyloxy)cyclobutan-1-one 6b

将1,2-双(三甲基硅氧基)环丁烯6a(100g，433.9mmol，江苏艾康)和苯甲醇(46.9g，433.9mmol)混于4M氯化氢的1,4-二氧六环溶液(300mL)，80℃反应4小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6b(外消旋体，43.8g，产率：57.3％)。1,2-Bis(trimethylsilyloxy)cyclobutene 6a (100 g, 433.9 mmol, Jiangsu Aikon) and benzyl alcohol (46.9 g, 433.9 mmol) were mixed in a 4 M hydrogen chloride solution in 1,4-dioxane (300 mL) and reacted at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent C to give the title compound 6b (racemic compound, 43.8 g, yield: 57.3%).

第二步Step 2

2-(苄氧基)环丁烷-1-醇6c2-(Benzyloxy)cyclobutan-1-ol 6c

将化合物6b(20.4g，115.7mmol)溶于四氢呋喃(200mL)中，置换氮气三次，冷却到-78℃，滴加入1M三仲丁基硼氢化锂的四氢呋喃溶液(127.3mL)，保持温度搅拌反应1小时，然后自然恢复室温后继续搅拌1小时，反应液冷却到0℃，依次加入水(30mL)，2M氢氧化钠水溶液(30mL)，双氧水(30mL)，加完搅拌10分钟后加入饱和亚硫酸钠溶液，用乙酸乙酯萃取(150mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6c(顺式异构体混合物，18g，产率：87.2％)。Compound 6b (20.4 g, 115.7 mmol) was dissolved in tetrahydrofuran (200 mL), nitrogen was replaced three times, and the mixture was cooled to -78°C. A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (127.3 mL) was added dropwise. The temperature was maintained and stirred for 1 hour. The mixture was then allowed to return to room temperature and stirred for another 1 hour. The reaction solution was cooled to 0°C, and water (30 mL), 2 M aqueous sodium hydroxide solution (30 mL), and hydrogen peroxide (30 mL) were added in sequence. After stirring for 10 minutes, a saturated sodium sulfite solution was added to the mixture, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the title compound 6c (cis-isomer mixture, 18 g, yield: 87.2%).

第三步Step 3

2-(2-(苄氧基)环丁氧基)-1,5-二氟-3-硝基苯6d2-(2-(Benzyloxy)cyclobutyloxy)-1,5-difluoro-3-nitrobenzene 6d

将化合物6c(18.1g，101.5mmol)溶于N,N-二甲基甲酰胺(350mL)，0℃下加入氢化钠(6.1g，152.5mmol，纯度60％)，保持温度搅拌反应1小时，-40℃下滴加2,3,5-三氟硝基苯(18g，101.5mmol)的N,N-二甲基甲酰胺(60mL)，自然恢复室温搅拌反应1小时，反应液中加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(150mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6d(顺式异构体混合物，27.9g，产率：81.9％)。Compound 6c (18.1 g, 101.5 mmol) was dissolved in N,N-dimethylformamide (350 mL), and sodium hydride (6.1 g, 152.5 mmol, purity 60%) was added at 0°C. The temperature was maintained with stirring for 1 hour. 2,3,5-trifluoronitrobenzene (18 g, 101.5 mmol) in N,N-dimethylformamide (60 mL) was added dropwise at -40°C, and the mixture was naturally returned to room temperature with stirring for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 6d (cis isomer mixture, 27.9 g, yield: 81.9%).

第四步Step 4

2-(2,4-二氟-6-硝基苯氧基)环丁烷-1-醇6e2-(2,4-Difluoro-6-nitrophenoxy)cyclobutan-1-ol 6e

2-(2,4-二氟-6-硝基苯氧基)2,2,2-三氟乙酸环丁酯6f2-(2,4-Difluoro-6-nitrophenoxy)cyclobutyl 2,2,2-trifluoroacetate 6f

将化合物6d(27.9g，83.2mmol)溶于三氟醋酸(100mL)，加热至80℃反应12小时，反应液减压浓缩，残余物溶于二氯甲烷(100mL)，依次用饱和碳酸氢钠溶液，饱和氯化钠溶液洗涤，有机相减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6e和6f的混合物(28g)。Compound 6d (27.9 g, 83.2 mmol) was dissolved in trifluoroacetic acid (100 mL) and heated to 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL) and washed sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent C to give a mixture of the title compounds 6e and 6f (28 g).

第五步Step 5

6-氟-4-硝基-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英6g6-Fluoro-4-nitro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin 6g

将化合物6e和6f的混合物(28g)，碳酸铯(40g，123mmol)溶于N,N-二甲基甲酰胺(200mL)中，120℃搅拌反应1小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6g(顺式异构体混合物，14.5g)。A mixture of compounds 6e and 6f (28 g) and cesium carbonate (40 g, 123 mmol) were dissolved in N,N-dimethylformamide (200 mL) and stirred at 120°C for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent C to give the title compound 6g (cis isomer mixture, 14.5 g).

第六步Step 6

6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-胺6h6-Fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin-4-amine 6h

(2aS,8aR)-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-胺6i-1(2aS,8aR)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin-4-amine 6i-1

(2aR,8aS)-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-胺6i-2(2aR,8aS)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin-4-amine 6i-2

将化合物6g(14.5g，64.4mmol)溶于四氢呋喃(100mL)和甲醇(20mL)，加入10％钯碳加氢催化剂(湿)(4g)，氢气置换，搅拌反应16小时，反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6h(顺式异构体混合物，10.5g，产率：83.5％)。Compound 6g (14.5g, 64.4mmol) was dissolved in tetrahydrofuran (100mL) and methanol (20mL), and 10% palladium carbon hydrogenation catalyst (wet) (4g) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6h (cis isomer mixture, 10.5g, yield: 83.5%).

MS m/z(ESI):196.2[M+1]。MS m/z(ESI):196.2[M+1].

化合物6h(10.4g)经手性柱拆分(Shimadzu LC-20AT XR，色谱柱：CHIRALPAK IG，50*250mm，10μm；流动相A：乙腈，流动相B：超临界二氧化碳，梯度配比：A:B＝15:85，流速：140mL/min)得到标题化合物6i-1(4.2g，产率：40.3％)，6i-2(3.97g，产率：38.1％)。Compound 6h (10.4 g) was separated by chiral column (Shimadzu LC-20AT XR, chromatographic column: CHIRALPAK IG, 50*250 mm, 10 μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 140 mL/min) to obtain the title compounds 6i-1 (4.2 g, yield: 40.3%), 6i-2 (3.97 g, yield: 38.1%).

单一构型化合物(较短保留时间)：6i-1(4.2g，产率：40.3％)Single configuration compound (shorter retention time): 6i-1 (4.2 g, yield: 40.3%)

手性HPLC分析：保留时间1.735分钟，纯度：99％(色谱柱:ChiralPak IG，150*3mm，5μm；流动相A：乙腈，流动相B：超临界二氧化碳，梯度配比：A:B＝15:85，流速：2mL/min)。Chiral HPLC analysis: retention time 1.735 minutes, purity: 99% (chromatographic column: ChiralPak IG, 150*3mm, 5μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 2mL/min).

单一构型化合物(较长保留时间)：6i-2(3.97g，产率：38.1％)Single configuration compound (longer retention time): 6i-2 (3.97 g, yield: 38.1%)

手性HPLC分析：保留时间1.993分钟，纯度：99％(色谱柱:ChiralPak IG,150*3mm,5μm；流动相A：乙腈，流动相B：超临界二氧化碳，梯度配比：A:B＝15:85，流速：2mL/min)。Chiral HPLC analysis: retention time 1.993 minutes, purity: 99% (chromatographic column: ChiralPak IG, 150*3mm, 5μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 2mL/min).

第七步Step 7

(2aS,8aR)-7-溴-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-胺6j(2aS,8aR)-7-Bromo-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-amine 6j

将化合物6i-1(3.2g，16.4mmol)溶于二氯甲烷(60mL)中，冷却到0℃，分批加入N-溴代丁二酰亚胺(3.91g，16.3mmol)，保持温度搅拌反应3小时，反应液中加入饱和硫代硫酸钠溶液淬灭，乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈32％-45％，流速：30mL/min)得到标题化合物6j(1.8g，产率：40％)。Compound 6i-1 (3.2 g, 16.4 mmol) was dissolved in dichloromethane (60 mL), cooled to 0°C, and N-bromosuccinimide (3.91 g, 16.3 mmol) was added in batches. The temperature was maintained and stirred for 3 hours. Saturated sodium thiosulfate solution was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL/min) to give the title compound 6j (1.8 g, yield: 40%).

MS m/z(ESI):273.9[M+1]。MS m/z(ESI):273.9[M+1].

第八步Step 8

(2aR,8aS)-7-氨基-5-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]-二噁英-4-羧酸甲酯6k(2aR,8aS)-7-amino-5-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]-dioxin-4-carboxylic acid methyl ester 6k

将化合物6j(500mg，1.83mmol)溶于甲醇(30mL)，加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(134mg，183.1μmol)，三乙胺(185mg，1.82mmol)，一氧化碳置换，80℃搅拌反应16小时，反应液冷却至室温，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6k(450mg，产率：97.4％)。Compound 6j (500 mg, 1.83 mmol) was dissolved in methanol (30 mL), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (134 mg, 183.1 μmol) and triethylamine (185 mg, 1.82 mmol) were added. Carbon monoxide was replaced, and the mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 6k (450 mg, yield: 97.4%).

MS m/z(ESI):254.3[M+1]。MS m/z(ESI):254.3[M+1].

第九步Step 9

5-氯-7-((4-甲氧基苄基)(甲基)氨基)-N-((1R,2R)-2-甲氧基环丁基)吡唑并[1,5-a]嘧啶-3-甲酰胺6l5-Chloro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

将化合物1b(1.5g，4.33mmol)溶于N,N-二甲基乙酰胺(100mL)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(1.97g，5.19mmol)，搅拌10分钟，加入化合物5d(714.29mg，5.19mmol)和N,N-二异丙基乙胺(1.68g，12.97mmol)，搅拌反应16小时，反应液倒入水中，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6l(1.5g，产率：80.6％)。Compound 1b (1.5 g, 4.33 mmol) was dissolved in N,N-dimethylacetamide (100 mL), and O-(7-azabenzotriazole-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.97 g, 5.19 mmol) was added. The mixture was stirred for 10 minutes, and compound 5d (714.29 mg, 5.19 mmol) and N,N-diisopropylethylamine (1.68 g, 12.97 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6l (1.5 g, yield: 80.6%).

MS m/z(ESI):430.2[M+1]。MS m/z(ESI):430.2[M+1].

第十步Step 10

(2aR,8aS)-5-氟-7-((7-((4-甲氧基苄基)(甲基)氨基)-3-(((1R,2R)-2-甲氧基环丁基)氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-羧酸甲酯6m(2aR,8aS)-5-fluoro-7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-carboxylic acid methyl ester 6m

将化合物6l(300mg，697.8μmol)溶于1,4-二氧六环(20mL)，加入化合物6k(200mg，789.8μmol)，醋酸钯(18mg，80.1μmol)，(S)-(-)-2,2'-双(二苯膦基)-1,1'-联萘(50mg，80.2μmol)，碳酸铯(515mg，1.58mmol)，氮气置换，100℃反应4小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6m(500mg，产率：97.8％)。Compound 6l (300 mg, 697.8 μmol) was dissolved in 1,4-dioxane (20 mL), and compound 6k (200 mg, 789.8 μmol), palladium acetate (18 mg, 80.1 μmol), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (50 mg, 80.2 μmol), and cesium carbonate (515 mg, 1.58 mmol) were added. The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to provide the title compound 6m (500 mg, 97.8% yield).

MS m/z(ESI):647.5[M+1]。MS m/z(ESI):647.5[M+1].

第十一步Step 11

(2aR,8aS)-5-氟-7-((7-((4-甲氧基苄基)(甲基)氨基)-3-(((1R,2R)-2-甲氧基环丁基)氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-羧酸6n(2aR,8aS)-5-Fluoro-7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-carboxylic acid 6n

将化合物6m(300mg，463.9μmol)溶于甲醇(5mL)，水(3mL)和四氢呋喃(5mL)，加入一水合氢氧化锂(185mg，4.62mmol)，50℃反应3小时，反应液降至室温后加入水稀释，用1M盐酸调节pH至5-6，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，即得到标题化合物6n(260mg)，产品不经纯化直接用于下一步反应。Compound 6m (300 mg, 463.9 μmol) was dissolved in methanol (5 mL), water (3 mL) and tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (185 mg, 4.62 mmol) was added. The reaction was allowed to react at 50°C for 3 hours. After the reaction solution was cooled to room temperature, it was diluted with water and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6n (260 mg). The product was used directly in the next reaction without purification.

MS m/z(ESI):633.3[M+1]。MS m/z(ESI):633.3[M+1].

第十二步Step 12

5-(((2aS,8aR)-6-氟-7-(4-氧代哌啶-1-羰基)-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-基)氨基)-7-((4-甲氧基苄基)(甲基)氨基)-N-((1R,2R)-2-甲氧基环丁基)吡唑并[1,5-a]嘧啶-3-甲酰胺6o5-(((2aS,8aR)-6-fluoro-7-(4-oxopiperidine-1-carbonyl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

将化合物6n(75mg，115.6μmol)，哌啶-4-酮(25mg，252.2μmol，上海毕得)溶于N,N-二甲基甲酰胺(3mL)，加入N,N-二异丙基乙胺(45mg，348.1μmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(88mg，231.4μmol)，搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6o(80mg，产率：94.8％)。Compound 6n (75 mg, 115.6 μmol) and piperidin-4-one (25 mg, 252.2 μmol, Shanghai Bidex) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (45 mg, 348.1 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) (88 mg, 231.4 μmol) were added. The reaction was stirred for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 6o (80 mg, yield: 94.8%).

MS m/z(ESI):714.5[M+1]。MS m/z(ESI):714.5[M+1].

第十三步Step 13

5-(((2aS,8aR)-7-(4-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬-2-基)哌啶-1-羰基)-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-基)氨基)-7-((4-甲氧基苄基)(甲基)氨基)-N-((1R,2R)-2-甲氧基环丁基)吡唑并[1,5-a]嘧啶-3-甲酰胺6p5-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidine-1-carbonyl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6p

将化合物6o(80mg，109.6μmol)，化合物1g(60mg，120.6μmol)溶于甲醇(10mL)，加入乙酸钠(40mg，487.6μmol)，搅拌30分钟后加入氰基硼氢化钠(27mg，451.3μmol)，搅拌反应6小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物6p(100mg，产率：83.1％)。Compound 6o (80 mg, 109.6 μmol) and compound 1g (60 mg, 120.6 μmol) were dissolved in methanol (10 mL), and sodium acetate (40 mg, 487.6 μmol) was added. After stirring for 30 minutes, sodium cyanoborohydride (27 mg, 451.3 μmol) was added. The reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent A to give the title compound 6p (100 mg, yield: 83.1%).

MS m/z(ESI):1082.0[M+1]。MS m/z(ESI):1082.0[M+1].

第十五步Step 15

5-(((2aS,8aR)-7-(4-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬-2-基)哌啶-1-羰基)-6-氟-1,2,2a,8a-四氢苯并[b]环丁烷并[e][1,4]二噁英-4-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺65-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidine-1-carbonyl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-4-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6

将化合物6p(100mg，92.3μmol)溶于二氯甲烷(3mL)，加入三氟醋酸(2mL)，搅拌反应2小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物6(一对非对映异构体混合物，23mg，产率：26.1％)。Compound 6p (100 mg, 92.3 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to give the title compound 6 (a pair of diastereoisomer mixture, 23 mg, yield: 26.1%).

MS m/z(ESI):961.9[M+1]。MS m/z(ESI):961.9[M+1].

1H NMR(500MHz,CDCl3):δ8.40(s,1H),8.10(s,1H),7.97-7.93(m,1H),7.83-7.79(m,1H),7.71-7.67(m,1H),7.18-7.15(m,1H),7.02-6.99(m,1H),6.91-6.88(m,1H),6.60-6.57(m,1H),6.33-6.32(m,1H),5.44(s,1H),5.38-5.35(m,1H),5.23-5.20(m,1H),4.80-4.74(m,2H),4.61-4.56(m,2H),3.91-3.83(m,1H),3.77(s,3H),3.37-3.35(m,3H),3.25-3.15(m,2H),3.13-3.12(m,3H),3.11-3.09(m,3H),2.99-2.94(m,1H),2.88-2.71(m,5H),2.35-2.22(m,6H),2.19-2.01(m,3H),1.93-1.85(m,4H),1.56-1.51(m,2H),1.34-1.28(m,4H)。 1 H NMR (500MHz, CDCl 3 ): δ8.40(s,1H),8.10(s,1H),7.97-7.93(m,1H),7.83-7.79(m,1H),7.71-7.67(m,1H),7.18-7.15(m,1H),7.02-6.99(m,1H),6. 91-6.88(m,1H),6.60-6.57(m,1H),6.33-6.32(m,1H),5.44(s,1H),5.38-5.35(m,1H),5.23-5.20(m,1H),4.80-4.74(m,2H),4.6 1-4.56(m,2H),3.91-3.83(m,1H),3.77(s,3H),3.37-3.35(m,3H),3.25-3.15(m,2H),3.13-3.12(m,3H),3.11-3.09(m,3H),2.99 -2.94(m,1H),2.88-2.71(m,5H),2.35-2.22(m,6H),2.19-2.01(m,3H),1.93-1.85(m,4H),1.56-1.51(m,2H),1.34-1.28(m,4H).

实施例7Example 7

5-((1-(5-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺7(一对非对映异构体混合物)
5-((1-(5-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7 (a mixture of diastereoisomers)

第一步first step

2-溴-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯7btert-Butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 7b

将2-氨基-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯7a(1g，4.2mmol，上海毕得)溶于乙腈(40mL)，加入亚硝酸叔丁酯(650mg，6.3mmol)，溴化亚酮(903mg，6.3mmol)，溴化锂(438mg，5.0mmol)，50℃搅拌反应2小时，反应液过滤，滤液减压浓缩，残余物以洗脱剂体系B纯化得到标题化合物7b(630mg，产率：49.7％)。2-Amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester 7a (1 g, 4.2 mmol, Shanghai Bidex) was dissolved in acetonitrile (40 mL), and tert-butyl nitrite (650 mg, 6.3 mmol), ketone bromide (903 mg, 6.3 mmol), and lithium bromide (438 mg, 5.0 mmol) were added. The reaction was stirred at 50°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to give the title compound 7b (630 mg, yield: 49.7%).

MS m/z(ESI):302.0[M+1]。MS m/z(ESI):302.0[M+1].

第二步Step 2

2-(3-氨基-2-氧代吡啶-1(2H)-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯7cTert-butyl 2-(3-amino-2-oxopyridin-1(2H)-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 7c

将化合物7b(630mg，2.08mmol)，3-氨基吡啶-2-酮(300mg，2.72mmol，上海毕得)溶于1,4-二氧六环(20mL)，加入碘化亚铜(80mg，420μmol)，碳酸钾(577mg，4.17mmol)，N,N'-二甲基乙二胺(37mg，419.7μmol)，氮气置换，100℃搅拌反应16小时，反应液降至室温，加入乙酸乙酯稀释，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7c(550mg，产率：79.6％)MS m/z(ESI):332.4[M+1]。Compound 7b (630 mg, 2.08 mmol) and 3-aminopyridin-2-one (300 mg, 2.72 mmol, Shanghai Bidex) were dissolved in 1,4-dioxane (20 mL), and cuprous iodide (80 mg, 420 μmol), potassium carbonate (577 mg, 4.17 mmol), and N,N'-dimethylethylenediamine (37 mg, 419.7 μmol) were added. The atmosphere was replaced with nitrogen and stirred at 100 °C for 16 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 7c (550 mg, yield: 79.6%). MS m/z (ESI): 332.4 [M+1].

第三步Step 3

2-(3-((7-((4-甲氧基苄基)(甲基)氨基)-3-(((1R,2R)-2-甲氧基环丁基)氨基羰基)吡唑并[1,5-a]嘧啶-5-基)氨基)-2-氧代吡啶-1(2H)-基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯7dtert-Butyl 2-(3-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-oxopyridin-1(2H)-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 7d

将化合物7c(550mg，1.66mol)、化合物6l(365mg，849μmol)溶于1,4-二氧六环(20mL)，加入醋酸钯(38mg，169.2μmol)、1,1'-联萘-2,2'-双二苯膦(104mg，167μmol)、碳酸铯(1.1g，3.34mmol)，氮气保护下加热至100℃反应2小时，反应液降至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7d(540mg，产率：44.8％)。Compound 7c (550 mg, 1.66 mol) and compound 6l (365 mg, 849 μmol) were dissolved in 1,4-dioxane (20 mL), and palladium acetate (38 mg, 169.2 μmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (104 mg, 167 μmol), and cesium carbonate (1.1 g, 3.34 mmol) were added. The mixture was heated to 100°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 7d (540 mg, yield: 44.8%).

MS m/z(ESI):725.7[M+1]。MS m/z(ESI):725.7[M+1].

第四步Step 4

N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)-5-((2-氧代-1-(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)-1,2-二氢吡啶-3-基)氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺7eN-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7e

将化合物7d(180mg，248.3μmol)溶于二氯甲烷(20mL)，加入溴化锌(480mg，2.13mol)，搅拌反应16小时，反应液中加入饱和碳酸氢钠溶液，分液，水相用二氯甲烷萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7e(100mg，产率：80％)。Compound 7d (180 mg, 248.3 μmol) was dissolved in dichloromethane (20 mL), and zinc bromide (480 mg, 2.13 mol) was added. The reaction mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 7e (100 mg, yield: 80%).

MS m/z(ESI):505.5[M+1]。MS m/z(ESI):505.5[M+1].

第五步Step 5

5-((1-(5-(7-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)-N-((1R,2R)-2-甲氧基环丁基)-7-(甲基氨基)吡唑并[1,5-a]嘧啶-3-5-((1-(5-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-yl

甲酰胺7Formamide 7

将化合物7e(80mg，158.5μmol)，N,N-二异丙基乙胺(30mg，232.1μmol)溶于二氯甲烷(10mL)，冰浴下加入三光气(48mg，161.7μmol)，保持温度搅拌反应0.5小时，加入化合物1g(122mg，245.3μmol)，加热至50℃反应1小时，反应液降至室温后加入水，用二氯甲烷萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈32％-45％，流速：30mL/min)得到标题化合物7(一对非对映异构体混合物，17.8mg，产率：12.2％)。Compound 7e (80 mg, 158.5 μmol) and N,N-diisopropylethylamine (30 mg, 232.1 μmol) were dissolved in dichloromethane (10 mL). Triphosgene (48 mg, 161.7 μmol) was added under ice bath, and the temperature was maintained with stirring for 0.5 hours. Compound 1g (122 mg, 245.3 μmol) was added, and the mixture was heated to 50°C for 1 hour. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined and washed with anhydrous water. The residue was dried over sodium sulfate and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30mL/min) to give the title compound 7 (a mixture of a pair of diastereomers, 17.8mg, yield: 12.2%).

MS m/z(ESI):914.9[M+1]。MS m/z(ESI):914.9[M+1].

1H NMR(500MHz,CDCl3):δ8.40-8.38(m,2H),8.12-8.10(m,2H),8.04(d,1H),7.63(dd,1H),7.04-7.01(m,2H),6.92-6.91(m,1H),6.72(s,1H),6.62-6.60(m,1H),6.40(t,1H),6.29-6.28(m,1H),5.49(s,1H),5.38-5.36(m,1H),5.24-5.21(m,1H),4.66(s,2H),4.63-4.58(m,1H),4.27-4.25(m,2H),3.95-3.90(m,2H),3.89-3.84(m,4H),3.78(s,3H),3.39(s,3H),3.14-3.12(m,2H),3.11(s,3H),2.98-2.94(m,1H),2.88-2.85(m,1H),2.82-2.72(m,3H),2.36-2.34(m,1H),2.26-2.23(m,2H),2.19-2.14(m,1H),1.78-1.70(m,2H),1.54-1.48(m,2H)。 1 H NMR (500MHz, CDCl 3 ): δ8.40-8.38(m,2H),8.12-8.10(m,2H),8.04(d,1H),7.63(dd,1H),7.04-7.01(m,2H),6.92-6.91(m,1H),6.72(s,1H),6.62-6.6 0(m,1H),6.40(t,1H),6.29-6.28(m,1H),5.49(s,1H),5.38-5.36(m,1H),5.24-5.21(m,1H),4.66(s,2H),4.63-4.58(m,1H),4.27- 4.25(m,2H),3.95-3.90(m,2H),3.89-3.84(m,4H),3.78(s,3H),3.39(s,3H),3.14-3.12(m,2H),3.11(s,3H),2.98-2.94(m,1H),2. 88-2.85(m,1H),2.82-2.72(m,3H),2.36-2.34(m,1H),2.26-2.23(m,2H),2.19-2.14(m,1H),1.78-1.70(m,2H),1.54-1.48(m,2H).

生物学评价Biological evaluation

测试例1、TYK2 JH2和JAK1 JH2体外酶结合实验Test Example 1: TYK2 JH2 and JAK1 JH2 in vitro enzyme binding assay

本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对TYK2 JH2和JAK1 JH2假激酶的抑制作用。该实验中TYK2 JH2或JAK1 JH2假激酶可同时与带荧光标签的Tracer以及Tb抗体相结合，Tb抗体作为荧光供体在一定波长激发光作用下产生495nm波长荧光，而Tracer作为荧光受体，只有在与Tb抗体足够靠近的情况下可以接收到495nm波长荧光从而产生520nm波长荧光，即荧光共振能量转移信号。当加入化合物与Tracer竞争结合假激酶JH2区域时，由于Tracer结合减少从而TR-FRET信号减弱，可通过520nm/495nm信号比值可反应出化合物与假激酶结合抑制活性强弱。This experiment uses fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effects of compounds on TYK2 JH2 and JAK1 JH2 pseudokinases. In this experiment, TYK2 JH2 or JAK1 JH2 pseudokinases are simultaneously bound to the fluorescently labeled Tracer and the Tb antibody. The Tb antibody acts as a fluorescence donor, generating 495nm fluorescence under the influence of excitation light of a certain wavelength. Tracer, acting as a fluorescence acceptor, can only receive 495nm fluorescence when it is sufficiently close to the Tb antibody, thereby generating 520nm fluorescence, i.e., the fluorescence resonance energy transfer signal. When a compound is added to compete with Tracer for binding to the pseudokinase JH2 region, the TR-FRET signal decreases due to reduced Tracer binding. The 520nm/495nm signal ratio can reflect the inhibitory activity of the compound binding to the pseudokinase.

1.实验试剂及仪器

1. Experimental reagents and instruments

·微量移液仪器:Echo(LABCYTE Echo550)Micropipette instrument: Echo (LABCYTE Echo550)

·酶标仪:Envision2105(Perkin Elmer)Microplate reader: Envision 2105 (Perkin Elmer)

·恒温孵育箱:CIMO,SPX-60BS-IIConstant temperature incubator: CIMO, SPX-60BS-II

·Thermo MATRIX多道移液器:Thermo Fisher,2-125μLThermo MATRIX multichannel pipette: Thermo Fisher, 2-125 μL

·离心机:Thermo Centrifuge ST 40RCentrifuge: Thermo Centrifuge ST 40R

·纯水仪:Millipore Milli-Q Reference systemWater Purifier: Millipore Milli-Q Reference System

·超低温冰箱:Haier ultralow temperature freezerUltra-low temperature freezer: Haier ultralow temperature freezer

·冰箱：Haier 4degree freezer；Haier-20degree freezer·Refrigerator: Haier 4degree freezer; Haier-20degree freezer

2.实验方法2. Experimental Methods

2.1.准备1×实验工作液
2.1. Prepare 1× experimental working solution

2.2.实验操作如下：2.2. Experimental operation is as follows:

2.2.1.用DMSO溶解化合物到10mM的存储浓度。2.2.1. Dissolve the compound in DMSO to a stock concentration of 10 mM.

2.2.2.在化合物稀释板子中配备200倍于终浓度的化合物不同浓度梯度，并转移到Echo板中。2.2.2. Prepare a compound dilution plate with a compound concentration gradient of 200 times the final concentration and transfer it to an Echo plate.

2.2.3.用Echo仪器将化合物从Echo板转移75nL到384实验板。2.2.3. Transfer 75 nL of compound from the Echo plate to the 384 assay plate using the Echo instrument.

2.2.4.分别加入5μL 3倍于终浓度(0.5nM为终浓度)TYK2 JH2与JAK1 JH2的假激酶到384孔实验板中，1000rpm离心30秒。2.2.4. Add 5 μL of TYK2 JH2 and JAK1 JH2 pseudokinases at 3 times the final concentration (0.5 nM) into a 384-well assay plate and centrifuge at 1000 rpm for 30 seconds.

2.2.5.分别加入5μL 3倍于终浓度(1×为终浓度)的Tb抗体到384孔实验板中，1000rpm离心30秒。2.2.5. Add 5 μL of Tb antibody 3 times the final concentration (1× is the final concentration) into each 384-well experimental plate and centrifuge at 1000 rpm for 30 seconds.

2.2.6.分别加入5μL 3倍于终浓度(终浓度分别：TYK2 JH2为1nM,JAK1 JH2为30nM)的Tracer到384孔实验板中，1000rpm离心30秒。2.2.6. Add 5 μL of Tracer at 3 times the final concentration (final concentration: 1 nM for TYK2 JH2, 30 nM for JAK1 JH2) into a 384-well assay plate and centrifuge at 1000 rpm for 30 seconds.

2.2.7.室温孵育60分钟，4℃过夜孵育。2.2.7. Incubate at room temperature for 60 minutes or at 4°C overnight.

2.2.8.Envision酶标仪(PerkinElmer)读取520nm/495nm荧光信号比值。2.2.8. The 520 nm/495 nm fluorescence signal ratio was read using Envision microplate reader (PerkinElmer).

3.数据分析3. Data Analysis

使用IDBS公司编写的，整合于Microsoft Excel环境的软件XLfit进行测试数据处理与分析。首先分别计算高信号对照孔和底信号对照孔反应信号平均值，再根据公式“单孔抑制率％＝100-(高信号对照组平均值-单孔信号值)/(高信号对照组平均值-底信号对照组平均值)”计算出每个化合物孔的反应抑制率。然后将浓度和对应的抑制率数据导入XLfit软件中，利用软件中的Dose Response One Site 205模型，采用四参数法抑制率-浓度曲线进行拟合，并计算出化合物的IC50值。Test data processing and analysis were performed using XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment. First, the average reaction signals for the high-signal control wells and the low-signal control wells were calculated. The inhibition rate for each compound well was then calculated using the formula: "Single-well inhibition rate % = 100 - (high-signal control average - single-well signal value) / (high-signal control average - low-signal control average)." The concentration and corresponding inhibition rate data were then imported into XLfit. Using the Dose Response One Site 205 model within the software, a four-parameter inhibition rate-concentration curve was fitted to calculate the compound's IC50 value.

表1 TYK2 JH2和JAK1 JH2假激酶结合抑制活性的IC50
Table 1 IC50 of TYK2 JH2 and JAK1 JH2 pseudokinase binding inhibitory activity

结论：本公开化合物对TYK2-JH2假激酶具有明显的抑制作用。Conclusion: The disclosed compounds have a significant inhibitory effect on TYK2-JH2 pseudokinase.

测试例2、本公开化合物对HeLa细胞IFNα诱导的STAT1蛋白磷酸化抑制实验Test Example 2: Inhibition of IFNα-induced STAT1 protein phosphorylation in HeLa cells by the disclosed compounds

利用AlphaLISA的方法检测本公开化合物对HeLa细胞IFNα诱导的STAT1蛋白磷酸化的抑制作用，具体内容如下：The AlphaLISA method was used to detect the inhibitory effect of the disclosed compounds on IFNα-induced STAT1 protein phosphorylation in HeLa cells. The specific content is as follows:

1.1试剂与仪器1.1 Reagents and Instruments

1.1.1试剂
1.1.1 Reagents

1.1.2仪器

1.1.2 Instruments

1.2细胞及培养方法1.2 Cells and culture methods

HeLa细胞购买于美国模式菌种收集中心(ATCC)，MEM培养基(10％FBS)，37℃，5％二氧化碳的培养箱中培养，一周传代2-3次。HeLa cells were purchased from the American Type Culture Collection (ATCC) and cultured in MEM medium (10% FBS) at 37° C. in a 5% carbon dioxide incubator, and passaged 2-3 times a week.

1.3化合物准备1.3 Compound preparation

a.测试化合物用DMSO溶解至0.5mM。a. Test compounds were dissolved in DMSO to 0.5 mM.

b.化合物起始浓度0.5mM，3倍稀释，10个浓度梯度。b. The initial concentration of the compound was 0.5 mM, diluted 3 times, and 10 concentration gradients were performed.

c.用培养液将所有浓度化合物稀释50倍，备用。c. Dilute all concentrations of compounds 50-fold with culture medium and set aside.

4.实验步骤4. Experimental Procedure

a.细胞计数，用新鲜培养液调整细胞密度至5×105/mL。a. Count the cells and adjust the cell density to 5×10 5 /mL with fresh culture medium.

b.96 Well Black Polystyrene Microplate，每孔接种80μL细胞，37℃培养4小时。b. 96-Well Black Polystyrene Microplate, inoculate 80 μL of cells per well and culture at 37°C for 4 hours.

c.每孔加入10μL化合物(第1列和12列加10μL 0.5％的DMSO)，37℃培养1小时。c. Add 10 μL of compound to each well (10 μL of 0.5% DMSO to columns 1 and 12) and incubate at 37°C for 1 hour.

d.用培养液配制100ng/mL的IFNα，每孔加入10μL IFNα(第1列加10μL培养液作为对照)，37℃培养15分钟。d. Prepare 100 ng/mL IFNα with culture medium, add 10 μL IFNα to each well (add 10 μL culture medium to the first column as a control), and incubate at 37°C for 15 minutes.

e.按照AlphaLISA SureFire Ultra STAT1 pY701试剂盒说明书配制裂解溶液。吸掉细胞培养上清液，每孔加入50μL裂解溶液，室温震荡裂解15分钟。e. Prepare lysis solution according to the AlphaLISA SureFire Ultra STAT1 pY701 kit instructions. Aspirate the cell culture supernatant and add 50 μL of lysis solution to each well. Incubate cells at room temperature with shaking for 15 minutes.

f.按照AlphaLISA SureFire Ultra STAT1 pY701试剂盒说明书配制Acceptor Mix。96-well low volume white plate中，每孔加入5μL of Acceptor Mix。f. Prepare Acceptor Mix according to the AlphaLISA SureFire Ultra STAT1 pY701 kit instructions. Add 5 μL of Acceptor Mix to each well of a 96-well low-volume white plate.

g.转移10μL细胞裂解液到96-well low volume white plate中，离心，室温孵育1小时。g. Transfer 10 μL of cell lysate to a 96-well low-volume white plate, centrifuge, and incubate at room temperature for 1 hour.

h.按照AlphaLISA SureFire Ultra STAT1 pY701试剂盒说明书配制Donor Mix。避光，每孔加入5μL Donor Mix，室温孵育过夜。h. Prepare Donor Mix according to the AlphaLISA SureFire Ultra STAT1 pY701 kit instructions. Add 5 μL of Donor Mix to each well and incubate overnight at room temperature, protected from light.

i.用PHERASTAR HS Microplate reader进行读板检测。i. Use PHERASTAR HS Microplate reader to read the plate.

j.Graphpad软件作图，计算本公开化合物的IC50值。j. Graphpad software was used to generate graphs and calculate the IC50 values of the disclosed compounds.

表2本公开化合物对HeLa细胞IFNα诱导的STAT1蛋白磷酸化的抑制活性
Table 2 Inhibitory activity of the disclosed compounds on IFNα-induced STAT1 protein phosphorylation in HeLa cells

结论：本公开化合物对HeLa细胞IFNα诱导的STAT1蛋白磷酸化具有较好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on IFNα-induced STAT1 protein phosphorylation in HeLa cells.

测试例3、本公开化合物抑制IFNα诱导人全血产生IP10的实验Test Example 3: Experiment on the inhibition of IFNα-induced IP10 production in human whole blood by the disclosed compounds

将新鲜全血使用肝素抗凝管收集。以每孔180ul体积全血加入到96孔圆底板中，每孔加入10μl含有不同浓度梯度的化合物(DMSO终浓度为0.5％)的培养基处理细胞，并设置复孔，于37度培养箱进行孵育60min。每孔加入10ul IFN-a(终浓度为20ng/m)，空白培养基作为阴性对照。于37度培养箱孵育24h左右。24h后收取上清：将细胞板从37度培养箱中取出，2000rpm/min离心5min,每孔取出80ul上清转移至新的96孔圆底板中，锡箔纸密封，于-80度冰箱保存，待测。用来自欣博盛生物的human IP-10/CXCL10 ELISA kit进行ELISA检测上清中的IP10。Fresh whole blood was collected using heparin anticoagulant tubes. 180ul of whole blood was added to each well of a 96-well round-bottom plate. 10μl of culture medium containing compounds with different concentration gradients (DMSO final concentration of 0.5%) was added to each well to treat the cells. Repeated wells were set up and incubated in a 37-degree incubator for 60 minutes. 10ul of IFN-a (final concentration of 20ng/m) was added to each well, and blank culture medium was used as a negative control. Incubate in a 37-degree incubator for about 24 hours. After 24 hours, the supernatant was collected: the cell plate was removed from the 37-degree incubator, centrifuged at 2000rpm/min for 5 minutes, 80ul of supernatant was taken out of each well and transferred to a new 96-well round-bottom plate, sealed with tin foil, and stored in a -80-degree refrigerator for testing. The IP10 in the supernatant was detected by ELISA using the human IP-10/CXCL10 ELISA kit from Xinbosheng Bio.

根据标准品绘制标准曲线，并得出相应的计算公式，Y＝aX+b，R squared>0.99。其中Y值代表OD450值，X代表IP10浓度。计算出各个OD450值相应的IP10浓度。最终浓度为100X(pg/ml)。将IFN-a刺激+DMSO处理孔作为阳性对照孔，IFN-a未刺激+DMSO处理孔作为阴性对照孔。抑制率为:(阳性对照孔-待测化合物)/(阳性对照孔-阴性对照孔)*100％。Draw a standard curve based on the standard and derive the corresponding calculation formula: Y = aX + b, R squared > 0.99. Y represents the OD450 value, and X represents the IP10 concentration. Calculate the IP10 concentration corresponding to each OD450 value. The final concentration is 100X (pg/ml). IFN-a-stimulated wells treated with DMSO serve as positive controls, while unstimulated wells treated with DMSO serve as negative controls. The inhibition rate is: (positive control well - test compound) / (positive control well - negative control well) * 100%.

使用Graphpad软件根据化合物个浓度点与相应的抑制率绘制抑制曲线，并计算抑制率为50％时的化合物浓度即IC50值。Graphpad software was used to draw an inhibition curve based on the compound concentration points and the corresponding inhibition rate, and the compound concentration at which the inhibition rate was 50%, i.e., the IC 50 value, was calculated.

表3本公开化合物抑制IFNα诱导人全血产生IP10的IC50值
Table 3 IC50 values of the disclosed compounds for inhibiting IFNα-induced IP10 production in human whole blood

结论：本公开化合物对IFNα诱导人全血产生IP10具有明显的抑制活性。Conclusion: The disclosed compounds have significant inhibitory activity on IFNα-induced IP10 production in human whole blood.

测试例4.本公开化合物在OCI-LY3人弥漫大B细胞淋巴瘤细胞内对TYK2的降解活性。Test Example 4. Degradation activity of the disclosed compounds on TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.

TYK2定位于细胞质内，参与多种细胞因子的信号传导。OCI-LY3是一种人弥漫大B细胞淋巴瘤细胞，其TYK2的表达量较高，且TYK2在该细胞内参与IL-10等细胞因子的信号传导。本实验是通过超敏电化学发光技术(Meso Scale Discovery,MSD)检测经化合物处理的细胞内TYK2的降解率，从而评估化合物对胞内TYK2的降解活性。将细胞用培养基(RPMI1640，美仑PWL015；含20％ FBS，Gibco10091-14；含55μM巯基乙醇，Gibco 31350010)配制为细胞密度为5E5/mL的细胞悬液，以每孔196μL体积加入到96孔细胞培养板(Corning,3599)中。于37度、5％CO2细胞培养箱中进行孵育。之后，将含4倍浓度梯度稀释的化合物的细胞培养基以4μL每孔加入实验孔中，或将含DMSO(终浓度0.1％)的培养基以4μL每孔加入阳性及阴性对照孔中。将细胞培养板以300rpm振荡5分钟混匀，于37度、5％CO2细胞培养箱中孵育24小时。将孵育后的细胞培养板以400g离心5分钟，弃掉上清得到细胞沉淀，再每孔加入45μL 1x lysis buffer(revvity，ALSU-LB-100ML)，常温振荡5分钟再超声裂解5分钟，最后以2000g离心5分钟，收集上清即为细胞裂解样品。MSD 96孔板(MSD，L15XA-6)提前一天每孔加入50μL含1μg/mL TYK2抗体(Santa Cruz，sc-5271)的PBS缓冲液，在4度过夜包被。MSD实验时弃去包被液，每孔加入150μL含5％ BSA的磷酸盐缓冲液封闭1小时。用PBS+0.05％Tween20洗涤液洗板3次，每孔中加入25μL细胞裂解样品或TYK2标准品(BPS Bioscience，100400)，以500rpm振荡孵育1.5小时。弃去样品后洗板3次。加入25μL含0.75μg/mL TYK2抗体(CST，9312)磷酸盐缓冲液，以500rpm振荡孵育1小时。弃去一抗后洗板3次。加入25μL含1μg/mL SULFO-TAG标记抗兔二抗(MSD，R32AB-1)的缓冲液，以500rpm振荡避光孵育1小时。弃去二抗后洗板3次，每孔加入150μL 1x MSD Read buffer(MSD,R92TC-2)，用MESO SECTOR S600读信号值。计算实验孔读数相对于DMSO对照孔读数的变化率为降解率，再用Graphpad Prism软件根据化合物各浓度与相应的降解率绘出降解曲线，并计算降解率达到50％时化合物的浓度，即DC50值。TYK2 is localized in the cytoplasm and participates in the signaling of multiple cytokines. OCI-LY3 cells are a human diffuse large B-cell lymphoma cell line that expresses high levels of TYK2, which is involved in the signaling of cytokines such as IL-10. In this experiment, the degradation rate of TYK2 in compound-treated cells was measured using ultrasensitive electrochemiluminescence (Meso Scale Discovery, MSD) to assess the compound's activity against intracellular TYK2. Cells were suspended at a density of 5E5/mL in RPMI 1640 medium (Mei Lun PWL015; containing 20% FBS, Gibco 10091-14; containing 55 μM mercaptoethanol, Gibco 31350010) and plated into 96-well cell culture plates (Corning, 3599) at a volume of 196 μL per well. The cells were incubated at 37°C in a 5% CO2 incubator. Afterwards, 4 μL of cell culture medium containing a 4-fold serial dilution of the compound was added to the experimental wells, or 4 μL of culture medium containing DMSO (final concentration 0.1%) was added to the positive and negative control wells. The cell culture plates were shaken at 300 rpm for 5 minutes to mix thoroughly and incubated in a 37°C, 5% CO2 incubator for 24 hours. After incubation, the plates were centrifuged at 400 g for 5 minutes, and the supernatant was discarded to obtain a cell pellet. 45 μL of 1x lysis buffer (revvity, ALSU-LB-100ML) was added to each well, shaken at room temperature for 5 minutes, and then sonicated for 5 minutes. Finally, the plates were centrifuged at 2000 g for 5 minutes, and the supernatant was collected as the cell lysate sample. MSD 96-well plates (MSD, L15XA-6) were coated overnight at 4°C with 50 μL of 1 μg/mL TYK2 antibody (Santa Cruz, sc-5271) in PBS buffer added to each well. For MSD experiments, the coating solution was discarded and 150 μL of phosphate-buffered saline (PBS) containing 5% BSA was added to each well for blocking for 1 hour. The plate was washed three times with PBS + 0.05% Tween 20. 25 μL of cell lysate sample or TYK2 standard (BPS Bioscience, 100400) was added to each well and incubated at 500 rpm for 1.5 hours. The sample was discarded and the plate was washed three times. 25 μL of phosphate-buffered saline containing 0.75 μg/mL TYK2 antibody (CST, 9312) was added and incubated at 500 rpm for 1 hour. The primary antibody was discarded and the plate was washed three times. 25 μL of buffer containing 1 μg/mL SULFO-TAG-labeled anti-rabbit secondary antibody (MSD, R32AB-1) was added and incubated at 500 rpm for 1 hour in the dark. After discarding the secondary antibody, wash the plate three times. Add 150 μL of 1x MSD Read Buffer (MSD, R92TC-2) to each well, and read the signal using a MESO SECTOR S600. Calculate the degradation rate by calculating the change in the reading of the experimental well relative to the reading of the DMSO control well. Use Graphpad Prism software to plot degradation curves based on compound concentrations and corresponding degradation rates. Calculate the compound concentration at which the degradation rate reaches 50%, the DC50 value.

表4本公开化合物在OCI-LY3人弥漫大B细胞淋巴瘤细胞内降解TYK2的DC50值
Table 4 DC50 values of the disclosed compounds in degrading TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells

结论：本公开化合物对OCI-LY3人弥漫大B细胞淋巴瘤细胞内TYK2具有明显的降解活性。Conclusion: The disclosed compounds have significant degradation activity against TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.

测试例5：本公开化合物对IFNα诱导的人T淋巴细胞中pSTAT3 ELISA实验Test Example 5: ELISA experiment on the effects of the disclosed compounds on pSTAT3 in human T lymphocytes induced by IFNα

用含有10％灭活FBS的RPMI 1640完全生长培养基复苏冻存的人的PBMC。依据T细胞分选试剂盒分选出PBMC中的T细胞，过夜培养。将过夜培养T细胞以1×105/孔接种在96孔板中。用系列稀释的化合物处理细胞，在37℃&5％ CO2培养箱中培养1小时。加入终浓度为200ng/mL IFNα，在37℃&5％ CO2培养箱中培养30分钟。然后将处理后的细胞裂解，并根据制造商的说明通过Elisa试剂盒测量细胞磷酸化STAT3的水平。通过与IFNα/DMSO对照孔进行0％抑制和与非刺激对照孔进行100％抑制进行比较，计算抑制数据。然后生成剂量反应曲线，以确定抑制50％细胞反应(IC50)所需的浓度，该浓度是使用GraphPad Prism通过非线性回归分析得出的。Cryopreserved human PBMCs were revived in RPMI 1640 complete growth medium containing 10% inactivated FBS. T cells were isolated from the PBMCs using a T cell isolation kit and cultured overnight. Overnight cultured T cells were seeded into 96-well plates at 1×10 5 /well. Cells were treated with serial dilutions of the compound and incubated in a 37°C & 5% CO 2 incubator for 1 hour. IFNα was added at a final concentration of 200 ng/mL and incubated in a 37°C & 5% CO 2 incubator for 30 minutes. The treated cells were then lysed, and the level of cellular phosphorylated STAT3 was measured using an ELISA kit according to the manufacturer's instructions. Inhibition data were calculated by comparing 0% inhibition with IFNα/DMSO control wells and 100% inhibition with non-stimulated control wells. Dose-response curves were then generated to determine the concentration required to inhibit the cellular response by 50% (IC 50 ), which was determined by nonlinear regression analysis using GraphPad Prism.

结论：本公开的化合物对人T淋巴细胞中TYK2介导的、IFNα诱导的STAT3磷酸化具有抑制作用。Conclusion: The compounds disclosed herein have an inhibitory effect on TYK2-mediated and IFNα-induced STAT3 phosphorylation in human T lymphocytes.

测试例6：本公开化合物对IL-12/IL-18诱导人PBMC细胞产生IFN-γ的抑制效应Test Example 6: Inhibitory effect of the disclosed compounds on IL-12/IL-18-induced IFN-γ production in human PBMC cells

将新鲜PBMC细胞离心(300g/min，10min)弃上清，加入新鲜培养基重悬细胞沉淀，计数。配制细胞密度为6.66E5/ml细胞悬液，混匀。以每孔150ul体积加入到96孔圆底板中。于37度培养箱放置。用DMSO将化合物配置成浓度为20mM储存液，然后在96孔圆底板中进行10倍稀释，至首浓度为2mM，再用DMSO依次进行4倍稀释，共9个浓度点，DMSO空白孔作为空白对照。将上述所得化合物DMSO溶液再进行25倍稀释：即6ul DMSO化合物溶液加入到144ul新鲜培养基中，于振板仪上进行振荡10min混匀。以25ul/孔加入到细胞板中，上下复孔，DMSO终浓度为0.5％，于37度培养箱进行孵育30min。将IL-12原液(200ug/ml)稀释12500倍，IL-18原液(100ug/ml)稀释1250倍，以1:1体积比混匀。以每孔25ul体积加入到细胞中，IL-12的终浓度为1ng/ml,IL-18的终浓度为5ng/ml。空白培养基作为阴性对照。于37度培养箱孵育24h左右。24h后收取上清：将细胞板从37度培养箱中取出，2000rpm/min离心5min,每孔取出100ul上清转移至新的96孔圆底板中，ELISA试剂盒检测IFN-γ。Fresh PBMC cells were centrifuged (300g/min, 10min), the supernatant was discarded, and fresh culture medium was added to resuspend the cell pellet and counted. A cell suspension with a cell density of 6.66E5/ml was prepared and mixed. 150ul of the cell suspension was added to each well of a 96-well round-bottom plate. The cells were placed in a 37-degree incubator. The compound was prepared with DMSO to a 20mM stock solution, and then diluted 10-fold in a 96-well round-bottom plate to a first concentration of 2mM. The compound was then diluted 4-fold with DMSO in sequence, for a total of 9 concentration points. The DMSO blank wells were used as blank controls. The DMSO solution of the compound obtained above was further diluted 25-fold: 6ul of the DMSO compound solution was added to 144ul of fresh culture medium and shaken on a plate shaker for 10 minutes to mix. 25ul/well was added to the cell plate, repeated up and down, with a final DMSO concentration of 0.5%, and incubated in a 37-degree incubator for 30 minutes. Dilute the IL-12 stock solution (200 μg/ml) 12,500-fold and the IL-18 stock solution (100 μg/ml) 1250-fold, and mix them in a 1:1 volume ratio. Add 25 μl per well to the cells, for a final concentration of 1 ng/ml for IL-12 and 5 ng/ml for IL-18. Use blank culture medium as a negative control. Incubate in a 37°C incubator for approximately 24 hours. After 24 hours, collect the supernatant: remove the cell plate from the 37°C incubator, centrifuge at 2,000 rpm/min for 5 minutes, remove 100 μl of supernatant from each well, transfer it to a new 96-well round-bottom plate, and detect IFN-γ using an ELISA kit.

将IL-12/IL-18刺激+DMSO处理孔作为阳性对照孔，未刺激+DMSO处理孔作为阴性对照孔。抑制率为:(阳性对照孔-待测化合物)/(阳性对照孔-阴性对照孔)*100％。使用Graphpad软件根据化合物各浓度点与相应的抑制率绘制抑制曲线，并计算抑制率为50％时的化合物浓度即IC50值。IL-12/IL-18-stimulated wells treated with DMSO served as positive controls, while unstimulated wells treated with DMSO served as negative controls. The inhibition rate was calculated as: (positive control well - test compound) / (positive control well - negative control well) * 100%. Inhibition curves were plotted using GraphPad software based on the compound concentrations and the corresponding inhibition rates. The compound concentration that achieved 50% inhibition ( IC50 ) was calculated.

结论：本公开化合物对IL-12/IL-18诱导的IFN-γ具有良好的抑制活性。Conclusion: The disclosed compounds have good inhibitory activity against IFN-γ induced by IL-12/IL-18.

Claims (10)

一种通式(I)所示的化合物，或其可药用的盐：
A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:
其中：in: G1选自N、NR0、O、S和CR’；G 1 is selected from N, NR 0 , O, S and CR′; G2为N或C；G 2 is N or C; G3为N或C；G 3 is N or C; Z1选自C(O)NR1R2、C(O)NR1aOR2、C(O)NR1aNR1R2、NR1aC(O)NR1R2、C(O)C(O)NR1R2、C(O)R2、C(＝NR1a)NR1R2、S(O)rR2、S(＝NR1a)R2和S(＝NR1a)(O)R2；Z 1 is selected from C(O)NR 1 R 2 , C(O)NR 1a OR 2 , C(O)NR 1a NR 1 R 2 , NR 1a C(O)NR 1 R 2 , C(O)C(O)NR 1 R 2 , C(O)R 2 , C(=NR 1a )NR 1 R 2 , S(O) r R 2 , S(=NR 1a )R 2 and S(=NR 1a )(O)R 2 ; R4、R5、R0和R1a相同或不同，且各自独立地选自氢原子、烷基、烷氧基、羟基、OR12、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；R 4 , R 5 , R 0 and R 1a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, OR 12 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 01 ; R1和R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、OR12、NR10R11、C(O)NR10R11、NR13C(O)R12、C(O)R12、C(O)OR12、OC(O)R12、S(O)rR12、S(O)rNR10R11、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；或R1、R2及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R01所取代； R1 and R2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, OR12 , NR10R11 , C(O) NR10R11 , NR13C (O) R12 , C(O) R12 , C(O) OR12 , OC ( O) R12 , S( O ) rR12 , S(O) rNR10R11 , a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group; and the alkyl group , alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group are each independently optionally substituted with one or more R01 ; or R1 , R 2 and the nitrogen atom to which it is attached together form a heterocyclic group, and the heterocyclic group is optionally substituted by one or more R 01 ; R10、R11、R12和R13相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR21R22、C(O)NR21R22、NR23C(O)R24、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rNR21R22、OR24、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；R 10 , R 11 , R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , C(O)R 24 , C(O)OR 24 , OC(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 01 ; 或R10、R11及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R01所取代；or R 10 , R 11 and the nitrogen atom to which they are attached together form a heterocyclic group, and the heterocyclic group is optionally substituted by one or more R 01 ; R3、R6和R’相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烯基、炔基、氰基、硝基、NR21R22、C(O)NR21R22、C(O)R24、C(O)OR24、S(O)rR24、S(O)rNR21R22、OR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；R 3 , R 6 and R 'are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O) OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(＝NR 23 )(O)R 24 , P(O)R 21 R 22 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally replaced by one or more R 02 replaced; L1、L3、L4、L5和L6相同或不同，且各自独立地选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、C(O)-杂环基、杂环基-C(O)、C(O)N(RL)、N(RL)C(O)、S(O)r、S(O)rN(RL)、N(RL)S(O)r、N(RL)、S(＝NR23)、S(＝NR23)(O)、亚烷基、烯基、炔基、环烷基、杂环基、亚烷基-杂环基、杂环基-亚烷基、杂环基-杂环基、芳基和杂芳基；所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；L 1 , L 3 , L 4 , L 5 and L 6 are the same or different and are each independently selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C( O ), C(O)N( RL ), N(RL)C(O), S(O)r , S( O ) rN ( RL ), N(RL)S(O)r, N( RL ), S(═NR 23 ), S(═NR 23 )(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl and heteroaryl; said alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R 03 ; L2选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、C(O)-杂环基、杂环基-C(O)、亚烷基、烯基、炔基、环烷基、杂环基、亚烷基-杂环基、杂环基-亚烷基、杂环基-杂环基、芳基、杂芳基和环B-Z2-环B1；所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环B1和环B各自独立地任选被一个或多个R03所取代；L 2 is selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, heteroaryl and ring BZ 2 -ring B1; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring B1 and ring B are each independently optionally substituted with one or more R 03 ; 环B1选自环烷基、杂环基、芳基和杂芳基；Ring B1 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; 环B选自环烷基、杂环基、芳基和杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Z2选自键、O、S、O-亚烷基、亚烷基-O、C(O)、C(O)-亚烷基、亚烷基-C(O)、亚烷基、N(RL)、S(O)r、S(＝NR23)、S(＝NR23)(O)、环烷基、杂环基、芳基和杂芳基；所述亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代； Z2 is selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), alkylene, N( RL ), S(O) r , S(= NR23 ), S(= NR23 )(O), cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R03 ; 各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR21R22、C(O)NR21R22、NR23C(O)R24、NR23C(O)NR21R22、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、S(O)rNR21R22、NR23S(O)rR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、OR24、＝CR15R16、＝NR23、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；Each of R 01 , R 02 , R 03 and R 04 is the same or different and is each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , NR 23 C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , OC(O)R 24 , S(O) r R 24 , S(O) r OR 24 , S(O) r NR 21 R 22 , NR 23 S(O) r R 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(═NR 23 )(O)R 24 , P(O)R 21 R 22 , OR 24 , ═CR 15 R 16 , ═NR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R * ; 或两个R03及与其相连的原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；or two R 03 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more R * ; R15和R16相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR21R22、C(O)NR21R22、C(O)R24、S(O)rR24、S(O)rNR21R22、OR24、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；或R15、R16及与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基和杂环基各自独立地任选被一个或多个R*所取代；R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, NR 21 R 22 , C(O)NR 21 R 22 , C(O) R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R * ; or R 15 , R 16 and the carbon atom to which they are attached together form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more R * ; R21、R22、R23、R24和RL相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR30R31、C(O)NR30R31、NR33C(O)R32、C(O)R32、C(O)OR32、OC(O)R32、OR32、S(O)rR32、S(O)rNR30R31、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；R 21 , R 22 , R 23 , R 24 and RL are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 30 R 31 , C(O)NR 30 R 31 , NR 33 C(O)R 32 , C(O)R 32 , C(O)OR 32 , OC(O)R 32 , OR 32 , S(O) r R 32 , S(O) r NR 30 R 31 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted with one or more R * ; R30、R31、R32和R33相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；R 30 , R 31 , R 32 and R 33 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group and a heteroaryl group; E选自：
E is selected from:
为单键或者双键； is a single bond or a double bond; Q1、Q2、Q3、Q4和Q5中的一者为碳原子且与L6连接，其它各自独立地选自N、CH和CRq；One of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is a carbon atom and is connected to L 6 , and the others are each independently selected from N, CH and CR q ; 各个Rq相同或不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR21R22、C(O)NR21R22、C(O)R24、C(O)OR24、S(O)rR24、S(O)rNR21R22、OR24、C(＝NR23)R24、S(＝NR23)R24、S(＝NR23)(O)R24、P(O)R21R22、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；each R q is the same or different and is independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(＝NR 23 )R 24 , S(＝NR 23 )R 24 , S(＝NR 23 )(O)R 24 , P(O)R 21 R 22 , cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 04 ; 或两个Rq及与其相连的碳原子一起形成环烷基或杂环基，所述环烷基和杂环基各自独立地任选被一个或多个R04所取代；or two R q together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 04 ; R7和R8相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基和杂环基，所述烷基、烷氧基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more R * ; Y1为N或CRY1； Y1 is N or CR Y1 ; Y2为CRY2RY4或C(O)； Y2 is CR Y2 R Y4 or C(O); Y3为N或CRY3； Y3 is N or CR Y3 ; RY1、RY2、RY3和RY4相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、环烷基和杂环基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；R Y1 , R Y2 , R Y3 and R Y4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group and a heterocyclic group; the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted with one or more R * ; 或，RY2、RY4及与其相连的碳原子一起形成环烷基或杂环基；所述的环烷基和杂环基各自独立地任选被一个或多个R*所取代；Or, RY2 , RY4 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * ; 各个R*相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、烷硫基、氨基、-NH烷基、-N(烷基)2、-亚烷基-氨基、-亚烷基-NH烷基、-亚烷基-N(烷基)2、酰胺基、硝基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基；each R * is the same or different and is independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, alkylthio, amino, -NHalkyl, -N(alkyl) 2 , -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl) 2 , amido, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl; 各个r相同或不同，且各自独立地为0、1或2。Each r is the same or different and is independently 0, 1 or 2. 根据权利要求1所述的化合物，或其可药用的盐，其为通式(V)、(V-1)或(V-2)所示的化合物，或其可药用的盐：

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt thereof:

其中，s为0、1、2或3；Where s is 0, 1, 2 or 3; L1至L6、R1a、R1至R7和Rq如权利要求1中所定义。L 1 to L 6 , R 1a , R 1 to R 7 and R q are as defined in claim 1 . 根据权利要求1或2所述的化合物，或其可药用的盐，其中：R1为氢原子或C1-6烷基，R2选自氢原子、C1-6烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被一个或多个R01所取代，或R1、R2及与其相连的氮原子一起形成3至6元杂环基，所述3至6元杂环基任选被一个或多个R01所取代；R01如权利要求1中所定义；和/或L1为键或NH；The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl group and the 3- to 6-membered heterocyclic group are each independently optionally substituted by one or more R 01 , or R 1 , R 2 , and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 01 ; R 01 is as defined in claim 1; and/or L 1 is a bond or NH; 和/或L2选自 优选u为1、2、3或4；Q和L相同或不同，且各自独立地选自键、(CRgRh)q、(CRgRh)qO、O(CRgRh)q、NRi、O和S；Rg和Rh相同或不同，且各自独立地为氢原子或R03，Ri为氢原子或烷基；n为0、1、2或3；b为0、1、2或3；a为0、1或2；q为0、1或2；R03如权利要求1中所定义；and/or L 2 is selected from Preferred u is 1, 2, 3 or 4; Q and L are the same or different and are each independently selected from a bond , ( CRgRh ) q , ( CRgRh ) qO , O ( CRgRh ) q , NRi , O and S; Rg and Rh are the same or different and are each independently a hydrogen atom or R03 , Ri is a hydrogen atom or an alkyl group; n is 0, 1, 2 or 3; b is 0, 1, 2 or 3; a is 0, 1 or 2; q is 0, 1 or 2; R03 is as defined in claim 1; 和/或L6-L5-L4-L3为U选自N、CH和CR03，V选自N、CH和CR03；c为0、1或2；d为0、1或2；e为0、1或2；f为1或2；v为0、1、2、3或4，p为0、1、2、3或4；R03如权利要求1中所定义；和/或各个Rq相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；和/或and/or L 6 -L 5 -L 4 -L 3 is U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4; R 03 is as defined in claim 1; and/or each R q is the same or different and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; and/or R3为氢原子，和/或R6为氢原子，和/或R4为氢原子，和/或R5为C1-6烷基。R 3 is a hydrogen atom, and/or R 6 is a hydrogen atom, and/or R 4 is a hydrogen atom, and/or R 5 is a C 1-6 alkyl group. 根据权利要求1至3中任一项所述的化合物，或其可药用的盐，其选自以下任一化合物：
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:
一种通式(IA)所示的化合物，或其盐：
A compound represented by general formula (IA), or a salt thereof:
其中，RP为氨基保护基，优选PMB；Wherein, R P is an amino protecting group, preferably PMB; Z1、G1、G2、G3、L1至L6、E、R3、R5和R6如权利要求1中所定义。Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in claim 1 . 化合物，或其盐，其选自以下任一结构：

A compound, or a salt thereof, selected from any of the following structures:

一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising:
通式(IA)所示的化合物或其盐发生脱保护反应得到通式(I)所示的化合物或其可药用的盐；The compound represented by the general formula (IA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; 其中，RP为氨基保护基，优选PMB；R4为氢原子；Wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom; Z1、G1、G2、G3、L1至L6、E、R3、R5和R6如权利要求1中所定义。Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in claim 1 . 一种药物组合物，所述药物组合物含有根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求8所述的药物组合物在制备TYK2抑制剂和/或降解剂的用途。Use of the compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a TYK2 inhibitor and/or degrader. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防自身免疫性疾病、炎性疾病和癌症的药物中的用途；优选在制备用于治疗和/或预防银屑病、狼疮、炎症性肠病、多发性硬化症、类风湿性关节炎、克罗恩病、斑块状银屑病、银屑病性关节炎、掌跖脓疱病、干燥综合征、溃疡性结肠炎、斑秃、化脓性汗腺炎、免疫紊乱、后葡萄膜炎、全葡萄膜炎、皮肌炎、瘢痕性脱发和哮喘的药物中的用途。Use of a compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating and/or preventing autoimmune diseases, inflammatory diseases and cancer; preferably in the preparation of a medicament for treating and/or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma.
PCT/CN2025/088477 2024-04-12 2025-04-11 Amino-substituted heteroaromatic cyclic compound, preparation method therefor and use thereof in medicine Pending WO2025214467A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111194317A (en) * 2017-07-28 2020-05-22 林伯士拉克许米公司 TYK2 inhibitor and application thereof
CN113677347A (en) * 2019-02-07 2021-11-19 温缇克斯生物科学公司 TYK2 pseudokinase ligands
WO2023076161A1 (en) * 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
CN118359618A (en) * 2023-01-17 2024-07-19 江苏恒瑞医药股份有限公司 Hydrazide substituted condensed heteroaryl compounds, preparation method and application thereof in medicine
CN118515674A (en) * 2023-02-17 2024-08-20 江苏恒瑞医药股份有限公司 Amide compound, preparation method thereof and application thereof in medicine
CN118684675A (en) * 2023-03-23 2024-09-24 江苏恒瑞医药股份有限公司 Amide substituted pyrazoloheteroaryl compounds, preparation methods thereof and their use in medicine
WO2024220937A2 (en) * 2023-04-21 2024-10-24 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111194317A (en) * 2017-07-28 2020-05-22 林伯士拉克许米公司 TYK2 inhibitor and application thereof
CN113677347A (en) * 2019-02-07 2021-11-19 温缇克斯生物科学公司 TYK2 pseudokinase ligands
WO2023076161A1 (en) * 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
CN118359618A (en) * 2023-01-17 2024-07-19 江苏恒瑞医药股份有限公司 Hydrazide substituted condensed heteroaryl compounds, preparation method and application thereof in medicine
CN118515674A (en) * 2023-02-17 2024-08-20 江苏恒瑞医药股份有限公司 Amide compound, preparation method thereof and application thereof in medicine
CN118684675A (en) * 2023-03-23 2024-09-24 江苏恒瑞医药股份有限公司 Amide substituted pyrazoloheteroaryl compounds, preparation methods thereof and their use in medicine
WO2024220937A2 (en) * 2023-04-21 2024-10-24 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

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