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WO2022247920A1 - 喹啉胺类化合物、其制备方法及其在医药上的应用 - Google Patents

喹啉胺类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2022247920A1
WO2022247920A1 PCT/CN2022/095441 CN2022095441W WO2022247920A1 WO 2022247920 A1 WO2022247920 A1 WO 2022247920A1 CN 2022095441 W CN2022095441 W CN 2022095441W WO 2022247920 A1 WO2022247920 A1 WO 2022247920A1
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general formula
alkyl
pharmaceutically acceptable
group
compound
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PCT/CN2022/095441
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English (en)
French (fr)
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WO2022247920A9 (zh
Inventor
杨方龙
贾敏强
汤焕宇
阙永雷
贺峰
陶维康
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN202280030768.6A priority Critical patent/CN117222639A/zh
Priority to MX2023013972A priority patent/MX2023013972A/es
Priority to CA3219657A priority patent/CA3219657A1/en
Priority to US18/564,512 priority patent/US20240327388A1/en
Priority to AU2022283404A priority patent/AU2022283404A1/en
Priority to KR1020237043944A priority patent/KR20240014059A/ko
Priority to JP2023572661A priority patent/JP2024519993A/ja
Priority to BR112023024741A priority patent/BR112023024741A2/pt
Priority to EP22810644.9A priority patent/EP4349831A4/en
Publication of WO2022247920A1 publication Critical patent/WO2022247920A1/zh
Publication of WO2022247920A9 publication Critical patent/WO2022247920A9/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the disclosure belongs to the field of medicine, and relates to a quinoline amine compound, its preparation method and its application in medicine.
  • the present disclosure relates to quinoline amine compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, especially as miRNA modulators and in Use in the manufacture of a medicament for treating a disease or condition improved by modulating miRNA levels.
  • MicroRNA is a class of non-coding single-stranded RNA molecules encoded by endogenous genes with a length of about 22 nucleotides. They participate in post-transcriptional gene expression regulation in animals and plants. Each miRNA can have multiple target genes, and several miRNAs can also regulate the same gene. This complex network can be used to precisely regulate target genes. miR-124 is widely expressed in various tissues throughout the body, especially highly expressed in brain tissues. Studies have shown that overexpression of miR-124 can promote the quiescent transition of activated macrophage-microglia, thereby suppressing the autoimmune disease encephalomyelitis (Ponomarev ED et al., Nat Med, 2011; 17:67-70).
  • miR-124 can promote the transformation of macrophages to M2 type, thereby exerting anti-inflammatory effects (Veremeyko T, et.al, Plos One, 2013; 8:e81774). miR-124 also affected T cell differentiation, and the levels of IFN- ⁇ and TNF ⁇ in miR-124-treated T cells were decreased. Overexpression of miR-124 reduces the expression of inflammatory cytokine IL-17 by down-regulating STAT3 protein, and inhibits the differentiation of Th17 cells to play an anti-inflammatory effect (Wei J et.al, Cancer Res, 2013; 73:3913-3926).
  • Inflammation is a protective response of the immune system to local infection or tissue damage, and severe inflammatory responses can damage the body.
  • the general manifestations of an inflammatory response are pain, heat, redness, swelling, and loss of function.
  • Inflammatory diseases encompass a variety of conditions and include inflammatory diseases related to autoimmunity, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the digestive tract, and inflammatory diseases in the skin disease etc.
  • Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are two of the most common inflammatory diseases that have received widespread attention.
  • IBD ulcerative colitis
  • CD Crohn's disease
  • IBD Crohn's disease
  • IBD IBD is usually manifested by an excess of immune cells invading the intestinal mucosa, an imbalance of T cell subsets including Th17, Th1, and Treg, and hyperactivated macrophages and dendritic cells.
  • Drugs currently on the market or in clinical trials include JAK inhibitors and TNF ⁇ antibodies that reduce inflammation, IL-12 and IL-23 antibodies that inhibit Th1 and Th17 differentiation, and integrin ⁇ 4 ⁇ 7 antibodies that block inflammatory cell infiltration.
  • Rheumatoid arthritis is a systemic inflammatory disease affecting the lining of the joints (called the synovium) and is characterized by polyarticular, symmetrical, aggressive joint inflammation of the small joints of the hands and feet, often with joint External organ involvement can lead to joint deformity and loss of function.
  • Inflammatory cytokines like tumor necrosis factor TNF ⁇ , interleukins IL-1 and IL-6 play an important role in the pathogenesis of rheumatoid arthritis (RA).
  • Treatment is usually with disease-modifying antirheumatic drugs (DMARDs) or biological drugs such as TNF ⁇ inhibitors.
  • DMARDs disease-modifying antirheumatic drugs
  • TNF ⁇ inhibitors biological drugs
  • Ring A is cycloalkyl or heterocyclyl
  • G is N atom or CR 2a ;
  • Each R is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, oxo, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, alkenyl , alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , ring Alkyl, heterocyclyl, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl, and heteroary
  • Each R is the same or different, and is independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;
  • Each R is the same or different and is independently selected from halogen, hydroxy, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of halogen, hydroxyl, Carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano are substituted by one or more of the same or different substituents;
  • R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; wherein said alkyl group, cycloalkyl group and heterocyclic group are each independently selected from halogen, hydroxyl, carboxyl, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, nitro, amino and cyano are substituted by one or more of the same or different substituents;
  • R 5 and R 6 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group and a heterocyclic group;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group and a heterocyclic group;
  • R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group and a heterocyclic group;
  • R 2a is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • p 1, 2, 3 or 4;
  • q 0, 1, 2 or 3.
  • Ring A is cycloalkyl or heterocyclyl
  • G is N atom or CR 2a ;
  • Each R is the same or different, and each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, oxo, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl , hydroxyl, cyano, nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , cycloalkyl, Heterocyclyl, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently Optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl
  • Each R is the same or different, and is independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;
  • Each R is the same or different and is independently selected from halogen, hydroxy, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of halogen, hydroxyl, Carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano are substituted by one or more of the same or different substituents;
  • R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; wherein said alkyl group, cycloalkyl group and heterocyclic group are each independently selected from halogen, hydroxyl, carboxyl, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, nitro, amino and cyano are substituted by one or more of the same or different substituents;
  • R 5 and R 6 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group and a heterocyclic group;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group and a heterocyclic group;
  • R 9 and R 10 are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group and a heterocyclic group;
  • R 2a is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • p 1, 2, 3 or 4;
  • q 0, 1, 2 or 3.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IC) or a pharmaceutically acceptable salt thereof:
  • Rings A, G, R 1 to R 3 , n, m and p are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (IC) or a pharmaceutically acceptable salt thereof wherein not for
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-1) or general formula (I-2) or its pharmaceutically acceptable salts:
  • Rings A, G, R 1 to R 3 , n, m and p are as defined in the general formula (I).
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-3) or general formula (I-4) or its pharmaceutically acceptable salts:
  • Ring B is cycloalkyl or heterocyclyl; wherein said cycloalkyl or heterocyclyl are each independently selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, One or more of the same or different substituents in hydroxyalkyl and cyano;
  • each R 3a is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano;
  • r 0, 1 or 2;
  • Rings A, G, R 1 , R 2 , R 4 , n and m are as defined in general formula (I).
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-3C) or general formula (I-4C) or its pharmaceutically acceptable salts:
  • Ring A, ring B, G, R 1 , R 2 , R 3a , n, r and m are as defined in general formula (I-3) or general formula (I-4).
  • the compound represented by general formula (I-3), general formula (I-3C), general formula (I-4) or general formula (I-4C) or its A pharmaceutically acceptable salt wherein ring B is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group; preferably, ring B is 5 or 6 membered cycloalkyl or 5 or 6 membered heterocyclic group; more preferably , Ring B is cyclopentyl.
  • each R 1 is the same or different, and each independently selected from a hydrogen atom , deuterium atom, halogen, -C(O)R 8 , C 1-6 alkyl, C 1-6 alkoxy and oxo; preferably selected from hydrogen atom, deuterium atom, halogen, -C(O)R 8 and C 1-6 alkyl; R 8 is as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), A compound represented by general formula (I-4), general formula (I-4C) or general formula (IC) or a pharmaceutically acceptable salt thereof wherein: R is selected from hydrogen atom, C 1-6 alkyl and halogen Substitute C 1-6 alkyl; preferably, R 8 is C 1-6 alkyl; more preferably, R 8 is methyl.
  • 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:
  • G 1 , G 2 and G 3 are the same or different, and each independently selected from O atom, S atom, NR 1a and CR 1b R 1c ;
  • R 1a is selected from hydrogen atom, alkyl, -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, One or more of the same or different substituents in cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1b and R 1c are the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxyl, Cyano, Nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , Cycloalkyl, Heterocyclyl , aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1b and R 1c together form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycl
  • G, R 2 to R 10 , m, p and q are as defined in the general formula (I).
  • G 1 , G 2 and G 3 are the same or different, and each independently selected from O atom, S atom, NR 1a and CR 1b R 1c ;
  • R 1a is selected from hydrogen atom, alkyl, -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, One or more of the same or different substituents in cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1b and R 1c are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxyl, cyano, Nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , Cycloalkyl, Heterocyclyl, Aryl Oxygen, heteroaryloxy, aryl and heteroaryl, or R 1b and R 1c together form oxo, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and The heteroaryl groups are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl,
  • G, R 2 to R 10 , m, p and q are as defined in the general formula (I).
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIC) or a pharmaceutically acceptable salt thereof Salt to use:
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (II).
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is general formula (IID-1) or (IID-2)
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein G 1 and G 2 are the same or different, and each independently selected from O atom, S atom, NR 1a and CR 1b R 1c ; G 3 is CR 1b R 1c ; R 1a , R 1b and R 1c are as in the general formula as defined in (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein G 1 is an O atom or NR 1a ; G 2 and G 3 are each independently CR 1b R 1c ; R 1a , R 1b and R 1c are as defined in the general formula (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein G 2 is an O atom or NR 1a ; G 1 and G 3 are each independently CR 1b R 1c ; R 1a , R 1b and R 1c are as defined in the general formula (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein G 1 and G 2 are both O atoms; G 3 is CR 1b R 1c ; R 1b and R 1c are as defined in the general formula (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are each independently CR 1b R 1c ; R 1b and R 1c are as defined in general formula (II).
  • the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof in for G 1 and G 2 are the same or different, and each independently selected from O atom, NR 1a and CR 1b R 1c , R 1a , R 1b and R 1c are as defined in general formula (II); preferably, selected from R 1a , R 1b and R 1c are as defined in general formula (II); more preferably, selected from
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:
  • L 1 , L 2 , L 3 and L 4 are the same or different, and each independently selected from O atom, S atom, NR 1d and CR 1e R 1f ;
  • R 1d is selected from hydrogen atom, alkyl, -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, One or more of the same or different substituents in cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1e and R 1f are the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxyl, Cyano, Nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , Cycloalkyl, Heterocyclyl , aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1e and R 1f together form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycl
  • G, R 2 to R 10 , m, p and q are as defined in the general formula (I).
  • L 1 , L 2 , L 3 and L 4 are the same or different, and each independently selected from O atom, S atom, NR 1d and CR 1e R 1f ;
  • R 1d is selected from hydrogen atom, alkyl, -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, One or more of the same or different substituents in cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1e and R 1f are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxyl, cyano, Nitro, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH 2 ) q NR 9 R 10 , Cycloalkyl, Heterocyclyl, Aryl Oxygen, heteroaryloxy, aryl and heteroaryl, or R 1e and R 1f together form an oxo group, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and The heteroaryl groups are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalky
  • G, R 2 to R 10 , m, p and q are as defined in the general formula (I).
  • the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof Salt to use:
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in the general formula (III).
  • the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof is general formula (IIID-1) or general formula (IIID- 2)
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 1 and L 2 are the same or different, and each independently selected from O atom, S atom, NR 1d and CR 1e R 1f ; L 3 and L 4 are each independently CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 1 is an O atom or NR 1d ; L 2 , L 3 and L 4 are each independently CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 2 is an O atom or NR 1d ; L 1 , L 3 and L 4 are each independently CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 3 is an O atom or NR 1d ; L 1 , L 2 and L 4 are each independently CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 4 is an O atom or NR 1d ; L 1 , L 2 and L 3 are each independently CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 1 and L 2 are both O atoms; L 3 and L 4 are each independently CR 1e R 1f ; R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof wherein L 1 , L 2 , L 3 and L 4 are each independently CR 1e R 1f ; R 1e and R 1f are as defined in general formula (III).
  • the compound represented by general formula (III), general formula (IIIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof in for L 1 and L 2 are the same or different, and each independently is an O atom or CR 1e R 1f , R 1e and R 1f are as defined in the general formula (III); preferably, for R 1e and R 1f are as defined in general formula (III); more preferably, selected from
  • each R 3a is the same or different, and each independently is halogen or C 1-6 alkyl; preferably, R 3a is halogen; more preferably, R 3a is Cl.
  • each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered Heterocyclyl and cyano; preferably, each R is the same or different, and each independently selected from Cl, Br, methyl, methoxy, cyano, cyclopropyl, tetrahydropyranyl and dihydropyryl More preferably, each R 3 is the same or different, and each independently selected from Cl, methyl, methoxy, cyano, cyclopropyl and t
  • the compound represented by general formula (I-3), general formula (I-4), general formula (I-3C) or general formula (I-4C) or its A pharmaceutically acceptable salt wherein each R 3a is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and cyano.
  • the cycloalkyl or heterocyclic groups are each independently optionally selected from one
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II-1) or Pharmaceutically acceptable salts:
  • G, R 3 , R 4 , G 1 , G 2 , R 1b and R 1c are as defined in the general formula (II).
  • the compound represented by general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof which is general formula (II- The compound shown in 1C) or a pharmaceutically acceptable salt thereof:
  • G, G 1 , G 2 , R 3 , R 1b and R 1c are as defined in the general formula (II-1);
  • the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or Pharmaceutically acceptable salts:
  • R 3 , R 4 , L 1 , L 2 , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by general formula (I), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof is general formula (III- The compound shown in 1C) or a pharmaceutically acceptable salt thereof:
  • G, L 1 , L 2 , R 3 , R 1e and R 1f are as defined in the general formula (III-1).
  • the compound represented by general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof wherein L 1 and L 2 are the same or different, and each independently selected from O atom, NR 1d and CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in general formula (III).
  • the compound represented by general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof wherein L 1 is an O atom or NR 1d ; L 2 is CR 1e R 1f ; or; L 2 is an O atom or NR 1d ; L 1 is CR 1e R 1f ; R 1d , R 1e and R 1f are as defined in the general formula (III).
  • the compound represented by the general formula (II-1), general formula (II-1C), general formula (III-1) or general formula (III-1C) or its A pharmaceutically acceptable salt wherein R 3 is halogen or C 1-6 alkyl; preferably, R 3 is halogen; more preferably Cl.
  • the general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID -1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C) The compound or pharmaceutically acceptable salt thereof, wherein R 1a or R 1d is selected from hydrogen atom, C 1-6 alkyl and -C(O)R 8 , R 8 is C 1-6 alkyl; preferably, R 1a and R 1d are the same or different, and are each independently methyl or acetyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 3 to 8 membered cycloalkyl group or a 3 to 8 membered heterocyclic group; G is N atom or CR 2a ; R 2a is selected from hydrogen atom, halogen and C 1-6 alkyl; each R 1 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, -C(O)R 8.
  • R 8 is C 1-6 alkyl, C 1-6 alkoxy and oxo;
  • R 8 is C 1-6 alkyl;
  • n is 0 (that is, R 1 is a hydrogen atom), 1, 2, 3 or 4 each R 2 is the same or different, and each independently selected from a hydrogen atom, halogen and C 1-6 alkyl;
  • m is 0 (that is, R 2 is a hydrogen atom), 1 or 2; each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and cyano;
  • p is 1, 2 or 3;
  • R 4 is a hydrogen atom or a 3- to 8-membered heterocyclic group, the The 3- to 8-membered heterocyclic group is substituted with one or more same or different substituents selected from hydroxyl and carboxyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclic group; G is CR 2a ; R 2a is a hydrogen atom; each R 1 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, -C(O)R 8 , C 1-6 alkyl and C 1-6 Alkoxy; R 8 is C 1-6 alkyl; n is 0 (that is, R 1 is a hydrogen atom), 1, 2, 3 or 4; each R 2 is a hydrogen atom; each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and cyano; p is 1, 2 or 3; R 4 is a hydrogen atom or a 3- to 8-membered heterocyclic group; wherein said The 3- to 8-membered
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein selected from R 1a is selected from hydrogen atom, C 1-6 alkyl and -C(O)R 8 , R 8 is C 1-6 alkyl; R 1b and R 1c are the same or different, and each independently selected from hydrogen atom, Deuterium atom, halogen and C 1-6 alkyl; G is N atom or CR 2a ; R 2a is hydrogen atom; m is 0; for R 3v is halogen, R 3w , R 3x and R 3y are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group, or R 3w , R 3x together with the attached carbon atoms form
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 1e and R 1f are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen and a C 1-6 alkyl group; G is a N atom or CR 2a ; R 2a is a hydrogen atom; m is 0; for R 3v is halogen, R 3w , R 3x and R 3y are the same or different, and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group; R 4 is a hydrogen atom or 3 to 8 membered heterocyclic group, the 3 to 8 membered heterocyclic group The group is substituted by one or more identical or different
  • the compound represented by general formula (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof wherein ring B is 3 to 8 membered cycloalkyl or 3 to 8-membered heterocyclyl; Ring A is 5 or 6-membered cycloalkyl or 5 or 6-membered heterocyclyl; G is CR 2a ; R 2a is a hydrogen atom; each R 1 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, -C(O)R 8 , C 1-6 alkyl and C 1-6 alkoxy; R 8 is C 1-6 alkyl; n is 0 (ie R 1 is a hydrogen atom), 1, 2, 3 or 4; R 2 is a hydrogen atom; each R 3a is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and cyano R is 0, 1 or 2; R is a hydrogen atom
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (I-1C) or (I-2C) or a salt thereof:
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IID-1A) or (IID-2A) or salts thereof:
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIID-1A) or (IIID-2A) or a salt thereof:
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).
  • said general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IID-1A) or (IID-2A) The compound or pharmaceutically acceptable salt thereof, wherein R is C 1-6 alkyl; preferably, R is methyl.
  • said general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IID-1A) or (IID-2A) The compound or pharmaceutically acceptable salt thereof, wherein R 11 is C 1-6 alkyl; preferably, R 11 is methyl.
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IC) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) or its salt reacts with the compound of general formula (IB) or its salt to obtain the compound of general formula (IC) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in general formula (IC).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-1C) or its salt undergoes an ester hydrolysis reaction to obtain the compound of general formula (I-1) or a pharmaceutically acceptable salt thereof;
  • R and R are as defined in general formula (I-1C);
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-2C) or its salt undergoes ester hydrolysis reaction to obtain the compound of general formula (I-2) or its pharmaceutically acceptable salt;
  • R and R are as defined in general formula (I-2C);
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-3) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-3C) or its pharmaceutically acceptable salt reacts with R 4' -Y compound, then removes the protecting group on R 4' , obtains the compound of general formula (I-3) or its pharmaceutically acceptable the salt used;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in the general formula (I-3).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-3C) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-3A) or its salt reacts with the compound of general formula (IB) or its salt to obtain the compound of general formula (I-3C) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in the general formula (I-3C).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-4) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in the general formula (I-4).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-4C) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-4A) or its salt reacts with the compound of general formula (IB) or its salt to obtain the compound of general formula (I-4C) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in the general formula (I-4C).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIC) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) or its salt reacts with the compound of general formula (IIB) or its salt to obtain the compound of general formula (IIC) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IIC).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IID-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IID-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound of general formula (IID-1) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (IID-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IID-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IID-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound of general formula (IID-2) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (IID-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , R 1b , R 1c and R 3 are as defined in the general formula (II-1); preferably, R 3 is halogen.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1C) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (II-1A) or its salt reacts with the compound of general formula (II-1B) or its salt to obtain the compound of general formula (II-1C) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, G 1 , G 2 , R 1b , R 1c and R 3 are as defined in the general formula (II-1C); preferably, R 3 is halogen.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) or its salt reacts with the compound of general formula (IIIB) or its salt to obtain the compound of general formula (IIIC) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIIC).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIID-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIID-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound of general formula (IIID-1) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIID-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIID-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound of general formula (IIID-2) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, L 1 , L 2 , R 1e , R 1f and R 3 are as defined in the general formula (III-1); preferably, R 3 is halogen.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1C) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (II-1A) or its salt reacts with the compound of general formula (III-1B) or its salt to obtain the compound of general formula (III-1C) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, L 1 , L 2 , R 1e , R 1f and R 3 are as defined in the general formula (III-1C); preferably, R 3 is halogen.
  • Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective amount of the general formula (I), general formula (IC), general formula (I-1), general formula (I- 2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula ( II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IID-2) , general formula (IIIC), general formula (III-1C), general formula (III-1) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluent or excipient.
  • a pharmaceutical composition which contains a therapeutically effective amount of the general formula (I), general formula (IC), general formula (I-1), general formula (I- 2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicine for regulating miRNA levels; preferably, the miRNA is miR-124.
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicine for treating a disease or condition improved by regulating miRNA levels.
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition comprising it in the preparation of a medicament for the treatment and/or prevention of a disease or condition selected from the group consisting of viruses Infection, inflammation and cancer.
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and a compound or a pharmaceutically acceptable salt thereof shown in Table A, or the use of a pharmaceutical composition comprising it in the preparation of a medicament for treating and/or preventing AIDS or AIDS-related conditions or human immunodeficiency virus (HIV) .
  • a pharmaceutical composition comprising it in the preparation of a medicament for treating and/or preventing AIDS or AIDS-related conditions or human immunodeficiency virus (HIV) .
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition comprising it in the preparation of a medicament for the treatment and/or prevention of a disease or condition, wherein the disease or condition is inflammation,
  • the inflammation is selected from autoimmunity-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in joints, inflammatory diseases in the digestive tract, inflammatory diseases in the skin, epithelial cell-related other inflammatory diseases
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicament for the treatment and/or prevention of a disease or condition, wherein said disease or condition is selected from viruses Infection, inflammation and cancer; wherein said inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis
  • the present disclosure further relates to general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1 ) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition comprising it in the preparation of a medicament for treating and/or preventing a disease or condition, wherein the disease or condition is cancer, so Said cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, se
  • the present disclosure further relates to a method for regulating miRNA levels, which comprises administering a therapeutically effective dose of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), General formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1 ), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it; preferably, the miRNA is miR -124.
  • the present disclosure further relates to a method for treating and/or preventing a disease or condition, which comprises administering to a patient in need of a therapeutically effective amount of general formula (I), general formula (IC), general formula (I-1), general formula ( I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general Formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IID- 2), the compound shown in general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, wherein said The disease or condition is selected from viral infection, inflammation and cancer; said inflammation is preferably selected from autoimmune-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in joints, inflammatory diseases in the digestive tract Inflammatory diseases,
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicament for the treatment and/or prevention of a disease or condition, wherein said disease or condition is selected from viruses Infection, inflammation and cancer; wherein said inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis
  • the present disclosure further relates to a method for treating and/or preventing a disease or condition, which comprises administering to a patient in need of a therapeutically effective amount of general formula (I), general formula (IC), general formula (I-1), general formula ( I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general Formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IID- 2), the compound shown in general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, wherein said The disease or condition is selected from viral infection, inflammation and cancer; said cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer,
  • the present disclosure further relates to a method for treating and/or preventing a disease or condition, which comprises administering to a patient in need of a therapeutically effective amount of general formula (I), general formula (IC), general formula (I-1), general formula ( I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general Formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IID- 2), the compound shown in general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, wherein said The disease or condition is selected from AIDS or an AIDS-related condition and Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and a compound shown in 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 general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for regulating miRNA; preferably, the miRNA is miR-124.
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and the compounds shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and/or prevention of diseases or conditions, wherein said diseases or conditions are selected from viruses Infection, inflammation and cancer; said inflammation is preferably selected from autoimmune-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the digestive tract, inflammatory diseases in the skin Inflammatory diseases, other inflammatory diseases of epithelial cells, inflammation
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and the compounds shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and/or prevention of diseases or conditions, wherein said diseases or conditions are selected from viruses Infection, inflammation and cancer; wherein said inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spine inflammation, psoriasis, derma
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and the compounds shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and/or prevention of diseases or conditions, wherein said diseases or conditions are selected from viruses Infection, inflammation and cancer; wherein said inflammation is inflammatory bowel disease; wherein said inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).
  • diseases or conditions are selected from viruses Infection, inflammation and cancer; wherein said inflammation is inflammatory
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and the compounds shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and/or prevention of diseases or conditions, wherein said diseases or conditions are selected from viruses Infection, inflammation and cancer; said cancer is selected from the group consisting of leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer,
  • the present disclosure further relates to a general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), General formula (I-4), general formula (I-4C), general formula (II), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), General formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III -1) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for the treatment and/or prevention of AIDS or AIDS-related conditions or human immunodeficiency virus (HIV) .
  • a pharmaceutical composition comprising it, which is used for the treatment and/or prevention of AIDS or AIDS-related conditions or human immunodeficiency virus (HIV) .
  • diseases or conditions described in the present disclosure are diseases or conditions that are treated and/or prevented by modulating miRNA levels; preferably, the miRNA is miR-124.
  • the viral infection of the present disclosure is a retroviral infection.
  • the inflammatory bowel disease described in the present disclosure is ulcerative colitis (UC) or Crohn's disease (CD).
  • UC ulcerative colitis
  • CD Crohn's disease
  • the lymphoma of the present disclosure is Hodgkin's disease or non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma , lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; lung cancer (also known as bronchial lung cancer) is selected from non-small cell lung cancer (NSCLC) (such as squamous cell carcinoma) and small cell lung cancer (SCLC ); kidney cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), T-cell Acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), and acute myelogenous
  • the active compounds are prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure are formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation.
  • the disclosed compounds can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in unit dose form, or in such a form that the patient can self-administer it as a single dose.
  • a unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing 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.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. Oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may 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 which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable saltkinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C 1-12 alkyl), more preferably containing 1 to 6 carbon atoms (i.e. C 1- 6 alkyl).
  • Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl Base-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
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon radical, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which is a group containing 1 Straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C 1-12 alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e. C 1-6 alkylene).
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkenyl, alkynyl, alkoxy, haloalkane Oxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, One or more of cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups containing 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms are preferred, more preferably alkenyl groups containing 2 to 6 carbon atoms ( i.e. C2-6 alkenyl).
  • Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • radical, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are examples of radical, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups containing 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms i.e. C 2-12 alkynyl
  • Alkynyl groups containing 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms i.e. C 2-12 alkynyl
  • Alkynyl to 6 carbon atoms ie C 2-6 alkynyl
  • Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are examples of radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (ie 3 to 12 membered cycloalkyl), preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl), most preferably 5 or 6 carbon atoms (ie 5 or 6 membered cycloalkyl).
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base and cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group that shares one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, spirocycloalkyl is divided into single spirocycloalkyl or polyspirocycloalkyl (such as double spirocycloalkyl), preferably single spirocycloalkyl and double spirocycloalkyl .
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or multiple double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic and other polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/6 Yuan, 6 Yuan/3 Yuan, 6 Yuan/4 Yuan, 6 Yuan/ 5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly connected, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the parent structure is bonded to
  • the rings taken together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy and butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, its substituent is preferably selected from deuterium atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyl
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur can be optionally oxoated (ie to form a sulfoxide or sulfone), excluding the -O-O-, -O-S- or -S-S- ring moieties, the remaining ring atoms being carbon.
  • 1, 2, 3 and 4) are hetero atoms (ie 3 to 12 membered heterocyclyl); more preferably contain 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocyclyl); more preferably contain 3 to 6 ring atoms, of which 1-3 are heteroatoms (ie 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms Ring atoms, 1-3 of which are heteroatoms (ie 5 or 6 membered heterocyclyl).
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to 5 to 20 membered polycyclic heterocyclic groups sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, said sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl or polyspiroheterocyclyl (such as double spiroheterocyclyl), preferably single spiroheterocyclyl and double spiroheterocyclyl .
  • spiroheterocyclyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan Monospiroheterocyclyl.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur optionally being oxo-substituted (ie to form sulfoxides or sulfones), and the remaining ring atoms being carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered 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-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 condensed heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, said sulfur being optionally substituted with oxo (ie to form a sulfoxide or sulfone), the remaining ring atoms being carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein with the parent
  • the rings the structures are joined together are heterocyclyl, non-limiting examples of which include:
  • the heterocyclyl group may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated ⁇ -electron system, Examples include phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrole base, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent
  • the residue from which the atom is derived is "divalent cycloalkyl", "divalent heterocyclyl", “arylene”, “heteroarylene”.
  • amino-protecting group is used to protect the amino group with a group that can be easily removed in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.
  • hydroxyl protecting group refers to a hydroxy derivative that is usually used to block or protect a hydroxy group to react on other functional groups of the compound.
  • the hydroxyl protecting group may be, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, Methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is 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 group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • Compounds of the present disclosure include isotopic derivatives thereof.
  • isotopically derivative refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • hydrogen is replaced by "deuterium” or “tritium”, or 18 F-fluorine label ( 18 F isotope) is used instead of fluorine, or 11 C-, 13 C-, or 14 C-enriched
  • carbon 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes
  • a deuterated form of a compound is one in which each available hydrogen atom attached to a carbon atom is independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
  • deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Deuterated compounds generally retain comparable activity to non-deuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs.
  • each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • a position is specifically designated as deuterium (D)
  • the position is understood to have an abundance of deuterium (i.e. at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) .
  • Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e.
  • deuterium incorporation at least 15% deuterium incorporation
  • at least 2000 times more abundant deuterium i.e. at least 30% deuterium incorporation
  • at least 3000 times the abundance of deuterium i.e. at least 45% deuterium incorporation
  • at least 3340 times the abundance of deuterium i.e. at least 50.1% deuterium incorporation
  • at least 3500 times the abundance of deuterium i.e. at least 52.5% deuterium incorporation
  • at least 4000-fold more abundant deuterium i.e. at least 60% deuterium incorporation
  • at least 4500-fold more abundant deuterium i.e. at least 67.5% deuterium incorporation
  • at least 5000-fold Deuterium in abundance i.e.
  • deuterium in at least 5500 times abundance i.e. at least 82.5% deuterium incorporation
  • deuterium in at least 6000 times abundance i.e. at least 90% deuterium incorporation deuterium incorporation
  • at least 6333.3 times the abundance of deuterium i.e. at least 95% deuterium incorporation
  • at least 6466.7 times the abundance of deuterium i.e. at least 97% deuterium incorporation
  • at least 6600 times the abundance of deuterium That is, at least 99% deuterium incorporation
  • at least 6633.3 times the abundance of deuterium ie, at least 99.5% deuterium incorporation
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary agent, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), Diastereomeric salts are formed with appropriate optically active acids or bases, followed by diastereomeric resolution to obtain the pure isomers by conventional methods well known in the art. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of a lactam-lactam equilibrium is shown below:
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients .
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate 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 as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • the term "pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (IC) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions to obtain the general A compound of formula (I) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (IC) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (IA) or its salt and the compound of general formula (IB) or its salt optionally undergoes aromatic nucleophilic substitution reaction under basic conditions or acidic conditions; Or optionally occurs under basic conditions and the presence of a catalyst A coupling reaction to obtain a compound of general formula (IC) or a pharmaceutically acceptable salt thereof;
  • X is a halogen; preferably a Cl atom;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in general formula (IC).
  • the preparation method of the compound represented by the general formula (I-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (I-1C) or a salt thereof undergoes an ester hydrolysis reaction under alkaline conditions to obtain a compound of general formula (I-1) or a pharmaceutically acceptable salt thereof;
  • R and R are as defined in general formula (I-1C);
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I-1).
  • the preparation method of the compound represented by the general formula (I-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (I-2C) or a salt thereof undergoes an ester hydrolysis reaction under alkaline conditions to obtain a compound of general formula (I-2) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl or heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Rings A, G, R 1 to R 3 , m, n and p are as defined in the general formula (I-2).
  • the preparation method of the compound represented by the general formula (I-3) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions, obtain a compound of general formula (I-3) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in the general formula (I-3).
  • the preparation method of the compound represented by the general formula (I-3C) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (I-3A) or its salt and the compound of general formula (IB) or its salt optionally undergo nucleophilic substitution reaction under basic conditions or acidic conditions; or optionally in the presence of basic conditions and catalysts A coupling reaction occurs to obtain a compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof;
  • X is a halogen; preferably a Cl atom;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in the general formula (I-3C).
  • the preparation method of the compound represented by the general formula (I-4) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (I-4C) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions, obtain a compound of general formula (I-4) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in the general formula (I-4).
  • the preparation method of the compound represented by the general formula (I-4C) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (I-4A) or its salt and the compound of general formula (IB) or its salt optionally undergo nucleophilic substitution reaction under basic conditions or acidic conditions; or optionally in the presence of basic conditions and catalysts A coupling reaction occurs to obtain a compound of general formula (I-4C) or a pharmaceutically acceptable salt thereof;
  • X is a halogen; preferably a Cl atom;
  • Ring A, ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in the general formula (I-4C).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (IIC) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions to obtain the general A compound of formula (II) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (IIC) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (IA) or its salt and the compound of general formula (IIB) or its salt optionally undergo nucleophilic substitution reaction under basic conditions or acidic conditions; Link reaction, obtain the compound of general formula (IIC) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IIC).
  • the preparation method of the compound represented by the general formula (IID-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (IID-1A) or a salt thereof undergoes an ester hydrolysis reaction under alkaline conditions to obtain a compound of general formula (IID-1) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (IID-1).
  • the preparation method of the compound represented by the general formula (IID-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of the general formula (IID-2A) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound of the general formula (IID-2) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in the general formula (IID-2).
  • the preparation method of the compound represented by the general formula (II-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, G 1 , G 2 , R 1b , R 1c and R 3 are as defined in the general formula (II-1); preferably, R 3 is halogen.
  • the preparation method of the compound represented by the general formula (II-1C) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (II-1A) or its salt and the compound of general formula (II-1B) or its salt optionally undergo nucleophilic substitution reaction under basic condition or acidic condition; Or optionally under basic condition and catalyst A coupling reaction occurs in the presence of a compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof;
  • X is a halogen; preferably a Cl atom;
  • G, G 1 , G 2 , R 1b , R 1c and R 3 are as defined in the general formula (II-1C); preferably, R 3 is halogen.
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions to obtain the general A compound of formula (III) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in the general formula (III).
  • the preparation method of the compound represented by the general formula (IIIC) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (IA) or its salt and the compound of general formula (IIIB) or its salt optionally undergo nucleophilic substitution reaction under basic conditions or acidic conditions; Link reaction, obtain the compound of general formula (IIIC) or its pharmaceutically acceptable salt;
  • X is a halogen; preferably a Cl atom;
  • G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIIC).
  • the preparation method of the compound represented by the general formula (IIID-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (IIID-1A) or a salt thereof undergoes an ester hydrolysis reaction under alkaline conditions to obtain a compound of general formula (IIID-1) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • a compound of general formula (IIID-2A) or a salt thereof undergoes an ester hydrolysis reaction under alkaline conditions to obtain a compound of general formula (IIID-2) or a pharmaceutically acceptable salt thereof;
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof and R 4' -Y compound undergoes a nucleophilic substitution reaction under basic conditions, and then removes the protecting group on R 4' under basic conditions, obtain a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof;
  • Y is a halogen; preferably a Br atom
  • R and R 11 are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R 11 is C 1-6 alkyl;
  • G, L 1 , L 2 , R 1e , R 1f and R 3 are as defined in the general formula (III-1); preferably, R 3 is halogen.
  • the preparation method of the compound represented by the general formula (III-1C) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound of general formula (II-1A) or its salt and the compound of general formula (III-1B) or its salt optionally undergo nucleophilic substitution reaction under basic condition or acidic condition; Or optionally under basic condition and catalyst A coupling reaction occurs in the presence of a compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof;
  • X is a halogen; preferably a Cl atom;
  • G, L 1 , L 2 , R 1e , R 1f and R 3 are as defined in the general formula (III-1C); preferably, R 3 is halogen.
  • the reagents that provide the basic conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyl Lithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but Not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; Lithium hydroxide monohydrate, potassium carbonate, cesium carbonate and cadmium carbonate; Reagents providing alkaline conditions described in schemes two, six, eight, ten, fourteen, sixteen and twenty are more preferably potassium carbonate or cesium carbonate ; The
  • the reagents for alkaline conditions described in Schemes 3, 4, 11, 12, 17 and 18 are preferably lithium hydroxide monohydrate, more preferably lithium hydroxide monohydrate and hydrogen peroxide.
  • the reagent that provides basic conditions in the reaction of removing the protecting group on R 4' described in Schemes 1, 5, 7, 9, 13, 15 and 19 is preferably lithium hydroxide monohydrate, more preferably a Lithium Hydroxide Hydrate and Hydrogen Peroxide.
  • the reagents that provide the acidic conditions in the above synthesis scheme include but are not limited to mellitic acid, thiosulfuric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the The reagent providing acidic conditions is trifluoroacetic acid.
  • ester hydrolysis reaction involved in the above synthesis scheme is preferably carried out under the conditions of lithium hydroxide monohydrate and hydrogen peroxide.
  • the catalysts described in the above synthesis scheme include but are not limited to tetrakis(triphenylphosphine)palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'- Bis(dibenzylphosphino)ferrocenepalladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino) ) ferrocene]palladium dichloride dichloromethane complex, tris(dibenzylideneacetone)dipalladium and 4,5-bis(dipheny
  • the reaction of 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, methylene chloride, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, Ethyl acetate, n-hex
  • Figure 1 Effect of compound 1 of the present disclosure on body weight of UC mice induced by sodium dextran sulfate (DSS).
  • #P ⁇ 0.05 means that there is a significant difference between the model group and the normal control group
  • ##P ⁇ 0.01 means that there is a highly significant difference between the model group and the normal control group
  • ###P ⁇ 0.001 means that the model group is compared with the normal control group
  • *P ⁇ 0.05 means that there is a significant difference between the drug treatment group and the model group
  • **P ⁇ 0.01 means that there is a highly significant difference between the drug treatment group and the model group
  • ***P ⁇ 0.001 means that there is a highly significant difference between the administration group and the model group.
  • Figure 2 The effect of compound 1 of the present disclosure on the colon length of dextran sodium sulfate (DSS)-induced UC mice.
  • #P ⁇ 0.05 means that there is a significant difference between the model group and the normal control group
  • ##P ⁇ 0.01 means that there is a highly significant difference between the model group and the normal control group
  • ###P ⁇ 0.001 means that the model group is compared with the normal control group
  • *P ⁇ 0.05 means that there is a significant difference between the drug treatment group and the model group
  • **P ⁇ 0.01 means that there is a highly significant difference between the drug treatment group and the model group
  • ***P ⁇ 0.001 means that there is a highly significant difference between the administration group and the model group.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • 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 of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • Dissolve compound 1 (500mg, 1.49mmol) in toluene (30mL), add cadmium carbonate (155mg, 0.90mmol), heat to 140°C for 12 hours, then add 1-bromo-1-deoxy-2,3 , 4-tri-O-acetyl- ⁇ -D-glucuronic acid methyl ester 2a (1.05g, 2.64mmol, Shaoyuan Chemical Technology), 140 °C water separation reaction for 24 hours. Cooled to room temperature, concentrated under reduced pressure to remove toluene, and purified by column chromatography with eluent system B to obtain the title compound 2b (340 mg, yield 35%).
  • Lithium hydroxide monohydrate (450 mg, 10.74 mmol) was dissolved in water (5 mL), hydrogen peroxide (1 mL) was added, and stirred at room temperature for 10 minutes. This solution was added to a tetrahydrofuran solution (15 mL) of compound 2b (340 mg, 0.52 mmol), and stirred at room temperature for 2 hours.
  • 5-aminoindane 4a (168 mg, 1.26 mmol, TCI), compound 1a (100 mg, 0.51 mmol, Shanghai Haohong) and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100°C for 12 hours. Cooled to room temperature, the reaction solution was filtered through preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 10mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 65%-85%, flow rate: 30mL/ min) separation and purification to obtain the title compound 4 (129 mg, yield: 87%).
  • reaction solution After being cooled to room temperature, the reaction solution was filtered and subjected to preparative high-performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 58%-78%, flow rate: 30mL /min) separation and purification to obtain the title compound 6 (63 mg, yield: 80%).
  • preparative high-performance liquid chromatography Waters 2767-SQ Detecor2, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 58%-78%, flow rate: 30mL /min
  • 2-Methoxy-4-nitrophenol 8a (2.0g, 11.82mmol, Bi De Pharmaceutical), cesium carbonate (5.8g, 17.74mmol), 1,2-dibromotetrafluoroethane 8b (6.2g, 23.65mmol, Shanghai Titan Technology) and 1-propanethiol (0.45g, 5.91mmol, TCI) were dissolved in 30mL dimethyl sulfoxide, raised to 100 ° C for 12 hours. Cool to room temperature, add 50mL of 2N sodium hydroxide solution, extract with ether (50mL ⁇ 3), combine the organic phases, then wash with 2N sodium hydroxide solution (50mL ⁇ 3), and wash with saturated sodium chloride solution (50mL ⁇ 3).
  • 2,3-Dihydroxy-5-bromopyridine 9a (2.0g, 10.53mmol, Bi De Pharmaceutical), anhydrous potassium carbonate (4.36g, 31.55mmol), dibromomethane (2.2g, 12.65mmol) were dissolved in 30mL N -Methylpyrrolidone, heated up to 100°C for 12 hours. Cool to room temperature, pour into 30 mL of water, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9b (300 mg, yield: 14%).
  • reaction solution was cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate (20 mL ⁇ 3), washed with saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the The resulting residue was purified by chromatography with eluent system B to afford the title compound 9c (50 mg, yield: 42%).
  • the reaction solution was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL ⁇ 3), washed with saturated sodium chloride solution (25 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to high-efficiency Preparative liquid chromatography (Waters-2545, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 10%-26%, flow rate: 30mL/min) purified to obtain the target compound 10 (750mg, Yield: 50%).
  • Lithium hydroxide monohydrate (645 mg, 15.35 mmol) was dissolved in water (4 mL), 30% hydrogen peroxide solution (1.83 mL) was added, and stirred at room temperature for 10 minutes. This solution was added to a tetrahydrofuran solution (16 mL) of compound 21a (450 mg, 0.51 mmol), and stirred at room temperature for 16 hours.
  • Dissolve compound 6 (500mg, 1.60mmol) in toluene (30mL), add cadmium carbonate (165mg, 0.96mmol), heat to 140°C for 12 hours, then add compound 2a (1.90g, 4.80mmol), 140 °C water separation reaction for 24 hours. Cooled to room temperature, concentrated under reduced pressure to remove toluene, and the residue was purified by column chromatography with eluent system B to obtain the title compound 22a (400 mg, yield 40%).
  • Lithium hydroxide monohydrate (534 mg, 12.72 mmol) was dissolved in water (5 mL), 30% hydrogen peroxide solution (1.1 mL) was added, and stirred at room temperature for 10 minutes. This solution was added to a tetrahydrofuran solution (15 mL) of compound 22a (400 mg, 0.64 mmol), and stirred at room temperature for 2 hours.

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Abstract

涉及喹啉胺类化合物、其制备方法及其在医药上的应用。具体而言，涉及一种通式(I)所示的喹啉胺类化合物、其制备方法及含有该类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miRNA调节剂的用途和在制备用于治疗通过调节miRNA水平而改善的疾病或病况的药物中的用途。

Description

喹啉胺类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种喹啉胺类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的喹啉胺类化合物、其制备方法、含有该类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miRNA调节剂的用途和在制备用于治疗通过调节miRNA水平而改善的疾病或病况的药物中的用途。
背景技术
MicroRNA(miRNA)是一类由内源基因编码的长度约为22个核苷酸的非编码单链RNA分子，它们在动植物中参与转录后基因表达调控。每个miRNA可以有多个靶基因，而几个miRNA也可以调节同一个基因。利用这种复杂的网络可以对靶基因进行精准的调控。miR-124在全身各组织有广泛表达，尤其在脑部组织中高表达。研究表明，过表达miR-124可促进激活的巨噬细胞-小胶质细胞向静态转变，从而抑制自身免疫疾病脑脊髓炎(Ponomarev ED等人,Nat Med,2011；17:67-70)。另外，miR-124可促进巨噬细胞向M2型转化，从而发挥抗炎作用(Veremeyko T,et.al,Plos One,2013；8:e81774)。miR-124也影响T细胞分化，miR-124处理的T细胞IFN-γ和TNFα水平都有所下降。过表达miR-124通过下调STAT3蛋白，进而减少炎症细胞因子IL-17的表达，抑制Th17细胞的分化发挥抗炎作用(Wei J et.al,Cancer Res,2013；73:3913-3926)。有统计研究报道，在小儿溃疡性结肠炎中miR-124的水平远低于健康人，暗示上调miR-124或可抑制肠道炎症反应(Koukos G,et.al,Gastroenterology,2013；145:842-852)。另外，Nakamachi团队发现，相比于骨关节炎病人，类风湿关节炎病人的滑膜细胞中miR-124显著下调(Nakamachi,Y,et.al,Arthritis Rheum,2009；60:1294-1304)。以上研究表明，发展一种新型的小分子药物，通过上调miR-124，可以用于有效地治疗相关炎症疾病。
炎症是免疫系统对局部感染或者组织损伤的一种保护性反应，严重的炎症反应可以损伤肌体。炎症反应的一般表现为疼痛、发热、发红、肿胀和功能丧失。炎性疾病包含多种情形，它包括与自身免疫有关的炎性疾病、中枢神经系统(CNS)中的炎性疾病、关节中的炎性疾病、消化道中的炎性疾病和皮肤中的炎性疾病等。炎性肠病(IBD)和类风湿性关节炎(RA)是两种最常见的炎性疾病，受到了人们广泛地关注。
炎性肠病是一种特发性肠道炎症性疾病，临床表现腹泻、腹痛，甚至可有血便。目前IBD病因和发病机制尚未完全明确，已知肠道黏膜免疫系统异常反应所导致的炎症反应在IBD发病中起重要作用，环境、遗传、感染和免疫因素等多因 素都可能导致该疾病。IBD通常是指溃疡性结肠炎(UC)和克罗恩病(CD)，溃疡性结肠炎是结肠黏膜层和黏膜下层连续性炎症，疾病通常先累及直肠，逐渐向全结肠蔓延，克罗恩病可累及全消化道，为非连续性全层炎症，最常累及部位为末端回肠、结肠和肛周。IBD通常表现为过多的免疫细胞侵染肠道粘膜，T细胞亚群包括Th17、Th1和Treg的失衡，过度激活的巨噬细胞和树突细胞。目前已上市或正在临床实验的药物包含减弱炎症反应的JAK抑制剂、TNFα抗体，抑制Th1和Th17分化的IL-12、IL-23的抗体，阻断炎症细胞浸润的整合素α4β7抗体等。
类风湿关节炎是一种影响关节内膜组织(被称为滑膜)的系统性炎性疾病，其特征是手、足小关节的多关节、对称性、侵袭性关节炎症，经常伴有关节外器官受累，可以导致关节畸形及功能丧失。炎症细胞因子(像肿瘤坏死因子TNFα、白细胞介素IL-1和IL-6)在类风湿关节炎(RA)的发病机理中起重要作用。通常使用缓解疾病的抗风湿类小分子药品(DMARD)或者TNFα抑制剂之类的生物药来治疗。然而，这些药物的应答患者通常在使用几年后变成无应答的。因此，需要发展新型作用机理的疗效好并可以长期安全使用的治疗方法。
公开的相关专利申请包括WO2010143169A2、WO2015001518A1、WO2016009065A2、WO2017158201A1和WO2020127843A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000001
其中：
环A为环烷基或杂环基；
G为N原子或CR 2a；
各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、氧代基、羟烷基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
各个R 2相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
各个R 3相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基；
或者其中的两个相邻的R 3和相连的苯环上的碳原子形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；
R 4选自氢原子、烷基、环烷基和杂环基；其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基和氰基中的一个或多个相同或不同的取代基取代；
R 5和R 6相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
R 7选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
R 8选自氢原子、烷基、卤代烷基、羟烷基、羟基、环烷基和杂环基；
R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
R 2a选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
n为0、1、2、3或4；
m为0、1或2；
p为1、2、3或4；
q为0、1、2或3。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：
环A为环烷基或杂环基；
G为N原子或CR 2a；
各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、氧代基、羟烷基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
各个R 2相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
各个R 3相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基；
或者其中的两个相邻的R 3和相连的苯环上的碳原子形成环烷基或杂环基，所 述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；
R 4选自氢原子、烷基、环烷基和杂环基；其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基和氰基中的一个或多个相同或不同的取代基取代；
R 5和R 6相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
R 7选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
R 8选自氢原子、烷基、卤代烷基、羟烷基、羟基、环烷基和杂环基；
R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
R 2a选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
n为0、1、2、3或4；
m为0、1或2；
p为1、2、3或4；且
q为0、1、2或3。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(IC)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000002
其中：
环A、G、R 1至R 3、n、m和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000003
不为
Figure PCTCN2022095441-appb-000004
Figure PCTCN2022095441-appb-000005
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(I-1)或通式(I-2)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000006
其中：
环A、G、R 1至R 3、n、m和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(I-3)或通式(I-4)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000007
其中：
环B为环烷基或杂环基；其中所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；
各个R 3a相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基；
r为0、1或2；
环A、G、R 1、R 2、R 4、n和m如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(I-3C)或通式(I-4C)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000008
其中：
环A、环B、G、R 1、R 2、R 3a、n、r和m如通式(I-3)或通式(I-4)中所定义。
在本公开的一些实施方案中，所述的通式(I-3)、通式(I-3C)、通式(I-4)或通式(I-4C)所示的化合物或其可药用的盐，其中环B为3至8元环烷基或3至8元杂环基；优选地，环B为5或6元环烷基或5或6元杂环基；更优选地，环B为环戊基。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)或通式(IC)所示的化合物或其可药用的盐，其中环A为3至8元环烷基或3至8元杂环基；优选地，环A为5或6元环烷基或5或6元杂环基。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)或通式(IC)所示的化合物或其可药用的盐，其中：各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、-C(O)R 8、C 1-6烷基、C 1-6烷氧基和氧代基；优选选自氢原子、氘原子、卤素、-C(O)R 8和C 1-6烷基；R 8如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)或通式(IC)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、氘原子、氟、乙酰基、甲基和氧代基。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)或通式(IC)所示的化合物或其可药用的盐，其中：各个R 1相同或不同，且各自独立地选自氢原子、卤素、-C(O)R 8、C 1-6烷基、C 1-6烷氧基和氧代基；R 8如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)或通式(IC)所示的化合物或其可药用的盐，其中：R 8选自氢原子、C 1-6烷基和卤代C 1-6烷基；优选地，R 8为C 1-6烷基；更优选地，R 8为甲基。
在本公开的一些实施方案中，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：
Figure PCTCN2022095441-appb-000009
其中：
G 1、G 2和G 3相同或不同，且各自独立地选自O原子、S原子、NR 1a和CR 1bR 1c；
R 1a选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
R 1b和R 1c相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，或者R 1b和R 1c一起形成氧代基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
G、R 2至R 10、m、p和q如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中：
G 1、G 2和G 3相同或不同，且各自独立地选自O原子、S原子、NR 1a和CR 1bR 1c；
R 1a选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
R 1b和R 1c相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，或者R 1b和R 1c一起形成氧代基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
G、R 2至R 10、m、p和q如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(IIC)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000010
其中：
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(IID-1)或(IID-2)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000011
其中：
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式(IID-2)所示的化合物或其可药用的盐，其中G 1和G 2相同或不同，且各自独立地选自O原子、S原子、NR 1a和CR 1bR 1c；G 3为CR 1bR 1c；R 1a、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式(IID-2)所示的化合物或其可药用的盐，其中G 1为O原子或NR 1a；G 2和G 3各自独立地为CR 1bR 1c；R 1a、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式(IID-2)所示的化合物或其可药用的盐，其中G 2为O原子或NR 1a；G 1和G 3各自独立地为CR 1bR 1c；R 1a、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式(IID-2)所示的化合物或其可药用的盐，其中G 1和G 2均为O原子；G 3为CR 1bR 1c；R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式(IID-2)所示的化合物或其可药用的盐，其中G 1、G 2和G 3各自独立地为CR 1bR 1c；R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(IID-1)或通式 (IID-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000012
为
Figure PCTCN2022095441-appb-000013
G 1和G 2相同或不同，且各自独立地选自O原子、NR 1a和CR 1bR 1c，R 1a、R 1b和R 1c如通式(II)中所定义；优选地，
Figure PCTCN2022095441-appb-000014
选自
Figure PCTCN2022095441-appb-000015
Figure PCTCN2022095441-appb-000016
R 1a、R 1b和R 1c如通式(II)中所定义；更优选地，
Figure PCTCN2022095441-appb-000017
选自
Figure PCTCN2022095441-appb-000018
Figure PCTCN2022095441-appb-000019
在本公开的一些实施方案中，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：
Figure PCTCN2022095441-appb-000020
其中：
L 1、L 2、L 3和L 4相同或不同，且各自独立地选自O原子、S原子、NR 1d和CR 1eR 1f；
R 1d选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
R 1e和R 1f相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，或者R 1e和R 1f一起形成氧代基，其中所述的烷基、烷氧基、环烷基、杂 环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
G、R 2至R 10、m、p和q如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：
L 1、L 2、L 3和L 4相同或不同，且各自独立地选自O原子、S原子、NR 1d和CR 1eR 1f；
R 1d选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
R 1e和R 1f相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，或者R 1e和R 1f一起形成氧代基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
G、R 2至R 10、m、p和q如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(III)所示的化合物或其可药用的盐，其为通式(IIIC)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000021
其中：
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(III)所示的化合物或其可药用的盐，其为通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000022
其中：
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 1和L 2相同或不同，且各自独立地选自O原子、S原子、NR 1d和CR 1eR 1f；L 3和L 4各自独立地为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 1为O原子或NR 1d；L 2、L 3和L 4各自独立地为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 2为O原子或NR 1d；L 1、L 3和L 4各自独立地为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 3为O原子或NR 1d；L 1、L 2和L 4各自独立地为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 4为O原子或NR 1d；L 1、L 2和L 3各自独立地为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 1和L 2均为O原子；L 3和L 4各自独立地为CR 1eR 1f；R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通式(IIID-2)所示的化合物或其可药用的盐，其中L 1、L 2、L 3和L 4各自独立地为CR 1eR 1f；R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III)、通式(IIIC)、通式(IIID-1)或通 式(IIID-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000023
为
Figure PCTCN2022095441-appb-000024
L 1和L 2相同或不同，且各自独立地为O原子或CR 1eR 1f，R 1e和R 1f如通式(III)中所定义；优选地，
Figure PCTCN2022095441-appb-000025
为
Figure PCTCN2022095441-appb-000026
R 1e和R 1f如通式(III)中所定义；更优选地，
Figure PCTCN2022095441-appb-000027
选自
Figure PCTCN2022095441-appb-000028
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-4)、通式(IC)、通式(I-3C)、通式(I-4C)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)和通式(III)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；优选地，R 2为氢原子。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地为卤素或C 1-6烷基；优选地，R 3为卤素；更优选地，R 3为Cl。
在本公开的一些实施方案中，所述的通式(I-3)、通式(I-4)、通式(I-3C)或通式(I-4C)所示的化合物或其可药用的盐，其中各个R 3a相同或不同，且各自独立地为卤素或C 1-6烷基；优选地，R 3a为卤素；更优选地，R 3a为Cl。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基和氰基。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基、3至8元环烷基、3至8元杂环基和氰基；优选地，各个R 3相同或不同，且各自独立地选自Cl、Br、甲基、甲氧基、氰基、环丙基、四氢吡喃基和二氢吡喃基；更优选地，各个R 3相同或不同，且各自独立地选自Cl、甲基、甲氧基、氰基、环丙基和四氢吡喃基。
在本公开的一些实施方案中，所述的通式(I-3)、通式(I-4)、通式(I-3C)或通式(I-4C)所示的化合物或其可药用的盐，其中各个R 3a相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基和氰基。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中p为2、3或4；且其中两个相邻的R 3和相连的苯环上的碳原子形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；优选地，p为3。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-4)、通式(IC)、通式(I-3C)、通式(I-4C)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中m为0。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中p为1或2。
在本公开的一些实施方案中，所述的通式(I)、通式(I-1)、通式(I-2)、通式(IC)、通式(IIC)、通式(IIIC)、通式(II)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)或通式(III)所示的化合物或其可药用的盐，其中p为3。
在本公开的一些实施方案中，所述的通式(I-3)、通式(I-3C)、通式(I-4C)、或通式(I-4)所示的化合物或其可药用的盐，其中r为1或0。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(II)、通式(IIC)、通式(IID-1)、通式(IID-2)、通式(III)、通式(IIIC)、通式(IIID-1)、通式(IIID-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000029
为
Figure PCTCN2022095441-appb-000030
R 3v、R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基，或者R 3v、R 3w、R 3x和R 3y中相邻的两个与所连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代，条件是R 3v、R 3w、R 3x和R 3y不同时为氢原 子；优选地，
Figure PCTCN2022095441-appb-000031
为
Figure PCTCN2022095441-appb-000032
R 3v为卤素，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、3至8元环烷基和3至8元杂环基，或者R 3w、R 3x与所连的碳原子一起形成3至8元环烷基；更优选地，
Figure PCTCN2022095441-appb-000033
为
Figure PCTCN2022095441-appb-000034
R 3v为卤素，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、3至6元环烷基和3至6元杂环基。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(II)、通式(IIC)、通式(IID-1)、通式(IID-2)、通式(III)、通式(IIIC)、通式(IIID-1)、通式(IIID-2)所示的化合物或其可药用的盐，当
Figure PCTCN2022095441-appb-000035
为
Figure PCTCN2022095441-appb-000036
时，R 3v为Cl。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(II)、通式(IIC)、通式(IID-1)、通式(IID-2)、通式(III)、通式(IIIC)、通式(IIID-1)、通式(IIID-2)所示的化合物或其可药用的盐，当
Figure PCTCN2022095441-appb-000037
为
Figure PCTCN2022095441-appb-000038
时，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、Cl、Br、甲基、甲氧基、氰基、环丙基、四氢吡喃基和二氢吡喃基；更优选地，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、Cl、甲基、甲氧基、氰基、环丙基和四氢吡喃基。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(II-1)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000039
其中：
G、R 3、R 4、G 1、G 2、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(II-1)所示的化合物或其可药用的盐，其为通式(II-1C)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000040
其中：
G、G 1、G 2、R 3、R 1b和R 1c如通式(II-1)中所定义；
在本公开的一些实施方案中，所述的通式(II-1)或(II-1C)所示的化合物或其可药用的盐，其中G 1和G 2相同或不同，且各自独立地选自O原子、NR 1a和CR 1bR 1c；R 1a、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II-1)或(II-1C)所示的化合物或其可药用的盐，其中G 1为O原子或NR 1a；G 2为CR 1bR 1c；或者；G 2为O原子或NR 1a；G 1为CR 1bR 1c；R 1a、R 1b和R 1c如通式(II)中所定义。
在本公开的一些实施方案中，所述的通式(II-1)或(II-1C)所示的化合物或其可药用的盐，其中G 1和G 2均为O原子。
在本公开的一些实施方案中，所述的通式(I)或通式(III)所示的化合物或其可药用的盐，其为通式(III-1)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000041
其中：
G、R 3、R 4、L 1、L 2、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其为通式(III-1C)所示的化合物或其可药用的盐：
Figure PCTCN2022095441-appb-000042
其中：
G、L 1、L 2、R 3、R 1e和R 1f如通式(III-1)中所定义。
在本公开的一些实施方案中，所述的通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中L 1和L 2相同或不同，且各自独立地选自O原子、NR 1d和CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中L 1为O原子或NR 1d；L 2为CR 1eR 1f；或者；L 2为O原子或NR 1d；L 1为CR 1eR 1f；R 1d、R 1e和R 1f如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中L 1和L 2均为O原子。
在本公开的一些实施方案中，所述的通式(II-1)、通式(II-1C)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 3选自卤素、C 1-6烷基、C 1-6烷氧基和氰基。
在本公开的一些实施方案中，所述的通式(II-1)、通式(II-1C)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 3为卤素或C 1-6烷基；优选地，R 3为卤素；更优选为Cl。
在本公开的一些实施方案中，所述的通式(I)、通式(I-3)、通式(I-4)、通式(II)、通式(II-1)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R 4为氢原子或3至8元杂环基，所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代；优选地，R 4为
Figure PCTCN2022095441-appb-000043
在本公开的一些实施方案中，所述的通式(I)、通式(I-3)、通式(I-4)、通式(II)、通式(II-1)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R 4为氢原子。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、 通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 1a或R 1d选自氢原子、C 1-6烷基和-C(O)R 8，R 8为C 1-6烷基；优选地，R 1a和R 1d相同或不同，且各自独立地为甲基或乙酰基。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 1b与R 1c或者R 1e与R 1f相同或不同，且各自独立地选自氢原子、氘原子、卤素和C 1-6烷基；优选地，R 1b与R 1c或者R 1e与R 1f相同或不同，且各自独立地选自氢原子、氘原子、氟和甲基。
在本公开的一些实施方案中，所述的通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 1b与R 1c或者R 1e与R 1f相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；优选地，R 1e为氢原子或卤素；R 1f为氢原子或卤素。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中G为CR 2a；R 2a如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1)或通式(III-1C)所示的化合物或其可药用的盐，其中R 2a选自氢原子、卤素和C 1-6烷基；优选地，R 2a为氢原子。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为3至8元环烷基或3至8元杂环基；G为N原子或CR 2a；R 2a选自氢原子、卤素和C 1-6烷基；各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、-C(O)R 8、C 1-6烷基、C 1-6烷氧基和氧代基；R 8为C 1-6烷基；n为0(即R 1为氢原子)、1、2、3或4；各个R 2相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；m为0(即R 2为氢原子)、1或2；各个R 3相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基和氰基；p为1、2或3；R 4为氢原子或3至8元杂环基，所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为5或6元环烷基或5或6元杂环基；G为CR 2a；R 2a为氢原子；各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、-C(O)R 8、C 1-6烷基和 C 1-6烷氧基；R 8为C 1-6烷基；n为0(即R 1为氢原子)、1、2、3或4；各个R 2为氢原子；各个R 3相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基和氰基；p为1、2或3；R 4为氢原子或3至8元杂环基；其中所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000044
选自
Figure PCTCN2022095441-appb-000045
Figure PCTCN2022095441-appb-000046
R 1a选自氢原子、C 1-6烷基和-C(O)R 8，R 8为C 1-6烷基；R 1b和R 1c相同或不同，且各自独立地选自氢原子、氘原子、卤素和C 1-6烷基；G为N原子或CR 2a；R 2a为氢原子；m为0；
Figure PCTCN2022095441-appb-000047
为
Figure PCTCN2022095441-appb-000048
R 3v为卤素，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、3至8元环烷基和3至8元杂环基，或者R 3w、R 3x与所连的碳原子一起形成3至8元环烷基；R 4为氢原子或3至8元杂环基，所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中
Figure PCTCN2022095441-appb-000049
为
Figure PCTCN2022095441-appb-000050
R 1e和R 1f相同或不同，且各自独立地选自氢原子、氘原子、卤素和C 1-6烷基；G为N原子或CR 2a；R 2a为氢原子；m为0；
Figure PCTCN2022095441-appb-000051
为
Figure PCTCN2022095441-appb-000052
R 3v为卤素，R 3w、R 3x和R 3y相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、3至6元环烷基和3至6元杂环基；R 4为氢原子或3至8元杂环基，所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
在本公开的一些实施方案中，所述的通式(I-3)或通式(I-4)所示的化合物或其可 药用的盐，其中环B为3至8元环烷基或3至8元杂环基；环A为5或6元环烷基或5或6元杂环基；G为CR 2a；R 2a为氢原子；各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、-C(O)R 8、C 1-6烷基和C 1-6烷氧基；R 8为C 1-6烷基；n为0(即R 1为氢原子)、1、2、3或4；R 2为氢原子；各个R 3a相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基和氰基，r为0、1或2；R 4为氢原子或3至8元杂环基；其中所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
表A 本公开的典型化合物包括但不限于：
Figure PCTCN2022095441-appb-000053
Figure PCTCN2022095441-appb-000054
Figure PCTCN2022095441-appb-000055
Figure PCTCN2022095441-appb-000056
Figure PCTCN2022095441-appb-000057
Figure PCTCN2022095441-appb-000058
本公开的另一方面涉及通式(I-1C)或(I-2C)所示的化合物或其盐：
Figure PCTCN2022095441-appb-000059
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
环A、G、R 1至R 3、m、n和p如通式(I)中所定义。
本公开的另一方面涉及通式(IID-1A)或(IID-2A)所示的化合物或其盐：
Figure PCTCN2022095441-appb-000060
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
环A、G、G 1、G 2、G 3、R 2、R 3、m和p如通式(II)中所定义。
本公开的另一方面涉及通式(IIID-1A)或(IIID-2A)所示的化合物或其盐：
Figure PCTCN2022095441-appb-000061
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
环A、G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(III)中所定义。
在本公开的一些实施方案中，所述的通式(I-1C)、(I-2C)、(IID-1A)、(IID-2A)、(IIID-1A)或(IIID-2A)所示的化合物或其可药用的盐，其中R为C 1-6烷基；优选地，R为甲基。
在本公开的一些实施方案中，所述的通式(I-1C)、(I-2C)、(IID-1A)、(IID-2A)、(IIID-1A)或(IIID-2A)所示的化合物或其可药用的盐，其中R 11为C 1-6烷基；优选地，R 11为甲基。
表B 本公开的典型中间体化合物包括但不限于：
Figure PCTCN2022095441-appb-000062
Figure PCTCN2022095441-appb-000063
Figure PCTCN2022095441-appb-000064
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000065
通式(IC)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(I)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000066
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000067
环A、G、R 1至R 3、m、n和p如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(IC)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000068
通式(IA)化合物或其盐与通式(IB)化合物或其盐反应，得到通式(IC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、G、R 1至R 3、m、n和p如通式(IC)中所定义。
本公开的另一方面涉及一种制备通式(I-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000069
通式(I-1C)化合物或其盐发生酯水解反应，得到通式(I-1)的化合物或其可药用的盐；
其中：
R和R 11如通式(I-1C)中所定义；
环A、G、R 1至R 3、m、n和p如通式(I-1)中所定义。
本公开的另一方面涉及一种制备通式(I-2)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000070
通式(I-2C)化合物或其盐发生酯水解反应，得到通式(I-2)的化合物或其可药用的盐；
其中：
R和R 11如通式(I-2C)中所定义；
环A、G、R 1至R 3、m、n和p如通式(I-2)中所定义。
本公开的另一方面涉及一种制备通式(I-3)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000071
通式(I-3C)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(I-3)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000072
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000073
环A、环B、G、R 1、R 2、R 3a、m、n和r如通式(I-3)中所定义。
本公开的另一方面涉及一种制备通式(I-3C)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000074
通式(I-3A)化合物或其盐与通式(IB)化合物或其盐反应，得到通式(I-3C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、环B、G、R 1、R 2、R 3a、m、n和r如通式(I-3C)中所定义。
本公开的另一方面涉及一种制备通式(I-4)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000075
通式(I-4C)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(I-4)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000076
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000077
环A、环B、G、R 1、R 2、R 3a、m、n和r如通式(I-4)中所定义。
本公开的另一方面涉及一种制备通式(I-4C)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000078
通式(I-4A)化合物或其盐与通式(IB)化合物或其盐反应，得到通式(I-4C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、环B、G、R 1、R 2、R 3a、m、n和r如通式(I-4C)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000079
通式(IIC)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(II)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000080
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000081
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(IIC)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000082
通式(IA)化合物或其盐与通式(IIB)化合物或其盐反应，得到通式(IIC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IIC)中所定义。
本公开的另一方面涉及一种制备通式(IID-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000083
通式(IID-1A)化合物或其盐发生酯水解反应，得到通式(IID-1)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IID-1)中所定义。
本公开的另一方面涉及一种制备通式(IID-2)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000084
通式(IID-2A)化合物或其盐发生酯水解反应，得到通式(IID-2)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IID-2)中所定义。
本公开的另一方面涉及一种制备通式(II-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000085
通式(II-1C)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的 保护基，得到通式(II-1)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000086
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000087
G、G 1、G 2、R 1b、R 1c和R 3如通式(II-1)中所定义；优选地，R 3为卤素。
本公开的另一方面涉及一种制备通式(II-1C)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000088
通式(II-1A)化合物或其盐与通式(II-1B)化合物或其盐反应，得到通式(II-1C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、G 1、G 2、R 1b、R 1c和R 3如通式(II-1C)中所定义；优选地，R 3为卤素。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000089
通式(IIIC)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(III)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000090
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000091
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(IIIC)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000092
通式(IA)化合物或其盐与通式(IIIB)化合物或其盐反应，得到通式(IIIC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIIC)中所定义。
本公开的另一方面涉及一种制备通式(IIID-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000093
通式(IIID-1A)化合物或其盐发生酯水解反应，得到通式(IIID-1)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIID-1)中所定义。
本公开的另一方面涉及一种制备通式(IIID-2)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000094
通式(IIID-2A)化合物或其盐发生酯水解反应，得到通式(IIID-2)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIID-2)中所定义。
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000095
通式(III-1C)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(III-1)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000096
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000097
G、L 1、L 2、R 1e、R 1f和R 3如通式(III-1)中所定义；优选地，R 3为卤素。
本公开的另一方面涉及一种制备通式(III-1C)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022095441-appb-000098
通式(II-1A)化合物或其盐与通式(III-1B)化合物或其盐反应，得到通式(III-1C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、L 1、L 2、R 1e、R 1f和R 3如通式(III-1C)中所定义；优选地，R 3为卤素。
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治疗有效量的本公开通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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调节miRNA水平的药物中的用途；优选地，所述miRNA为miR-124。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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通过调节miRNA水平而改善的疾病或病况的药物中的用途。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式 (III-1C)、通式(III-1)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/或预防疾病或病况的药物中的用途，所述的疾病或病况选自病毒感染、炎症和癌症。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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AIDS或AIDS相关的病况或人类免疫缺陷病毒(HIV)药物中的用途。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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/或预防疾病或病况的药物中的用途，所述的疾病或病况为炎症，所述的炎症选自自身免疫有关的炎性疾病、中枢神经系统(CNS)中的炎性疾病、关节中的炎性疾病、消化道中的炎性疾病、皮肤中的炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防疾病或病况的药物，其中所述的疾病或病况选自病毒感染、炎症和癌症；其中所述的炎症选自炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、系统性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症；优选地，所述炎症为炎性肠病。
本公开进一步涉及通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况为癌症，所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞癌、汗腺癌、皮脂腺癌、乳头状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏肿瘤、宫颈癌、子宫癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、 视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结肠直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤。
本公开进一步涉及一种调节miRNA水平的方法，其包括给予所需患者治疗有效量的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述miRNA为miR-124。
本公开进一步涉及一种治疗和/或预防疾病或病况的方法，其包括给予所需患者治疗有效量的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病或病况选自病毒感染、炎症和癌症；所述的炎症优选选自自身免疫有关的炎性疾病、中枢神经系统(CNS)中的炎性疾病、关节中的炎性疾病、消化道中的炎性疾病、皮肤中的炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防疾病或病况的药物，其中所述的疾病或病况选自病毒感染、炎症和癌症；其中所述的炎症选自炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、系统性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症；优选地，所述炎症为炎性肠病。
本公开进一步涉及一种治疗和/或预防疾病或病况的方法，其包括给予所需患者治疗有效量的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病或病况选自病毒感染、炎症和癌症；所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞癌、汗腺癌、皮脂腺癌、乳头状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏肿瘤、宫颈癌、子宫癌、睾丸癌、肺 癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结肠直肠癌、直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤。
本公开进一步涉及一种治疗和/或预防疾病或病况的方法，其包括给予所需患者治疗有效量的通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病或病况选自AIDS或AIDS相关的病况和人类免疫缺陷病毒(HIV)。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于调节miRNA；优选地，所述miRNA为miR-124。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疾病或病况的用途，其中所述的疾病或病况选自病毒感染、炎症和癌症；所述的炎症优选选自自身免疫有关的炎性疾病、中枢神经系统(CNS)中的炎性疾病、关节中的炎性疾病、消化道中的炎性疾病、皮肤中的炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疾病或病况的用途，其中所述的疾病或病况选自病毒感染、炎症和癌症；其中所述的炎症选自炎性肠病、类风湿性关节炎、多发性硬 化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、系统性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症；优选地，所述炎症为炎性肠病。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疾病或病况的用途，其中所述的疾病或病况选自病毒感染、炎症和癌症；其中所述的炎症为炎性肠病；其中所述的炎性肠病为溃疡性结肠炎(UC)或克罗恩病(CD)。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疾病或病况的用途，其中所述的疾病或病况选自病毒感染、炎症和癌症；所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞癌、汗腺癌、皮脂腺癌、乳头状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏肿瘤、宫颈癌、子宫癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结肠直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤。
本公开进一步涉及一种通式(I)、通式(IC)、通式(I-1)、通式(I-2)、通式(I-3)、通式(I-3C)、通式(I-4)、通式(I-4C)、通式(II)、通式(IIC)、通式(II-1)、通式(II-1C)、通式(III)、通式(IID-1)、通式(IID-2)、通式(IIID-1)、通式(IIID-2)、通式(IIIC)、通式(III-1C)、通式(III-1)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，其用于治疗和/或预防AIDS或AIDS相关的病况或人类免疫缺陷病毒(HIV)的用途。
本公开所述的疾病或病况是通过调节miRNA水平来治疗和/或预防的疾病或病况；优选地，所述miRNA为miR-124。
优选地，本公开所述的病毒感染为逆转录病毒感染。
优选地，本公开所述的炎性肠病为溃疡性结肠炎(UC)或克罗恩病(CD)。
优选地，本公开所述的淋巴瘤为霍奇金氏疾病或非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤)；肝癌优选为肝细胞癌；肺癌(又称支气管肺 癌)选自非小细胞肺癌(NSCLC)(例如鳞状细胞癌)和小细胞肺癌(SCLC)；肾癌选自肾细胞癌、透明细胞和肾嗜酸细胞瘤；白血病选自慢性淋巴细胞性白血病(CLL)、慢性粒细胞性白血病、急性成淋巴细胞性白血病(ALL)、T-细胞急性成淋巴细胞性白血病(T-ALL)、慢性髓细胞性白血病(CML)和急性骨髓性白血病(AML)；皮肤癌选自恶性黑色素瘤、鳞状细胞癌、基底细胞癌和血管肉瘤；骨髓瘤优选为多发性骨髓瘤；结直肠癌优选为结肠癌或直肠癌；神经胶质瘤(即胶质瘤或胶质细胞瘤)优选选自胶质母细胞瘤、星形细胞瘤和少突胶质细胞瘤。
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，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药，注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，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。合适的单位剂量可以是0.1～1000mg。
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。
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。
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。
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。
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。油混悬液可含有增稠剂。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。
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、或矿物油或其混合物。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。
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。
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，用上述那些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。
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。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
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。
术语说明
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。
术语“烷基”指饱和的直链或支链脂肪族烃基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基(即C 1-12烷基)，更优选含有1至6个碳原子的烷基(即C 1-6烷基)。烷基的非限制性实例包括：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上被取代，取代基优选选自氘原子、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、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。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 1-12亚烷基)，更优选含有1至6个碳原子的亚烷基(即C 1-6亚烷基)。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)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上被取代，取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基和氧代基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基，更优选含有2至6个碳原子的烯基(即C 2-6烯基)。烯基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、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、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。
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的炔基(即C 2-12炔基)，更优选含有2至6个碳原子的炔基(即C 2-6炔基)。炔基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、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。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)碳原子(即3至12元环烷基)，优选包含3至8个碳原子(即3至8元环烷基)，更优选包含3至6个碳原子(即3至6元环烷基)，最优选包含5或6个碳原子(即5或6元环烷基)。单环环烷基的非限制性实例包括环丙基、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；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基或多螺环烷基(如双螺环烷基)，优选单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/4元、6元/5元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2022095441-appb-000099
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠环烷基，优选双环或三环，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/4元、5元/5元、5元/6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元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2022095441-appb-000100
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环桥环烷基，优选双环、三环或四环桥环烷基，更优选双环或三环桥环烷基。桥环烷基的非限制性实例包括：
Figure PCTCN2022095441-appb-000101
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非 限制性实例包括
Figure PCTCN2022095441-appb-000102
等；优选
Figure PCTCN2022095441-appb-000103
Figure PCTCN2022095441-appb-000104
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上被取代，取代基优选选自卤素、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。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，其取代基优选选自氘原子、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。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，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-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子(即3至12元杂环基)；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)(即3至8元杂环基)；更优选包含3至6个环原子，其中1-3个是杂原子(即3至6元杂环基)；最优选包含5或6个环原子，其中1-3个是杂原子(即5或6元杂环基)。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分单螺杂环基或多螺杂环基(如双螺杂环基)，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2022095441-appb-000105
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分双环、三环、四环等多环稠杂环基，优选双环或三环，更优选为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。稠杂环基的非限制性实例包括：
Figure PCTCN2022095441-appb-000106
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分双环、三环、四环等多环桥杂环基，优选双环、三环或四环桥杂环基，更优选双环或三环桥杂环基。桥杂环基的非限制性实例包括：
Figure PCTCN2022095441-appb-000107
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022095441-appb-000108
等。
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上被取代，取代基优选选自卤素、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。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022095441-appb-000109
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上被取代，取代基优选选自卤素、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。
术语“杂芳基”指包含1至4个杂原子(例如1、2、3和4个)、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选5至10元(例如5、6、7、8、9或10元)，更优选5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022095441-appb-000110
Figure PCTCN2022095441-appb-000111
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上被取代，取代基优选选自卤素、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。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基和硝基中的1-3个取代基所取代。
术语“羟基保护基”是指通常用于阻断或保护羟基而反应在化合物的其它官能团上进行的羟基衍生物。作为示例，优选地，所述的羟基保护基可以是例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
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。
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。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
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。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开的化合物包括其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-、或者 14C-富集的碳( 11C-、 13C-、或者 14C-碳标记； 11C-、 13C-、或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。其中氘化形式的化合物为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。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。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代，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。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。
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。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。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具有手性助剂的衍生作用来制备，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。
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-内酰亚胺的平衡实例如下所示：
Figure PCTCN2022095441-appb-000112
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：
Figure PCTCN2022095441-appb-000113
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。
本公开所述化合物的化学结构中，键
Figure PCTCN2022095441-appb-000114
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022095441-appb-000115
可以为
Figure PCTCN2022095441-appb-000116
或
Figure PCTCN2022095441-appb-000117
或者同时包含
Figure PCTCN2022095441-appb-000118
和
Figure PCTCN2022095441-appb-000119
两种构型。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取 代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3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(如烯属)键的碳原子结合时可能是不稳定的。
“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或前体药物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。
“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盐。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。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以能达到或至少部分达到预期效果的药物或药剂的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
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。
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。
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。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
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：
Figure PCTCN2022095441-appb-000120
通式(IC)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(I)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000121
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000122
环A、G、R 1至R 3、m、n和p如通式(I)中所定义。
方案二
本公开通式(IC)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000123
通式(IA)化合物或其盐与通式(IB)化合物或其盐任选地在碱性条件或酸性条件下发生芳香亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(IC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、G、R 1至R 3、m、n和p如通式(IC)中所定义。
方案三
本公开通式(I-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000124
通式(I-1C)化合物或其盐在碱性条件下发生酯水解反应，得到通式(I-1)的化合物或其可药用的盐；
其中：
R和R 11如通式(I-1C)中所定义；
环A、G、R 1至R 3、m、n和p如通式(I-1)中所定义。
方案四
本公开通式(I-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：
Figure PCTCN2022095441-appb-000125
通式(I-2C)化合物或其盐在碱性条件下发生酯水解反应，得到通式(I-2)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基或杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
环A、G、R 1至R 3、m、n和p如通式(I-2)中所定义。
方案五
本公开通式(I-3)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000126
通式(I-3C)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(I-3)的化合物或其可药 用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000127
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000128
环A、环B、G、R 1、R 2、R 3a、n、m和r如通式(I-3)中所定义。
方案六
本公开通式(I-3C)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000129
通式(I-3A)化合物或其盐与通式(IB)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(I-3C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、环B、G、R 1、R 2、R 3a、n、m和r如通式(I-3C)中所定义。
方案七
本公开通式(I-4)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000130
通式(I-4C)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(I-4)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000131
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000132
环A、环B、G、R 1、R 2、R 3a、n、m和r如通式(I-4)中所定义。
方案八
本公开通式(I-4C)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000133
通式(I-4A)化合物或其盐与通式(IB)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(I-4C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
环A、环B、G、R 1、R 2、R 3a、n、m和r如通式(I-4C)中所定义。
方案九
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：
Figure PCTCN2022095441-appb-000134
通式(IIC)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(II)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000135
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000136
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(II)中所定义。
方案十
本公开通式(IIC)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000137
通式(IA)化合物或其盐与通式(IIB)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(IIC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IIC)中所定义。
方案十一
本公开通式(IID-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000138
通式(IID-1A)化合物或其盐在碱性条件下发生酯水解反应，得到通式(IID-1)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IID-1)中所定义。
方案十二
本公开通式(IID-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：
Figure PCTCN2022095441-appb-000139
通式(IID-2A)化合物或其盐在碱性条件下发生酯水解反应，得到通式(IID-2)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、G 1、G 2、G 3、R 2、R 3、m和p如通式(IID-2)中所定义。
方案十三
本公开通式(II-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000140
通式(II-1C)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(II-1)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000141
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000142
G、G 1、G 2、R 1b、R 1c和R 3如通式(II-1)中所定义；优选地，R 3为卤素。
方案十四
本公开通式(II-1C)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000143
通式(II-1A)化合物或其盐与通式(II-1B)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(II-1C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、G 1、G 2、R 1b、R 1c和R 3如通式(II-1C)中所定义；优选地，R 3为卤素。
方案十五
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：
Figure PCTCN2022095441-appb-000144
通式(IIIC)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(III)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000145
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000146
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(III)中所定义。
方案十六
本公开通式(IIIC)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000147
通式(IA)化合物或其盐与通式(IIIB)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(IIIC)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIIC)中所定义。
方案十七
本公开通式(IIID-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000148
通式(IIID-1A)化合物或其盐在碱性条件下发生酯水解反应，得到通式(IIID-1) 的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIID-1)中所定义。
方案十八
Figure PCTCN2022095441-appb-000149
通式(IIID-2A)化合物或其盐在碱性条件下发生酯水解反应，得到通式(IIID-2)的化合物或其可药用的盐；
其中：
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
G、L 1、L 2、L 3、L 4、R 2、R 3、m和p如通式(IIID-2)中所定义。
方案十九
本公开通式(III-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000150
通式(III-1C)的化合物或其可药用的盐与R 4’-Y化合物在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R 4’上的保护基，得到通式(III-1)的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br原子；
R 4’为
Figure PCTCN2022095441-appb-000151
R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
R 4为
Figure PCTCN2022095441-appb-000152
G、L 1、L 2、R 1e、R 1f和R 3如通式(III-1)中所定义；优选地，R 3为卤素。
方案二十
本公开通式(III-1C)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022095441-appb-000153
通式(II-1A)化合物或其盐与通式(III-1B)化合物或其盐任选地在碱性条件或酸性条件下发生亲核取代反应；或者任选地在碱性条件和催化剂存在下发生偶联反应，得到通式(III-1C)的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl原子；
G、L 1、L 2、R 1e、R 1f和R 3如通式(III-1C)中所定义；优选地，R 3为卤素。
以上合成方案中提供所述碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、碳酸镉、氢氧化钠、一水合氢氧化锂、氢氧化锂和氢氧化钾；优选地，所述提供碱性条件的试剂选自一水合氢氧化锂、碳酸钾、碳酸铯和碳酸镉；方案二、六、八、十、十四、十六和二十中所述提供碱性条件的试剂更优选为碳酸钾或碳酸铯；方案一、五、七、九、十三、十五和十九中所述亲核取代反应中提供碱性条件的试剂更优选为碳酸镉。
方案三、四、十一、十二、十七和十八中所述碱性条件的试剂优选为一水合氢氧化锂，更优选为一水合氢氧化锂和过氧化氢。
方案一、五、七、九、十三、十五和十九中所述脱去R 4’上的保护基的反应中提供碱性条件的试剂优选为一水合氢氧化锂，更优选为一水合氢氧化锂和过氧化氢。
以上合成方案中提供所述酸性条件的试剂包括但不限于苯六甲酸、氮硫方酸、三氯乙酸、三硝基苯磺酸、三氟甲磺酸和三氟乙酸；优选地，所述提供酸性条件的试剂为三氟乙酸。
以上合成方案中所涉及的酯水解反应优选在一水合氢氧化锂和过氧化氢条件下进行。
以上合成方案中所述的催化剂包括但不限于四(三苯基膦)钯、二氯化钯、醋酸钯、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)、1,1’-双(二苄基膦)二氯二茂铁钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物、三(二亚苄基丙酮)二钯和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；优选地，催化剂选自甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)、三(二亚苄基丙酮)二钯和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。
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。
附图说明
图1：本公开化合物1对硫酸钠葡聚糖(DSS)诱导的UC小鼠体重的影响。其中，#P<0.05表示模型组与正常对照组比较具有显著性差异，##P<0.01表示模型组与正常对照组比较具有高度显著性差异，###P<0.001表示模型组与正常对照组比较具有极高度显著性差异；*P<0.05表示给药组与模型组比较具有显著性差异，**P<0.01表示给药组与模型组比较具有高度显著性差异，***P<0.001表示给药组与模型组比较具有极高度显著性差异。
图2：本公开化合物1对硫酸钠葡聚糖(DSS)诱导的UC小鼠结肠长度的影响。其中，#P<0.05表示模型组与正常对照组比较具有显著性差异，##P<0.01表示模型组与正常对照组比较具有高度显著性差异，###P<0.001表示模型组与正常对照组比较具有极高度显著性差异；*P<0.05表示给药组与模型组比较具有显著性差异，**P<0.01表示给药组与模型组比较具有高度显著性差异，***P<0.001表示给药组与模型组比较具有极高度显著性差异。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
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，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：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高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
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。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用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。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
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。
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。
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。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
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。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
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，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。
实施例1
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺1
Figure PCTCN2022095441-appb-000154
将2,8-二氯喹啉1a(100mg，0.51mmol，毕得医药)、5-氨基-2,2-二氟-1,3-苯并[1,3]二氧杂环戊烷1b(105mg，0.61mmol，上海皓鸿)溶解在异丙醇(1mL)中，加热升温至90℃反应12小时。冷却至室温，反应液过滤后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：0.1％的甲酸水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)分离纯化，得到标题化合物1(150mg，产率89％)。
MS m/z(ESI)：335.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ9.99(s,1H),8.88(d,1H),8.17(d,1H),7.81(dd,1H),7.77(dd,1H),7.50(dd,1H),7.39(d,1H),7.32(t,1H),7.14(d,1H)。
实施例2
(2S,3S,4S,5R,6R)-6-((8-氯喹啉-2-基)(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸2
Figure PCTCN2022095441-appb-000155
Figure PCTCN2022095441-appb-000156
第一步
(2R,3R,4S,5S,6S)-2-((8-氯喹啉-2-基)(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)氨基)-6-(甲氧基羰基)四氢-2H-吡喃-3,4,5-三醋酸酯2b
将化合物1(500mg，1.49mmol)溶解在甲苯(30mL)中，加入碳酸镉(155mg,0.90mmol)，加热至140℃分水反应12小时，再加入1-溴-1-脱氧-2,3,4-三-O-乙酰基-α-D-葡萄糖醛酸甲酯2a(1.05g，2.64mmol，韶远化学科技)，140℃分水反应24小时。冷却至室温，减压浓缩除去甲苯，用柱层析色谱法以洗脱剂体系B纯化得到标题化合物2b(340mg，产率35％)。
MS m/z(ESI)：651.0[M+1]。
第二步
(2S,3S,4S,5R,6R)-6-((8-氯喹啉-2-基)(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸2
将一水合氢氧化锂(450mg，10.74mmol)溶解在水(5mL)中，加入过氧化氢(1mL)，室温搅拌10分钟。将该溶液加入到化合物2b(340mg，0.52mmol)的四氢呋喃溶液(15mL)中，室温搅拌2小时。用饱和硫代硫酸钠溶液(20mL)淬灭后，用1N盐酸溶液调节至pH为3，用乙酸乙酯(50mL×3)萃取，饱和氯化钠溶液(100mL)洗涤，有机相减压浓缩后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：25％-45％，流速：30mL/min)分离纯化，得到标题化合物2(95mg，产率36％)。
MS m/z(ESI)：511.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.06(d,1H),7.79(d,1H),7.75(d,1H),7.58(d,1H),7.42(d,1H),7.34-7.22(m,2H),6.60(d,1H),6.30(d,1H),5.05-4.82(m,2H),3.55-3.36(m,4H),2.98(t,1H)。
实施例3
8-氯-N-(2,3-二氢苯并呋喃-5-基)喹啉-2-胺3
Figure PCTCN2022095441-appb-000157
将化合物1a(100mg，0.51mmol，毕得医药)、5-氨基-2,3-二氢苯并呋喃3a(105mg，0.61mmol，毕得医药)、三氟乙酸(0.15mL，2.0mmol)加入到异丙醇(1mL)中，加热升温至90℃反应12小时。冷却至室温，反应液过滤后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：0.1％的甲酸水溶液和乙腈，乙腈的梯度：45％-65％，流速：30mL/min)分离纯化，得到标题化合物3(115mg，产率77％)。
MS m/z(ESI)：297.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ9.51(s,1H),8.20(d,1H),8.05(d,1H),7.80-7.65(m,3H),7.23(t,1H),7.07(d,1H),6.75(d,1H),4.52(t,2H),3.22(t,2H)。
实施例4
8-氯-N-(2,3-二氢-1H-茚-5-基)喹啉-2-胺
Figure PCTCN2022095441-appb-000158
将5-氨基茚满4a(168mg，1.26mmol，TCI)、化合物1a(100mg，0.51mmol，上海皓鸿)和三氟乙酸(173mg，1.51mmol)溶于异丙醇(3mL)中。将反应加热至100℃反应12小时。冷却至室温，反应液过滤经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)分离纯化，得到标题化合物4(129mg，产率：87％)。
MS m/z(ESI)：295.1[M+1]。
1H NMR(500MHz,CDCl 3)7.90(d,1H),7.69(dd,1H),7.63(s,1H),7.57dd,1H),7.34(d,1H),7.25(d,1H),7.21(t,1H),7.01(d,1H),6.96(s,1H),3.04-2.90(m,4H),2.17-2.09(m,2H)。
实施例5
1-(5-((8-氯喹啉-2-基)氨基)吲哚啉-1-基)乙烷-1-酮5
Figure PCTCN2022095441-appb-000159
第一步
1-(5-硝基吲哚啉-1-基)乙烷-1-酮5b
将5-硝基二氢吲哚5a(2.0g，12.19mmol，毕得医药)、三乙胺(1.6g，15.85mmol)加入到40mL二氯甲烷，0℃缓慢加入乙酰氯(1.24g，15.85mmol)。然后自然升至室温，继续反应2小时。向体系内加入30mL水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5b(1.8g，产率：72％)。
MS m/z(ESI)：207.1[M+1]。
第二步
1-(5-氨基吲哚啉-1-基)乙烷-1-酮5c
将化合物5b(0.8g，3.88mmol)加入到10mL甲醇中，加入钯碳(10％，0.2g)，氢气置换三次排出空气，在氢气氛下反应2小时。过滤除去钯碳，减压浓缩滤液，得到粗品标题化合物5c(0.5g)，粗产品直接用于下一步反应。
MS m/z(ESI)：177.1[M+1]。
第三步
1-(5-((8-氯喹啉-2-基)氨基)吲哚啉-1-基)乙烷-1-酮5
将化合物5c(100mg，0.57mmol)、2,8-二氯喹啉1a(112mg，0.57mmol，毕得医药)、三氟乙酸(64.72mg，0.57mmol)溶于异丙醇(1mL)中，然后加热至90℃反应12小时。冷却至室温，反应液减压浓缩除去溶剂，残余物用薄层色谱法(TLC)，以展开剂体系B纯化得到标题产物5(48mg，产率：25％)。
MS m/z(ESI)：338.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),8.27(s,1H),8.10(d,1H),8.01(d,1H),7.89-7.65(m,3H),7.26(t,1H),7.12(d,1H),4.11(t,2H),3.19(t,2H),2.15(s,3H)。
实施例6
8-氯-N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)喹啉-2-胺6
Figure PCTCN2022095441-appb-000160
将6-氨基-1,4-苯并二氧杂环己烷6a(95mg，0.63mmol，TCI)、2,8-二氯喹啉1a(50mg，0.25mmol，毕得医药)溶于异丙醇(3mL)中。将反应液加热至100℃反应12小时。冷却至室温，反应液过滤后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：58％-78％，流速：30mL/min)分离纯化，得到标题化合物6(63mg，产率：80％)。
MS m/z(ESI)：313.1[M+1]。
1H NMR(500MHz,CDCl 3)7.90(d,1H),7.73(dd,1H),7.57(dd,1H),7.40(s,1H),7.21(t,1H),7.04(dd,1H),6.96(d,1H),6.90(d,1H),6.83(s,1H),4.35-4.26(m,4H)。
实施例7
8-氯-N-(5,6,7,8-四氢萘-2-基)喹啉-2-胺7
Figure PCTCN2022095441-appb-000161
Figure PCTCN2022095441-appb-000162
将5,6,7,8-四氢-2-萘胺7a(147mg，0.51mmol，TCI)、2,8-二氯喹啉1a(100mg，0.51mmol，毕得医药)和三氟乙酸(173mg，1.51mmol)溶于异丙醇(3mL)中。将反应加热至100℃反应12小时。冷却至室温，反应液过滤，经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：60％-80％，流速：30mL/min)分离纯化，得到标题化合物7(136mg，产率：87％)。
MS m/z(ESI)：309.1[M+1]。
1H NMR(500MHz,CDCl 3)7.88(d,1H),7.70(d,1H),7.60-7.47(m,2H),7.29(dd,1H),7.18(t,1H),7.07(d,1H),6.96(d,1H),6.86(s,1H),2.88-2.68(m,4H),1.90-1.74(m,4H)。
实施例8
8-氯-N-(2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)喹啉-2-胺8
Figure PCTCN2022095441-appb-000163
第一步
1-(2-溴-1,1,2,2-四氟乙氧基)-2-甲氧基-4-硝基苯8c
将2-甲氧基-4-硝基苯酚8a(2.0g，11.82mmol，毕得医药)、碳酸铯(5.8g，17.74mmol)、1,2-二溴四氟乙烷8b(6.2g，23.65mmol，上海泰坦科技)和1-丙硫醇(0.45g，5.91mmol，TCI)溶于30mL二甲亚砜，升至100℃反应12小时。冷却至室温，加入50mL的2N氢氧化钠溶液，用乙醚萃取(50mL×3)，合并有机相，随 后用2N的氢氧化钠溶液洗涤(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8c(2.6g，产率：64％)。
第二步
2-(2-溴-1,1,2,2-四氟乙氧基)-5-硝基苯酚8d
将化合物8c(2.6g，7.56mmol)加入到46mL醋酸中，加入氢溴酸溶液(40％质量分数，19mL)，升温至120℃，反应30小时。冷却至室温，反应加入50mL水，使用二氯甲烷萃取(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8d(2.0g，产率：79％)。
MS m/z(ESI)：331.9[M-1]。
第三步
2,2,3,3-四氟-6-硝基-2,3-二氢苯并[b][1,4]二氧杂环己烷8e
将化合物8d(200mg，0.60mmol)溶于甲醇中，随后加入氢氧化钾(37mg，0.66mmol)，反应1小时。减压除去溶剂，加入4mL环丁砜，加热至140℃反应8小时。冷却至室温，反应加入20mL水，用乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8e(98mg，产率：65％)。
第四步
2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二氧杂环己烷-6-胺8f
将化合物8e(95mg，0.38mmol)溶于3mL甲醇中，随后加入二氧化铂，氢气置换三次排出空气，在氢气氛下反应4小时。反应液过滤，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8f(60mg，产率：72％)。
MS m/z(ESI)：224.0[M+1]。
第五步
8-氯-N-(2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)喹啉-2-胺8
将化合物8f(60mg，0.27mmol)、2,8-二氯喹啉1a(50mg，0.25mmol，毕得医药)、碳酸钾(32mg，0.30mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(52mg，0.1mmol)和三(二亚苄基丙酮)二钯(28mg，0.03mmol)溶于3mL 1,4-二氧六环中，将反应液加热至100℃反应12小时。反应冷却至室温，加入30mL水，用乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：80％-95％，流速：30mL/min)纯化，得到标题化合物8(23mg，产率：24％)。
MS m/z(ESI)：385.0[M+1]。
1H NMR(500MHz,CDCl 3)8.34(s,1H),7.93(d,1H),7.75(d,1H),7.57(d,1H),7.34(dd,1H),7.25(t,1H),7.09(d,1H),6.96-6.76(m,2H)。
实施例9
N-(8-氯喹啉-2-基)-[1,3]二氧杂戊环并[4,5-b]吡啶-6-胺9
Figure PCTCN2022095441-appb-000164
第一步
6-溴-[1,3]二氧杂戊环并[4,5-b]吡啶9b
将2,3-二羟基-5-溴吡啶9a(2.0g，10.53mmol，毕得医药)、无水碳酸钾(4.36g，31.55mmol)、二溴甲烷(2.2g，12.65mmol)溶于30mL N-甲基吡咯烷酮，升温至100℃反应12小时。冷至室温，倒入30mL水中，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物9b(300mg，产率：14％)。
MS m/z(ESI)：201.9[M+1],203.9[M+3]。
第二步
[1,3]二氧杂戊环并[4,5-b]吡啶-6-基氨基甲酸叔丁酯9c
将化合物9b(100mg，0.49mmol)、氨基甲酸叔丁酯(104mg，0.89mmol)溶于8mL 1,4-二氧六环中，氮气氛下加入三(二亚苄基丙酮)二钯(45mg，0.049mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(47mg，0.098mmol)和叔丁醇钠(85mg，0.89mmol)，升温至105℃，反应20小时。反应液冷却至室温，加入20mL水，用乙酸乙酯萃取(20mL×3)，饱和氯化钠溶液洗涤(30mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物9c(50mg，产率：42％)。
MS m/z(ESI)：239.1[M+1]。
第三步
[1,3]二氧杂戊环并[4,5-b]吡啶-6-胺盐酸盐9d
将化合物9c(50mg，0.21mmol)溶于5mL二氯甲烷中，冰浴下滴加4N氯化氢的二氧六环溶液(425μL，1.7mmol)，滴完后自然升至室温，室温反应3小时。反应液减压浓缩，得到粗产品标题化合物9d(36mg)，粗产品直接用于下一步反应。
MS m/z(ESI)：139.0[M+1]。
第四步
N-(8-氯喹啉-2-基)-[1,3]二氧杂戊环并[4,5-b]吡啶-6-胺9
将化合物9d(36mg，0.21mmol)、2,8-二氯喹啉1a(30mg，0.15mmol，毕得医药)、碳酸铯(148mg，0.45mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(20mg，0.02mmol)溶于5mL 1,4-二氧六环中，将反应液加热至100℃反应12小时。冷却至室温，加入30mL水，用乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：千分之一的三氟乙酸水溶液和乙腈，乙腈的梯度：50％-95％，流速：30mL/min)分离纯化，得到标题化合物9(12mg，产率：26％)。
MS m/z(ESI)：300.0[M+1]。
1H NMR(500MHz,DMSO-d 6)9.80(s,1H),8.46(d,1H),8.18(d,1H),8.13(d,1H),7.78(d,1H),7.74(d,1H),7.28(t,1H),7.10(d,1H),6.14(s,2H)。
实施例10
N-(苯并[d][1,3]二氧杂环戊烷-5-基)-8-氯喹啉-2-胺10
Figure PCTCN2022095441-appb-000165
将化合物苯并[d][1,3]二氧杂环戊烷-5-胺10a(693mg，5.05mmol，毕得医药)、化合物1a(1.0g，5.05mmol)、碳酸铯(2.64g，8.10mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(584mg，1.01mmol)、三(二亚苄基丙酮)二钯(462mg，0.50mol)溶于30mL 1,4-二氧六环中，将反应液加热至105℃反应12小时。反应液冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters-2545，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：10％-26％，流速：30mL/min)纯化，得到目标化合物10(750mg，产率：50％)。
MS m/z(ESI)：299.0[M+1]。
1H NMR(500MHz,DMSO-d 6)9.64(s,1H),8.30(d,1H),8.08(d,1H),7.75(dd,1H),7.70(dd,1H),7.28(dd,1H),7.25(t,1H),7.07(d,1H),6.90(d,1H),5.99(s,2H)。
实施例11
N-(苯并[d][1,3]二氧杂环戊烷-5-基2,2-二氘)-8-氯喹啉-2-胺11
Figure PCTCN2022095441-appb-000166
将化合物苯并[d][1,3]二氧杂环戊烷-2,2-二氘-5-胺11a(170mg，1.21mmol，采用专利申请“WO2012037351A1中说明书第41页的中间体合成method 2”公开的方法制备而得)、化合物1a(240mg，1.21mmol)、碳酸铯(636mg，1.95mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(141mg，0.24mmol)、三(二亚苄基丙酮)二钯(111mg，0.12mol)溶于10mL 1,4-二氧六环中，将反应加热至105℃反应12小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters-2767 Autopurification，洗脱体系：千分之一的甲酸水溶液和乙腈，乙腈的梯度：45％-95％，流速：30mL/min)分离纯化，得到目标化合物11(100mg，产率：27％)。
MS m/z(ESI)：300.9[M+1]。
1H NMR(500MHz,DMSO-d 6)9.64(s,1H),8.29(d,1H),8.08(d,1H),7.75(dd,1H),7.71(dd,1H),7.32-7.18(m,2H),7.07(d,1H),6.89(d,1H)。
实施例12
8-氯-N-(2,2-二甲基苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺12
Figure PCTCN2022095441-appb-000167
Figure PCTCN2022095441-appb-000168
将化合物2,2-二甲基苯并[d][1,3]二氧杂环戊烷-5-胺12a(141mg，0.85mmol，上海皓鸿生物医药)、化合物1a(146mg，0.74mmol)、碳酸铯(362mg,1.11mmol)、三(二亚苄基丙酮)二钯(68mg，0.074mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(86mg,0.15mmol)溶于5mL 1,4-二氧六环中，将反应加热至105℃反应12小时。反应冷却至室温，加入30mL水，用乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，经高效液相制备色谱法(Waters-2545，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：60％-95％，流速：30mL/min)分离纯化，得到目标化合物12(132mg，产率：55％)。
MS m/z(ESI)：327.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ9.59(s,1H),8.18(d,1H),8.06(d,1H),7.74(dd,1H),7.69(dd,1H),7.30-7.17(m,2H),7.06(d,1H),6.79(d,1H),1.65(s,6H)。
实施例13
8-氯-N-(2,2-二甲基-2,3-二氢苯并呋喃-5-基)喹啉-2-胺13
Figure PCTCN2022095441-appb-000169
将化合物2,2-二甲基-2,3-二氢苯并呋喃-5-胺13a(59mg，0.36mmol，采用专利申请“WO2014169845中说明书第72页的实施例13”公开的方法制备而得)、化合物1a(60mg，0.30mmol)、三氟乙酸(62mg，0.54mmol)和2mL异丙醇置于25mL封管中，将反应加热至90℃反应12小时。反应液冷却至室温，加入15mL水，用饱和碳酸氢钠溶液调节至pH为8左右，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters-2767 Autopurification，洗脱体系：千分之一的甲酸水溶液和甲醇，甲醇的梯度：60％-95％，流速：30mL/min)分离纯化，得到目标化合物13(55mg，产率：56％)。
MS m/z(ESI)：325.1[M+1]。
1H NMR(500MHz,DMSO-d 6)9.47(s,1H),8.18(s,1H),8.04(dd,1H),7.78-7.60(m,3H),7.22(td,1H),7.05(dd,1H),6.67(dd,1H),3.03(s,2H),1.42(s,6H)。
实施例14
5-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-8,9-二氢-7H-环戊烷并[f]喹啉-3-胺14
Figure PCTCN2022095441-appb-000170
第一步
6-氯-2,3-二氢-1H-茚-5-胺14b
向100mL单口瓶中依次加入50mL二氯甲烷、(6-氯-2,3-二氢-1H-茚-5-基)氨基甲酸叔丁酯14a(3.4g，12.73mmol，采用公知的方法“ACS Catalysis,2018,8,4783–4788”制备而得)、三氟乙酸10mL，室温反应3小时。减压浓缩除去溶剂，用100mL二氯甲烷稀释，用饱和碳酸氢钠溶液洗涤(50mL×2)，饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品标题化合物14b(1.55g，产率：73％)，粗产品直接用于下一步反应。
MS m/z(ESI)：168.1[M+1]。
第二步
N-(6-氯-2,3-二氢-1H-茚-5-基)-3,3-二甲氧基丙酰胺14d
向100mL三口瓶中依次加入16mL四氢呋喃、化合物14b(1.55g,9.28mmol)、3,3-二甲氧基丙酸甲酯14c(1.65g，11.14mmol，百灵威)，然后0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，6.96mL，13.92mmol)。反应自然升至室温，反应12小时。冰浴下向体系内加入50mL饱和碳酸氢铵溶液淬灭反应，用乙酸乙酯萃取(50mL×3)。合并有机相，用饱和氯化钠溶液洗涤(50mL×3)，有机 相干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物14d(950mg,产率：36％)。
第三步
5-氯-4,7,8,9-四氢-3H-环戊烷并[f]喹啉-3-酮14e
向50mL单口瓶中依次加入10mL二氯甲烷、化合物14d(800mg,2.83mmol)，0℃向体系内缓慢滴加浓硫酸(2.27mL，42.40mmol)，加完后室温反应30分钟。减压浓缩除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物14e(500mg，产率：81％)。
MS m/z(ESI)：220.0[M+1]。
第四步
3,5-二氯-8,9-二氢-7H-环戊烷并[f]喹啉14f
向50mL单口瓶中依次加入2mL N,N-二甲基甲酰胺、化合物14e(300mg，1.37mmol)，将体系温度升至95℃后缓慢滴加三氯氧磷(0.1mL，1.10mmol)，继续反应30分钟。减压浓缩除去三氯氧磷，加入20mL乙酸乙酯稀释，用0.2N氢氧化钠溶液洗涤(30mL×2)，饱和氯化钠溶液洗涤(30mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物14f(0.25g，产率：78％)，粗品直接用于下一步反应。
MS m/z(ESI)：238.0[M+1]。
第五步
5-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-8,9-二氢-7H-环戊烷并[f]喹啉-3-胺14
向25mL单口瓶中依次加入2mL异丙醇、化合物14f(100mg,0.42mmol)、三氟乙酸(47.89mg,0.42mmol)、化合物1b(73mg,0.42mmol)，然后将温度升至85℃反应16小时。减压除去溶剂，用1mL甲醇稀释，采用薄层色谱法(TLC)，展开剂体系B纯化得标题化合物14(78mg,产率：49％)。
MS m/z(ESI)：375.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.89(d,1H),8.08(d,1H),7.72(s,1H),7.48-7.45(m,1H),7.37(d,1H),7.13(d,1H),3.15(t,2H),3.02(t,2H),2.12-2.14(m,2H)。
实施例15
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-甲基喹啉-2-胺15
Figure PCTCN2022095441-appb-000171
Figure PCTCN2022095441-appb-000172
第一步
N-(2-氯-3-甲基苯基)-3,3-二甲氧基丙酰胺15b
向100mL三口瓶中依次加入25mL四氢呋喃、2-氯-3-甲基苯胺15a(1.5g，10.59mmol，毕得医药)、化合物14c(1.88g，11.69mmol)，将体系温度降至0℃后缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液,10.57mL，21.14mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相并用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物15b(2.70g，产率：98％)，粗产品直接用于下一步反应。
第二步
8-氯-7-甲基喹啉-2(1H)-酮15c
向100mL单口瓶中依次加入15mL二氯甲烷、化合物15b(2.70g，10.48mmol)，0℃缓慢滴加浓硫酸(8.37mL，157.11mmol)，加完后撤去冰浴，继续反应16小时。减压除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物15c(1.8g，产率：89％)。
MS m/z(ESI)：194.0[M+1]。
第三步
2,8-二氯-7-甲基喹啉15d
向50mL单口瓶中依次加入化合物15c(800mg，4.67mmol)、三氯氧磷(3.16g，20.66mmol)，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用饱和碳酸氢钠溶液调节至pH为8左右，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物15d(620mg，产率：71％)。
MS m/z(ESI)：211.9[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-甲基喹啉-2-胺15
向25mL封管中依次加入8mL异丙醇、化合物15d(300mg,1.29mmol)、化合物1b(268mg,1.54mmol)、三氟乙酸(260mg,2.28mmol)。然后将反应升温至95℃反应16小时。减压除去溶剂，加入乙酸乙酯100mL稀释，用饱和碳酸氢钠溶液洗涤(50mL×2)，饱和氯化钠溶液洗涤(50mL×2)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters-2767 Autopurification，洗脱体系：千分之一的甲酸水溶液和甲醇，甲醇的梯度：65％-95％，流速：30mL/min)纯化，得到标题化合物15(300mg，产率：73％)。
MS m/z(ESI)：349.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ9.93(s,1H),8.90(s,1H),8.11(d,1H),7.65(d,1H),7.49(d,1H),7.37(d,1H),7.30(d,1H),7.07(d,1H),2.55(s,3H)。
实施例16
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-甲氧基喹啉-2-胺16
Figure PCTCN2022095441-appb-000173
第一步
N-(2-氯-3-甲氧基苯基)-3,3-二甲氧基丙酰胺16b
向100mL三口瓶中依次加入25mL四氢呋喃、2-氯-3-甲氧基苯胺16a(1.5g,9.51mmol，毕得医药)、化合物14c(1.69g,11.40mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，9.51mL，19.03mmol)，自然升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品标题化合物16b(2.50g，产率：96％)，粗产品直接用于下一步反应。
第二步
8-氯-7-甲氧基喹啉-2(1H)-酮16c
向100mL单口瓶中依次加入10mL二氯甲烷、化合物16b(2.50g,9.13mmol)，0℃缓慢滴加浓硫酸(7.29mL，136.93mmol)，撤去冰浴，继续反应16小时。减压除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物16c(1.6g，产率：84％)。
MS m/z(ESI)：210.0[M+1]。
第三步
2,8-二氯-7-甲氧基喹啉16d
向50mL单口瓶中依次加入甲苯8mL、化合物16c(800mg，3.81mmol)、三氯氧磷(1.17g，7.63mmol)，将体系温度升至100℃反应3小时。反应冷至室温，加入20mL冰水，用饱和碳酸氢钠调节至pH为8左右，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物16d(680mg，产率：78％)。
MS m/z(ESI)：227.9[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-甲氧基喹啉-2-胺16
向25mL封管中依次加入4mL异丙醇、化合物16d(250mg,1.09mmol)、化合物1b(227mg,1.31mmol)、三氟乙酸(224mg,1.96mmol)，然后将温度升至95℃后反应16小时。减压浓缩除去溶剂，加入乙酸乙酯100mL稀释，用饱和碳酸氢钠溶液洗涤(50mL×2)，饱和氯化钠溶液洗涤(50mL×2)。有机相用无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得目标产物16(280mg，产率：70％)。
MS m/z(ESI)：365.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),8.92(s,1H),8.09(d,1H),7.76(d,1H),7.49(d,1H),7.38(d,1H),7.31(d,1H),6.97(d,1H),4.00(s,3H)。
实施例17
7,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-喹啉-2-胺17
Figure PCTCN2022095441-appb-000174
Figure PCTCN2022095441-appb-000175
第一步
N-((2,3-二氯苯基)-3,3-二甲氧基丙酰胺17b
向100mL三口瓶中依次加入25mL四氢呋喃、2,3-二氯苯胺17a(1.5g,9.26mmol,百灵威)、化合物14c(1.65g,11.11mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，9.30mL，18.60mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物17b(2.50g，产率：97％)，粗产品直接用于下一步反应。
第二步
7,8-二氯喹啉-2(1H)-酮17c
向100mL单口瓶中依次加入15mL二氯甲烷、化合物17b(2.50g，8.99mmol)，0℃缓慢滴加浓硫酸(7.18mL，134.79mmol)，然后撤去冰浴，继续反应16小时。减压除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物17c(1.70g，产率：89％)。
MS m/z(ESI)：214.0[M+1]。
第三步
2,7,8-三氯喹啉17d
向50mL单口瓶中依次加入化合物17c(1.0g,4.67mmol)、三氯氧磷(3.58g，23.36mmol)，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入50mL冰水，用饱和碳酸氢钠调节至pH为8左右，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题化合物17d(950mg，产率：87％)。
MS m/z(ESI)：231.9[M+1]。
第四步
7,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-喹啉-2-胺17
向25mL封管反应瓶中依次加入8mL异丙醇、化合物17d(300mg，1.29 mmol)、化合物1b(268mg,1.54mmol)、三氟乙酸(260mg，2.28mmol)，然后将温度升至95℃反应16小时。减压除去溶剂，加入100mL乙酸乙酯稀释，用饱和碳酸氢钠溶液洗涤(50mL×2)，饱和氯化钠溶液洗涤(50mL×2)。有机相用无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得目标产物17(300mg，产率：63％)。
MS m/z(ESI)：369.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),8.76(s,1H),8.16(d,1H),7.76(d,1H),7.54-7.45(m,2H),7.38(d,1H),7.12(d,1H)。
实施例18
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-甲基喹啉-2-胺18
Figure PCTCN2022095441-appb-000176
第一步
N-(2-氯-4-甲基苯基)-3,3-二甲氧基丙酰胺18b
向100mL三口瓶中依次加入25mL四氢呋喃、2-氯-4-甲基苯胺18a(1g，7.06mmol，毕得医药)、化合物14c(1.26g，8.47mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，5.30mL，10.60mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物18b(1.50g,产率：82％)。
第二步
8-氯-6-甲基喹啉-2(1H)-酮18c
向100mL单口瓶中依次加入2mL二氯甲烷、化合物18b(1.50g，5.82mmol)， 0℃缓慢滴加浓硫酸(4.7mL，87.31mmol)，然后撤去冰浴，继续反应4小时。减压浓缩除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物18c(0.8g，产率：71％)。
MS m/z(ESI)：194.0[M+1]。
第三步
2,8-二氯-6-甲基喹啉18d
向50mL单口瓶中依次加入化合物18c(0.5g，2.58mmol)、三氯氧磷2mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物18d(0.3g，产率：55％)。
MS m/z(ESI)：212.0[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-甲基喹啉-2-胺18
向25mL封管中依次加入3mL异丙醇、化合物18d(50mg，0.24mmol)、化合物1b(102mg，0.59mmol)、三氟乙酸(67mg，0.59mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压浓缩除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：70％-90％，流速：30mL/min)纯化，得到标题化合物18(55mg，产率：67％)。
MS m/z(ESI)：349.1[M+1]。
1H NMR(500MHz,CDCl 3)8.26(s,1H),7.87(d,1H),7.60(s,1H),7.35(s,1H),7.14(m,1H),7.02(d,1H),6.85(d,1H),6.79(s,1H),2.46(s,3H)。
实施例19
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-甲氧基喹啉-2-胺19
Figure PCTCN2022095441-appb-000177
Figure PCTCN2022095441-appb-000178
第一步
N-(2-氯-4-甲氧基苯基)-3,3-二甲氧基丙酰胺19b
向100mL三口瓶中依次加入25mL四氢呋喃、2-氯-4-甲氧基苯胺19a(1g，6.35mmol，毕得医药)、化合物14c(1.13g，7.61mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，4.76mL，9.52mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相并用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物19b(1.20g，产率：69％)。
第二步
8-氯-6-甲氧基喹啉-2(1H)-酮19c
向100mL单口瓶中依次加入2mL二氯甲烷、化合物19b(1.20g，4.38mmol)，0℃缓慢滴加浓硫酸(3.52mL，65.76mmol)，然后撤去冰浴，继续反应4小时。减压除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物19c(0.6g，产率：65％)。
MS m/z(ESI)：210.0[M+1]。
第三步
2,8-二氯-6-甲氧基喹啉19d
向50mL单口瓶中依次加入化合物19c(500mg，2.39mmol)、三氯氧磷2.5mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷后，加入50mL冰水，用乙酸乙酯萃取(50mL×3)，有机层用饱和氯化钠溶液洗(50mL×2)，无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物19d(75mg，产率：14％)。
MS m/z(ESI)：228.0[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-甲氧基喹啉-2-胺19
向25mL封管反应瓶中依次加入3mL异丙醇、化合物19d(75mg，0.33 mmol)、化合物1b(142mg，0.82mmol)、三氟乙酸(94mg，0.82mmol)，然后将温度升至95℃后反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)纯化，得到标题化合物19(55mg，产率：67％)。
MS m/z(ESI)：365.1[M+1]。
1H NMR(500MHz,CDCl 3)8.22(s,1H),7.85(d,1H),7.45(s,1H),7.11(s,1H),7.00(d,1H),6.94(s,1H),6.85(d,1H),6.73(s,1H),3.89(s,3H)。
实施例20
6,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺20
Figure PCTCN2022095441-appb-000179
第一步
N-(2,4-二氯苯基)-3,3-二甲氧基丙酰胺20b
向100mL三口瓶中依次加入25mL四氢呋喃、2,4-二氯苯胺20a(1.0g，6.17mmol，百灵威)、化合物14c(1.10g，7.41mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，4.63mL，9.26mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，反应液减压浓缩除去大部分有机相，用乙酸乙酯萃取(50mL×3)，合并有机相用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物20b(1.40g,产率：82％)。
第二步
6,8-二氯喹啉-2(1H)-酮20c
向100mL单口瓶中依次加入2mL二氯甲烷、化合物20b(1.20g，4.31mmol)，0℃缓慢滴加浓硫酸(3.52mL,65.76mmol)，然后撤去冰浴，加热至90℃继续反应4小时。减压除去溶剂，将残余物滴入到冰水中析出固体，过滤，固体干燥得到标题化合物20c(0.5g，产率：54％)。
MS m/z(ESI)：213.9[M+1]。
第三步
2,6,8-三氯喹啉20d
向50mL单口瓶中依次加入化合物20c(300mg，1.40mmol)、三氯氧磷2mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物20d(240mg，产率：74％)。
MS m/z(ESI)：231.9[M+1]。
第四步
6,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺20
向25mL封管中依次加入3mL异丙醇、化合物20d(100mg，0.43mmol)、化合物1b(82mg，0.47mmol)、三氟乙酸(123mg，1.08mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压浓缩除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：80％-95％，流速：30mL/min)纯化，得到标题化合物20(55mg，产率：63％)。
MS m/z(ESI)：369.0[M+1]。
1H NMR(500MHz,CDCl 3)8.23(s,1H),7.86(d,1H),7.72(s,1H),7.56(s,1H),7.14(d,1H),7.03(s,1H),6.94-6.72(m,2H)。
实施例21
(2S,3S,4S,5R,6R)-6-(苯并[d][1,3]二氧杂环戊烷-5-基(8-氯喹啉-2-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸21
Figure PCTCN2022095441-appb-000180
Figure PCTCN2022095441-appb-000181
第一步
(2R,3R,4S,5S,6S)-2-(苯并[d][1,3]二氧杂环戊烷-5-基)(8-氯喹啉-2-基)氨基)-6-(甲氧基羰基)四氢-2H-吡喃-3,4,5-三醋酸酯21a
将化合物10(380mg，1.27mmol)溶解在甲苯(15mL)中，加入碳酸镉(131mg,0.76mmol)，加热至145℃分水反应12小时，再加入化合物2a(606mg，1.53mmol)，145℃分水反应24小时。冷却至室温，减压浓缩除去甲苯，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物21a(450mg，产率58％)。
MS m/z(ESI)：615.0[M+1]。
第二步
(2S,3S,4S,5R,6R)-6-(苯并[d][1,3]二氧杂环戊烷-5-基(8-氯喹啉-2-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸21
将一水合氢氧化锂(645mg，15.35mmol)溶解在水(4mL)中，加入30％过氧化氢溶液(1.83mL)，室温搅拌10分钟。将该溶液加入到化合物21a(450mg，0.51mmol)的四氢呋喃溶液(16mL)中，室温搅拌16小时。用饱和硫代硫酸钠溶液(20mL)淬灭后，用1N盐酸溶液调节至pH为4，用乙酸乙酯(50mL×3)萃取，饱和氯化钠溶液(100mL)洗涤，有机相减压浓缩后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：15％-95％，流速：30mL/min)纯化，得到标题化合物21(85mg，产率35％)。
MS m/z(ESI)：475.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.03(d,1H),7.78(d,1H),7.72(d,1H),7.26(t,1H),7.06(d,1H),7.00-6.86(m,2H),6.50(d,1H),6.34(d,1H),6.13(d,2H),5.08-4.82(m,2H),3.51(d,1H),3.40-3.25(m,2H),3.06(t,1H),2.98-2.82(m,1H)。
实施例22
(2S,3S,4S,5R,6R)-6-((8-氯喹啉-2-基)(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸22
Figure PCTCN2022095441-appb-000182
第一步
(2R,3R,4S,5S,6S)-2-((8-氯喹啉-2-基)(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)氨基)-6-(甲氧基羰基)四氢-2H-吡喃-3,4,5-三醋酸酯22a
将化合物6(500mg，1.60mmol)溶解在甲苯(30mL)中，加入碳酸镉(165mg,0.96mmol)，加热至140℃分水反应12小时，再加入化合物2a(1.90g，4.80mmol)，140℃分水反应24小时。冷却至室温，减压浓缩除去甲苯，残余物用柱层析色谱法以洗脱剂体系B纯化得到标题化合物22a(400mg，产率40％)。
MS m/z(ESI)：629.0[M+1]。
第二步
(2S,3S,4S,5R,6R)-6-((8-氯喹啉-2-基)(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸22
将一水合氢氧化锂(534mg，12.72mmol)溶解在水(5mL)中，加入30％过氧化氢溶液(1.1mL)，室温搅拌10分钟。将该溶液加入到化合物22a(400mg，0.64mmol)的四氢呋喃溶液(15mL)中，室温搅拌2小时。用饱和硫代硫酸钠溶液(20mL)淬灭后，用1N盐酸溶液调节至pH为4，用乙酸乙酯(50mL×3)萃取，饱和氯化钠溶液(100mL)洗涤，有机相减压浓缩后经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：20％-65％， 流速：30mL/min)纯化，得到标题化合物22(95mg，产率36％)。
MS m/z(ESI)：489.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.01(d,1H),7.77(dd,1H),7.70(dd,1H),7.25(t,1H),6.99(d,1H),6.94(d,1H),6.89(dd,1H),6.46(d,1H),6.33(d,1H),5.03-4.83(m,2H),4.40-4.20(m,4H),3.54(d,1H),3.43-3.36(m,2H),3.08(t,1H),2.97-2.81(m,1H)。
实施例23
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-5-甲基喹啉-2-胺23
Figure PCTCN2022095441-appb-000183
第一步
N-(2-氯-5-甲基苯基)-3,3-二乙氧基丙酰胺23c
向100mL三口瓶中依次加入5mL N,N-二甲基甲酰胺、2-氯-5-甲基苯胺23a(0.5g，3.53mmol，毕得医药)、3,3-二乙氧基丙酸23b(0.63g，3.88mmol，百灵威)，0℃缓慢加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.01g，5.29mmol)、N,N-二异丙基乙胺(0.91g，7.06mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品标题化合物23c(1.0g,产率：99％)，粗产品直接用于下一步反应。
第二步
8-氯-5-甲基喹啉-2(1H)-酮23d
向100mL单口瓶中依次加入2mL二氯甲烷、化合物23c(1.00g，3.5mmol)，0℃缓慢滴加浓硫酸(3.35mL，62.98mmol)，然后撤去冰浴，继续反应4小时。减 压除去溶剂，将残余物滴入到50mL冰水中，用乙酸乙酯萃取(50mL×5)，合并有机相，用饱和氯化钠溶液洗(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物23d(0.26g，产率：38％)。
MS m/z(ESI)：194.0[M+1]。
第三步
2,8-二氯-5-甲基喹啉23e
向50mL单口瓶中依次加入化合物23d(0.26g，1.34mmol)、三氯氧磷(2mL)，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水(50mL)，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，得到粗产品标题化合物23e(0.28g，产率：99％)，粗产品直接用于下一步反应。
MS m/z(ESI)：212.0[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-5-甲基喹啉-2-胺23
向25mL封管中依次加入3mL异丙醇、化合物23e(100mg，0.47mmol)、化合物1b(97mg，0.56mmol)、三氟乙酸(161mg，1.41mmol),然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：70％-90％，流速：30mL/min)纯化，得到标题化合物23(80mg，产率：48％)。
MS m/z(ESI)：349.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ9.96(s,1H),8.88(d,1H),8.27(d,1H),7.69(d,1H),7.48(dd,1H),7.37(d,1H),7.19-7.12(m,2H),2.57(s,3H)。
实施例24
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-5-甲氧基喹啉-2-胺24
Figure PCTCN2022095441-appb-000184
Figure PCTCN2022095441-appb-000185
第一步
N-(2-氯-5-甲氧基苯基)-3,3-二乙氧基丙酰胺24b
向100mL三口瓶中依次加入5mL N,N-二甲基甲酰胺、2-氯-5-甲氧基苯胺24a(0.5g，3.17mmol，毕得医药)、化合物23b(0.63g，3.88mmol)，0℃缓慢加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.01g，5.29mmol)、N,N-二异丙基乙胺(0.91g，7.06mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品标题化合物24b(0.95g,产率：99％)，粗产品直接用于下一步反应。
第二步
8-氯-5-甲氧基喹啉-2(1H)-酮24c
向100mL单口瓶中依次加入2mL二氯甲烷、化合物24b(0.95g，3.14mmol)，0℃缓慢滴加浓硫酸(2.52mL，47.22mmol)，然后撤去冰浴，继续反应4小时。减压除去溶剂，将残余物滴入到50mL冰水中，用乙酸乙酯萃取(50mL×5)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物24c(0.26g，产率：40％)。
MS m/z(ESI)：210.0[M+1]。
第三步
2,8-二氯-5-甲氧基喹啉24d
向50mL单口瓶中依次加入化合物24c(365mg，1.26mmol)、三氯氧磷2.5mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机层用饱和氯化钠溶液洗(50mL×2)，无水硫酸钠干燥，过滤，浓缩，得到粗产品标题化合物24d(288mg，产率：99％)，粗产品直接用于下一步反应。
MS m/z(ESI)：228.0[M+1]。
第四步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-5-甲氧基喹啉-2-胺24
向25mL封管中依次加入3mL异丙醇、化合物24d(288mg，1.26mmol)、化合物1b(218mg，1.26mmol)、三氟乙酸(431mg，3.78mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)纯化，得到标题化合物24(230mg，产率：49％)。
MS m/z(ESI)：365.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),8.87(s,1H),8.31(d,1H),7.72(d,1H),7.48(d,1H),7.37(d,1H),7.09(d,1H),6.83(d,1H),3.95(s,3H)。
实施例25
5,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺25
Figure PCTCN2022095441-appb-000186
第一步
N-(2,5-二氯苯基)-3,3-二乙氧基丙酰胺25b
向100mL三口瓶中依次加入5mL N,N-二甲基甲酰胺、2,5-二氯苯胺25a(0.5g，3.08mmol，毕得医药)、化合物23b(0.50g，3.39mmol)，0℃缓慢加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.01g，5.29mmol)、N,N-二异丙基乙胺(0.91g，7.06mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和碳酸氢钠水溶液淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品标题化合物25b(0.94g,产率：99％)，粗产品直接用于下一步反应。
第二步
5,8-二氯喹啉-2(1H)-酮25c
向100mL单口瓶中依次加入2mL二氯甲烷、化合物25b(0.51g，1.67mmol)，0℃缓慢滴加浓硫酸(1.33mL,25.05mmol)，然后撤去冰浴，继续反应4小时。减压除去溶剂，将反应液滴入到50mL冰水中，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物25c(0.21g，产率：56％)。
MS m/z(ESI)：214.1[M+1]。
第三步
2,5,8-三氯喹啉25d
向50mL单口瓶中依次加入化合物25c(213mg，0.99mmol)、三氯氧磷2mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，得到粗产品标题化合物25d(230mg，产率：99％)，粗产品直接用于下一步反应。
MS m/z(ESI)：231.9[M+1]。
第四步
5,8-二氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺25
向25mL封管中依次加入3mL异丙醇、化合物25d(234mg，1.01mmol)、化合物1b(174mg，1.01mmol)、三氟乙酸(344mg，3.02mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：80％-95％，流速：30mL/min)纯化，得到标题化合物25(230mg，产率：59％)。
MS m/z(ESI)：369.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),8.79(d,1H),8.35(d,1H),7.81(d,1H),7.51(dd,1H),7.46(d,1H),7.40(d,1H),7.27(d,1H)。
实施例26
8-氯-2-((2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)氨基)喹啉-6-腈26
Figure PCTCN2022095441-appb-000187
Figure PCTCN2022095441-appb-000188
第一步
N-(4-溴-2-氯苯基)-3,3-二甲氧基丙酰胺26b
向100mL三口瓶中依次加入25mL四氢呋喃、4-溴-2-氯苯胺26a(3.0g，14.53mmol，百灵威)、化合物14c(2.36g，15.98mmol)，0℃缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，10.89mL，21.79mmol)，然后体系升至室温，反应24小时。向体系内加入50mL饱和氯化铵溶液淬灭反应，减压除去溶剂，用乙酸乙酯萃取(50mL×3)，合并有机相用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品标题化合物26b(4.60g，产率：98％)，粗产品直接用于下一步反应。
第二步
6-溴-8-氯喹啉-2(1H)-酮26c
向100mL单口瓶中依次加入5mL二氯甲烷、化合物26b(4.60g，14.25mmol)，0℃缓慢滴加浓硫酸(11.40mL，213.89mmol)，然后撤去冰浴，加热至90℃继续反应2小时。减压除去溶剂，将残余物滴入到50mL冰水中，用乙酸乙酯萃取(50mL×5)，合并有机相用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物26c(0.46g,产率：12％)。
MS m/z(ESI)：257.9[M+1]。
第三步
6-溴-2,8-二氯喹啉26d
向50mL单口瓶中依次加入化合物26c(460mg，1.78mmol)、三氯氧磷2mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，得到粗产品标题化合物26d(440mg，产率：89％)，粗产品直接用于下一步反应。
第四步
6-溴-8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺26e
向25mL封管中依次加入3mL异丙醇、化合物26d(280mg，1.01mmol)、化 合物1b(175mg，1.01mmol)、三氟乙酸(345mg，3.03mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(25mL×3)。有机相用饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物26e(260mg，产率：62％)。
MS m/z(ESI)：412.9[M+1]。
第五步
8-氯-2-((2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)氨基)喹啉-6-腈26
向25mL三口瓶中依次加入3mL N,N-二甲基乙酰胺、化合物26e(150mg，0.36mmol)、氰化锌(126mg，1.01mmol)、锌粉(3.50mg，0.05mmol)、三(二亚苄基丙酮)二钯(36mg，0.04mmol)、1,1'-双(二苯基膦)二茂铁(46mg，0.08mmol)，加热至135℃反应3小时。反应冷却至室温，加入25mL水，用乙酸乙酯萃取(25mL×3)，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：80％-95％，流速：30mL/min)纯化，得到标题化合物26(55mg，产率：63％)。
MS m/z(ESI)：360.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),8.74(s,1H),8.36(s,1H),8.22-8.12(m,2H),7.53(d,1H),7.41(d,1H),7.22(d,1H)。
实施例27
8-氯-6-环丙基-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺27
Figure PCTCN2022095441-appb-000189
将化合物26e(165mg，0.40mmol)溶于7.5mL 1,4-二氧六环和水(V/V＝4:1)中，加入环丙基硼酸27a(41mg，0.48mmol，韶远化学科技(上海)有限公司)、碳酸钠(127mg，1.20mmol)、二氯[1,1’-双(二叔丁基膦)二茂铁钯(II)(39mg，0.06mmol，毕得医药)。氮气置换三次后，升温到100℃反应3小时。反应冷却至室温，向反应液中加入饱和碳酸氢钠溶液(25mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters  2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：75％-95％，流速：30mL/min)纯化，得到标题化合物27(20mg，产率：13％)。
MS m/z(ESI)：375.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.85(d,1H),8.05(d,1H),7.55(d,1H),7.48-7.44(m,2H),7.36(d,1H),7.09(d,1H),2.08-2.03(m,1H),1.06-0.97(m,2H),0.81-0.75(m,2H)。
实施例28
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-(四氢-2H-吡喃-4-基)喹啉-2-胺28
Figure PCTCN2022095441-appb-000190
第一步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-(3,6-二氢-2H-吡喃-4-基)喹啉-2-胺28b
将化合物26e(181mg，0.44mmol)溶于7.5mL 1,4-二氧六环和水(V/V＝4:1)中，加入3,6-二氢-2H-吡喃-4-硼酸频那醇酯28a(92mg，0.44mmol，韶远化学科技(上海)有限公司)、碳酸钠(140mg，1.31mmol)、二氯[1,1’-双(二叔丁基膦)二茂铁钯(II)(29mg，0.044mmol)。氮气置换三次后，升温到100℃反应3小时。反应冷却至室温，向反应液中加入饱和碳酸氢钠溶液(25mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，无水硫酸钠干燥。减压除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物28b(140mg，产率：77％)。
MS m/z(ESI)：417.0[M+1]。
第二步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-6-(四氢-2H-吡喃-4-基)喹啉-2-胺 28
将化合物28b(140mg，0.34mmol)溶于10mL乙酸乙酯中，加入铂碳(70mg，5％Wt.，50-70％含水量，韶远化学科技(上海)有限公司)，氢气置换三次，氢气氛下反应24小时。用硅藻土过滤反应液，减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：70％-95％，流速：30mL/min)纯化，得到标题化合物28(70mg，产率：50％)。
MS m/z(ESI)：419.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),8.86(d,1H),8.11(d,1H),7.74(d,1H),7.61(d,1H),7.47(dd,1H),7.37(d,1H),7.10(d,1H),3.99(dd,2H),3.46(td,2H),2.93-2.85(m,1H),1.83-1.68(m,4H)。
实施例29
8-氯-7-环丙基-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺29
Figure PCTCN2022095441-appb-000191
第一步
N-(3-溴-2-氯苯基)-3,3-二甲氧基丙酰胺29b
将3-溴-2-氯-苯胺29a(2.0g，9.72mmol，毕得医药)溶于15mL四氢呋喃中，加入化合物14c(1.58g，10.68mmol)，反应降温到0℃，滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，5.4mL，10.7mmol)，然后体系升至室温，反应16小时。向反应液中加入饱和氯化铵溶液(100mL)，用乙酸乙酯萃取(100mL×3)，饱和氯化钠溶液洗涤(100mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，真空干燥，得到粗产品标题化合物29b(3.1g，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI)：321.9[M+1]。
第二步
7-溴-8-氯喹啉-2(1H)-酮29c
将化合物29b(3.1g，9.61mmol)溶于3mL二氯甲烷中，降温到0℃，加入浓硫酸(7.7mL，144mmol)。然后撤去冰浴，加热到90℃继续反应2小时。反应液冷却至室温，减压除去溶剂，将残余物滴入到50mL冰水中，用乙酸乙酯萃取(50mL×5)，合并有机相用饱和氯化钠溶液洗涤(50mL×2)，有机相用无水硫酸钠干燥，过滤，减压除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物29c(0.56g,产率：23％)。
MS m/z(ESI)：257.9[M+1]。
第三步
7-溴-2,8-二氯喹啉29d
向50mL单口瓶中依次加入化合物29c(560mg，2.17mmol)、三氯氧磷3mL，将体系温度升至95℃反应90分钟。减压除去三氯氧磷，加入冰水50mL，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，浓缩，得到粗产品标题化合物29d(599mg，产率：99％)，粗产品不经纯化直接用于下一步反应。
第四步
7-溴-8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺29e
向25mL封管中依次加入3mL异丙醇、化合物29d(600mg，2.17mmol)、化合物1b(319mg，1.84mmol)、三氟乙酸(741mg，6.50mmol)，然后将温度升至95℃反应16小时。反应冷却至室温，加入25mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(25mL×3)。有机相用饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。过滤，滤液减压除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物29e(554mg，产率：62％)。
MS m/z(ESI)：412.9[M+1]。
第五步
8-氯-7-环丙基-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺29
将化合物29e(140mg，0.34mmol)溶于7.5mL 1,4-二氧六环和水(V/V＝4:1)中，加入化合物27a(37.8mg，0.44mmol)、碳酸钠(107.6mg，1.02mmol)、二氯[1,1’-双(二叔丁基膦)二茂铁钯(II)(33.0mg，0.051mmol)。氮气置换三次后，升温至100℃反应3小时。反应冷却至室温，向反应液中加入饱和碳酸氢钠溶液(25mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥。减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：55％-95％，流速：30mL/min)纯化，得到标题化合物29(30mg，产率：23％)。
MS m/z(ESI)：375.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),8.92(d,1H),8.08(d,1H),7.64(d,1H),7.48(dd,1H),7.37(d,1H),7.05(d,1H),6.90(d,1H),2.50-2.42(m,1H),1.15-1.10(m,2H),0.86-0.81(m,2H)。
实施例30
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-(四氢-2H-吡喃-4-基)喹啉-2-胺30
Figure PCTCN2022095441-appb-000192
第一步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-(3,6-二氢-2H-吡喃-4-基)喹啉-2-胺30a
将化合物29e(170mg，0.41mmol)溶于7.5mL 1,4-二氧六环和水(V/V＝4:1)中，加入化合物28a(104mg，0.49mmol)、碳酸钠(131mg，1.23mmol)、二氯[1,1’-双(二叔丁基膦)二茂铁钯(II)(16mg，0.025mmol)。氮气置换三次后，升温到100℃反应3小时。反应冷却至室温，向反应液中加入饱和碳酸氢钠溶液(25mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥。过滤，滤液减压除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物30a(70mg，产率：41％)。
MS m/z(ESI)：417.0[M+1]。
第二步
8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)-7-(四氢-2H-吡喃-4-基)喹啉-2-胺30
将化合物30a(70mg，0.17mmol)溶于5mL乙酸乙酯中，加入铂碳(35mg， 5％Wt.，50-70％含水量，韶远化学科技(上海)有限公司)，氢气置换三次，氢气氛下反应24小时。用硅藻土过滤反应液，减压除去溶剂，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和甲醇，甲醇的梯度：75％-95％，流速：30mL/min)纯化，得到标题化合物30(10mg，产率：14％)。
MS m/z(ESI)：419.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),8.90(d,1H),8.12(d,1H),7.74(d,1H),7.48(dd,1H),7.40-7.35(m,2H),7.08(d,1H),4.01(dd,2H),3.54(td,2H),2.04-1.95(m,1H),1.87-1.69(m,4H)。
实施例31
5-((8-氯喹啉-2-基)氨基)-3-甲基苯并[d]噁唑-2(3H)-酮31
Figure PCTCN2022095441-appb-000193
将5-氨基-3-甲基-1,3-苯并噁唑-2(3H)-酮31a(123mg，0.75mmol，毕得医药)、化合物1a(135mg，0.68mmol)、碳酸铯(333mg，1.02mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(78.9mg，0.14mmol)和三(二亚苄基丙酮)二钯(63mg，0.068mmol)溶于5mL 1,4-二氧六环中，将反应加热到100℃反应12小时。反应冷却至室温，加入30mL水，用乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：45％-95％，流速：30mL/min)纯化，得到标题化合物31(74mg，产率：33％)。
MS m/z(ESI)：324.1[M-1]。
1H NMR(500MHz,CDCl 3)δ9.89(s,1H),9.00(d,1H),8.14(d,1H),7.80(d,1H),7.75(d,1H),7.33-7.22(m,3H),7.14(d,1H),3.39(s,3H)。
生物学评价
以下内容中出现的简称说明：
p.o.：口服
bid：一日两次
qd：一日一次
MC：羧甲基纤维素钠
测试例1、本公开化合物对小鼠溃疡性结肠炎(UC)的预防治疗作用
1、摘要
本实验选用维通利华C57BL/6雌性小鼠建立由硫酸钠葡聚糖(DSS)诱导的溃疡性结肠炎(Ulcerative Colitis，UC)模型，评估阳性化合物ABX-464(见WO2015001518A1化合物90)与本公开化合物1对DSS诱导的溃疡性结肠炎的预防治疗作用。
Figure PCTCN2022095441-appb-000194
2.实验方法和实验材料
2.1.实验动物和饲养条件
实验用C57BL/6雌性小鼠，维通利华实验动物有限公司(生产许可证编号：SCXK(浙)2019-0001，动物合格证编号：20210401Abzz0619000795，购入时体重20-22g，5只/笼饲养于独立SPF空间，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养至少1周后开始实验。
2.2.实验试剂和仪器
右旋糖酐硫酸酯钠盐(Dextrane sulfate sodium salt,DSS)：MP Biomedicals，货号160110，批号S5036。无菌水配制，过滤，不能高压灭菌，每两天更换一次。
乙醇：上海百特医疗用品有限公司，批号S2001050。
橄榄油：国药集团化学试剂有限公司，货号30189828，批号20180104。
甲基纤维素M450：国药集团化学试剂有限公司，货号69016460，批号20170308。
酶标仪：厂家BMGlabtech，型号PHERAstar Fs。
台式低速离心机：厂家Eppendorf，型号5417R。
电子天平：梅特勒-托利多仪器有限公司，型号AL204。
2.3.实验设计和实验方法
2.3.1.动物分组：
小鼠适应性饲养后，分组如下：
Figure PCTCN2022095441-appb-000195
Figure PCTCN2022095441-appb-000196
溶剂：0.5％MC混悬液
2.3.2.药物配制：
DSS配制方法：25g DSS+1L超纯水，无菌过滤，4℃保存。
50mg/kg ABX-464配制方法：100mg ABX-464+20mL 0.5％MC，研磨，4℃保存。配制2次。
50mg/kg本公开化合物1配制方法：100mg本公开化合物1+20mL 0.5％MC，研磨，4℃保存。
2.3.3.实验方法：
小鼠按照体重随机分成5组：正常对照组(
Figure PCTCN2022095441-appb-000197
组)、模型组(DSS组)、ABX-464(50mg/kg，p.o.，qd)、ABX-464(50mg/kg，p.o.，bid)、本公开化合物1(50mg/kg，p.o.，bid)。小鼠经过适应性饲养后，于第0天开始换成2.5％DSS饲喂，DSS饲喂7天后换成正常水直到第10天，并于第0天至第10天开始连续10天灌胃相应的溶剂和药物，第0天至第10天期间每天观察小鼠体重变化。第10天小鼠于称重后测量结肠长度。
2.4.数据表达和统计学处理
实验数据表示为平均数(Mean)±标准误(SEM)。采用Excel软件t检验进行统计比较。将模型组与正常对照组数据进行分析比较，#P<0.05表示模型组与正常对照组比较具有显著性差异，##P<0.01表示模型组与正常对照组比较具有高度显著性差异，###P<0.001表示模型组与正常对照组比较具有极高度显著性差异。*P<0.05表示给药组与模型组比较具有显著性差异，**P<0.01表示给药组与模型组比较具有高度显著性差异，***P<0.001表示给药组与模型组比较具有极高度显著性差异。
3.结果
3.1本公开化合物1对DSS诱导的UC小鼠体重的影响
体重实验结果显示(图1)：与正常对照组相比，DSS模型组小鼠自第4天开始体重明显降低，体重下降幅度逐步增加，第10天体重下降幅度达到30.0％(P<0.001)；与DSS模型组比较，所有给药组自第7天开始体重均明显回升，第10天50mg/kg的ABX-464(qd)、ABX-464(bid)、本公开化合物1(bid)其体重下降幅度分别降低到14.1％(P<0.001)、10.3％(P<0.001)和0.4％(P<0.001)。实验终点时体重恢复幅度从强到弱依次为：本公开化合物1 50mg/kg(bid)>ABX-464 50mg/kg(bid)>ABX-464 50mg/kg(qd)。
3.2本公开化合物1对DSS诱导的UC小鼠结肠长度的影响
结肠长度结果显示(图2)：与正常对照组相比，DSS模型组结肠长度明显缩 短(P<0.001)，仅为正常对照组的75.4％；与DSS模型组比较，所有给药组结肠长度明显增长，50mg/kg的ABX-464(qd)、ABX-464(bid)、本公开化合物1(bid)其结肠长度分别为正常对照组的85.5％(P<0.05)、89.3％(P<0.05)和91.9％(P<0.01)。结肠长度从长到短依次为：本公开化合物1 50mg/kg(bid)>ABX-464 50mg/kg(bid)>ABX-464 50mg/kg(qd)。
4.结论
DSS模型作为IBD疾病的UC模拟动物模型，DSS的分子量(36000-50000)、批号、保存配置和小鼠饲养环境、系别等均影响模型的效果，本次造模比较成功，小鼠体重和结肠长度均有明显的变化。结果显示：本公开化合物1在体重和结肠长度方面表现出强于阳性药ABX-464的良好药效。因此，50mg/kg ABX-464和本公开化合物1对DSS诱导的UC有一定的预防治疗效果，本公开化合物1药效最强，高于同剂量ABX-464。
测试例2.本公开化合物对miR-124的上调作用
一、摘要
本试验用于评估本公开化合物对miR-124的上调作用。
二、实验材料及仪器
1.人T细胞活化CD3/CD28磁珠(Dynabead Human T-Activator CD3/CD28 for T Cell Expansion and Activation)(Gibco，11131D)
2.人总T细胞分离试剂盒(Pan T Cell Isolation Kit,human)(Miltenyi，130-096-535)
3.人白介素2(Human IL-2)(Peprotech，200-02-100)
4.小RNA抽提试剂盒(microRNA抽提试剂盒)(Qiagen，217004)
5.小RNA反转录试剂盒(miScript II RT Kit)(Qiagen，218161)
6.小RNA SYBR Green PCR试剂盒(miScript SYBR Green PCR Kit)(Qiagen，218073)
7.磷酸缓冲液PBS，pH7.4(上海源培生物科技股份有限公司，B320)
8.牛血清白蛋白，BSA(碧云天，ST023)
9.EDTA(0.5M),pH 8.0(Invitrogen，AM9260G)
10.LS分离柱(LS Columns)(Miltenyi,130-042-401)
11. 24孔细胞培养板(Corning，3524)
12. 96孔板(Corning，3788)
13.细胞培养箱(Thermo，Steri cycle i160)
14.实时荧光定量PCR仪(Applied biosystem，QuantStudio6 Flex)
15.PCR仪(Applied biosystem，ProFlex)
16. 96孔透明PCR板，0.2mL(Applied biosystems，N8010560)
17.RPMI1640培养基(Gibco，11875119)
18.胎牛血清，FBS(Gibco，10099-141)
19.磁力架(Invitrogen，DynaMag TM-2)
20.六孔细胞培养板(Thermo，150239)
21.分光光度计(IMPLEN，NP80)
22.磁珠分离铁架(QuadroMACS Separator)(美天旎，130-090-976)
23.miR124-3P-F引物(金唯智公司定制)
24.hsa-U6检测引物(天根，CD201-0145)
三、实验步骤
化合物对miR-124表达水平的影响在CD3/CD28抗体激活后的T细胞中检测。激活的T细胞经过化合物处理后，提取细胞的总RNA，反转录所得的cDNA作为模板，使用特异性miR-124引物用SYBR green荧光定量PCR法来定量。
T细胞的分离：购买所得的人外周血单核细胞(PBMC)，计数离心后用分离缓冲液(PBS pH 7.4,含有0.5％BSA和2mM EDTA))洗一遍，弃去上清，按每1×10 7个细胞加40μL缓冲液和10μL T细胞分离生物素化混合抗体(pan T Cell Biotin-Antibody Cocktail)的量，加入各成分重悬沉淀并混匀，4℃冰箱孵育5分钟。孵育完成后，按照每1×10 7个细胞加30μL缓冲液和20μL T细胞分离磁珠(Pan T Cell MicroBeads Cocktail)的量加入各成分，混匀后4℃冰箱孵育10分钟。用3毫升细胞分离缓冲液提前润洗分离柱子LS column，将上述细胞混悬液过柱，细胞悬液过柱后用1毫升细胞分离缓冲液重复洗柱子3遍，流出细胞液被收集在15毫升离心管中即是富集的T细胞。对细胞进行计数，按1×10 6细胞/mL的密度加入含有10％FBS和40U/mL IL-2的RPMI1640培养基(完全培养基)，保存于冰上备用。
T细胞的活化：按每1×10 6个细胞加25μL活化磁珠的量，取出相应的T细胞活化CD3/CD28磁珠于1.5mL离心管中，吸出前应在振荡器上振荡30s左右。在离心管中以体积比大于1：1比例，使用培养基将活化磁珠洗3遍，最后一遍去除所有洗液，加入与起始体积等量的完全培养基重悬活化磁珠。将清洗好的活化磁珠加入细胞重悬液中，混合均匀。取出六孔板，以每孔3mL的量加入细胞，37℃，5％CO 2细胞培养箱中培养2天。
化合物处理：化合物储存液为20mM，用DMSO稀释至200μM，再用完全培养基将化合物稀释4倍至50μM(50×)，混匀待用。DMSO稀释4倍(25％DMSO)为阴性对照孔。活化两天的T细胞，将细胞吹打均匀，使用磁力架并安装上1.5mL离心管，去除活化磁珠，并收集细胞悬液。对细胞进行计数后，300xg，10min离心弃上清，重悬细胞至1.02×10 6/mL，每个24孔板加入980μL细胞悬液和20μL 50×化合物，化合物最终浓度为1μM。将细胞置于37℃，5％CO 2细胞培养箱中继续培养3天。
RNA抽提：将T细胞离心收集，1500rpm离心3分钟，PBS清洗1次，离心后弃 上清。使用小RNA抽提试剂盒，根据说明书抽提细胞总RNA。细胞沉淀加入700μL Trizol细胞裂解液，枪头吹打均匀，于室温放置5分钟。加入140μL氯仿，振荡混匀，于室温静置3分钟。将氯仿-细胞裂解液混合物于4℃以12000xg离心15分钟。将上层溶液转移至新的无RNA酶(RNase-free)的离心管中，加入1.5倍体积的无水乙醇，枪头吹打数次。将溶液转移至RNA吸附柱中，8000xg离心15s。将离心柱用700μL RWT溶液洗一遍，8000xg离心15s，加入500μL RPE溶液洗两遍，8000xg离心2分钟。将吸附柱放入新的2mL离心管中，12000xg离心1min去除残余洗液。将吸附柱放入新的1.5mL离心管中，加入30-50μL无RNA酶水(RNase-free water)，12000xg离心2分钟，收集的溶液为RNA溶液，使用分光光度计测量RNA浓度。RNA溶液保存于-80度冰箱。
反转录：上述提取的RNA模板放置在冰上，取出小RNA反转录试剂盒，于室温解冻部分成分(包含5×miScript HiSpec Buffer，10×miScript nucleics Mix和无RNA酶水)，于冰上解冻miScript Reverse Transcriptase mix成分。每个反应(10μL)成分为：5×miScript HiSpec Buffer(2μL)，10×miScript nucleics Mix(1μL)，miScript Reverse Transcriptase mix(1μL)，无RNA酶水(2μL)，RNA模板(4μL)，在冰上配制上述反应。将样品放置于PCR仪中，设置程序如下：37℃，60分钟；95℃，5分钟；4℃保存。反应完成的样品为cDNA样品。
荧光定量PCR：使用SYBR green染色法检测miR-124的转录水平，同时检测管家基因U6的转录水平作为内参。解冻所有小RNA SYBR green PCR试剂盒所需试剂至常温，将每个cDNA样品模板用无RNA酶水稀释10倍，再稀释5倍。按照下表1配制反应混合物，并将反应混合物加入到96孔PCR板中，用封板膜封板，离心。将PCR反应在荧光定量PCR仪上按照表2步骤进行。
表1 荧光定量PCR反应成分表
Figure PCTCN2022095441-appb-000198
表2 荧光定量PCR步骤
Figure PCTCN2022095441-appb-000199
Figure PCTCN2022095441-appb-000200
表3 荧光定量PCR检测引物表
Figure PCTCN2022095441-appb-000201
数据分析：根据软件所算得的CT值，计算每个样品miR-124与内参U6表达水平的比值，即ΔCT(测试化合物)＝CT miRNA-124(测试化合物)-CT U6(测试化合物)。相对表达量由以下公式计算，相对表达量(测试化合物)＝2 (-[ΔCT(测试化合物)-ΔCT(DMSO)])。
表4 本公开化合物对miR-124上调的活性情况
化合物 miR-124上调(倍数)
DMSO 1.0
1 3.9
2 1.2
3 5.2
4 5.4
5 1.4
6 2.7
7 5.2
8 5.4
9 2.4
10 2.1
11 2.4
12 1.8
13 2.8
14 1.5
15 5.7
16 3.9
17 5.9
18 2.7
20 5.0
21 1.9
22 1.7
23 2.3
24 3.0
25 6.7
26 2.4
结论：本公开化合物具有良好的促进miR124上调的活性。
测试例3、本公开化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃和静脉注射给予实施例2化合物和对比化合物A(参见WO2016135052A1实施例3的化合物(1))后不同时刻血浆中的药物浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
Figure PCTCN2022095441-appb-000202
2、试验方案
2.1试验药品
实施例2化合物、对比化合物A。
2.2试验动物
健康成年SD大鼠16只，雌雄各半，平均分成4组，购自维通利华实验动物技术有限公司。
2.3药物配制
称取一定量药物，加入5％DMSO、5％吐温80和90％生理盐水配制成澄明溶液。
2.4给药
灌胃组：SD大鼠禁食过夜后灌胃给药，给药剂量为2mg/kg，给药体积均为10.0mL/kg。
静脉组：SD大鼠禁食过夜后静脉注射给药，给药剂量为1mg/kg，给药体积均为5.0mL/kg。
3、操作
灌胃组：大鼠灌胃给药实施例2化合物和对比化合物A，于给药前及给药后0.25小时、0.5小时、1.0小时、2.0小时、4.0小时、6.0小时、8.0小时、11.0小时、24.0小时由眼眶采血0.1mL，置于EDTA-K2抗凝试管中，4℃、10000转/分钟离心1分钟，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2h进食。
静脉组：大鼠静脉注射实施例2化合物和对比化合物A，于给药前及给药后5分钟、15分钟、0.5小时、1.0小时、2.0小时、4.0小时、8.0小时、11.0小时、24.0 小时采血，处理同灌胃组。
测定不同浓度的药物灌胃、静脉注射给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆20μL，加入内标溶液(喜树碱100ng/mL)50μL、乙腈200μL，涡旋混合5分钟，离心10分钟(3700-4000转/分钟)，血浆样品取上清液1.0-2.0μL进行LC/MS/MS分析。
4、药代动力学参数结果
表5 本公开化合物的灌胃给药药代动力学参数
Figure PCTCN2022095441-appb-000203
表6 本公开化合物的静脉注射给药药代动力学参数
Figure PCTCN2022095441-appb-000204
结论：由表5和表6可知，相比于对比化合物A，本公开实施例2化合物的药代吸收良好，具有明显的药代动力学优势。
Figure PCTCN2022095441-appb-000205
Figure PCTCN2022095441-appb-000206
Figure PCTCN2022095441-appb-000207
Figure PCTCN2022095441-appb-000208
Figure PCTCN2022095441-appb-000209
Figure PCTCN2022095441-appb-000210
Figure PCTCN2022095441-appb-000211
Figure PCTCN2022095441-appb-000212
Figure PCTCN2022095441-appb-000213
Figure PCTCN2022095441-appb-000214
Figure PCTCN2022095441-appb-000215
Figure PCTCN2022095441-appb-000216

Claims (29)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100001
    其中：
    环A为环烷基或杂环基；
    G为N原子或CR 2a；
    各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、氧代基、羟烷基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
    各个R 2相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
    各个R 3相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基；
    或者其中的两个相邻的R 3和相连的苯环上的碳原子形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；
    R 4选自氢原子、烷基、环烷基和杂环基；其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基和氰基中的一个或多个相同或不同的取代基取代；
    R 5和R 6相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
    R 7选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
    R 8选自氢原子、烷基、卤代烷基、羟烷基、羟基、环烷基和杂环基；
    R 9和R 10相同或不同，各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
    R 2a选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基和氨基；
    n为0、1、2、3或4；
    m为0、1或2；
    p为1、2、3或4；且
    q为0、1、2或3。
  2. 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，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、氧代基、羟烷基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；R 5至R 10和q如权利要求1中所定义。
  3. 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，其为通式(IC)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100002
    其中：
    环A、G、R 1至R 3、n、m和p如权利要求1中所定义。
  4. 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，其为通式(I-1)或通式(I-2)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100003
    其中：
    环A、G、R 1至R 3、n、m和p如权利要求1中所定义。
  5. 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，其为通式(I-3) 或通式(I-4)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100004
    其中：
    环B为环烷基或杂环基；其中所述的环烷基或杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基中的一个或多个相同或不同的取代基取代；
    各个R 3a相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和氰基；
    r为0、1或2；
    环A、G、R 1、R 2、R 4、n和m如权利要求1中所定义。
  6. 根据权利要求5中所述的通式(I)所示的化合物或其可药用的盐，其中：环B为3至8元环烷基或3至8元杂环基；优选地，环B为5或6元环烷基或5或6元杂环基。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：环A为3至8元环烷基或3至8元杂环基；优选地，环A为5或6元环烷基或5或6元杂环基。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：各个R 1相同或不同，且各自独立地选自氢原子、氘原子、卤素、-C(O)R 8、C 1-6烷基、C 1-6烷氧基和氧代基；R 8如权利要求1中所定义。
  9. 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，其为通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100005
    其中：
    G 1、G 2和G 3相同或不同，且各自独立地选自O原子、S原子、NR 1a和CR 1bR 1c；
    R 1a选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳 基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
    R 1b和R 1c相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，或者R 1b和R 1c一起形成氧代基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
    G、R 2至R 10、m、p和q如权利要求1中所定义。
  10. 根据权利要求9所述的通式(I)所示的化合物或其可药用的盐，其中：
    G 1和G 2相同或不同，且各自独立地选自O原子、S原子、NR 1a和CR 1bR 1c；
    G 3为CR 1bR 1c；
    R 1a、R 1b和R 1c如权利要求9中所定义。
  11. 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，其为通式(III)所示的化合物或其可药用的盐：
    Figure PCTCN2022095441-appb-100006
    其中：
    L 1、L 2、L 3和L 4相同或不同，且各自独立地选自O原子、S原子、NR 1d和CR 1eR 1f；
    R 1d选自氢原子、烷基、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
    R 1e和R 1f相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、环烷基氧基、杂环基氧基、烯基、炔基、羟基、氰基、硝基、-NR 5R 6、-NHC(O)R 7、-C(O)R 8、-C(O)(CH 2) qNR 9R 10、环烷基、杂环基、芳基氧基、杂芳基氧基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、 氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基取代；
    G、R 2至R 10、m、p和q如权利要求1中所定义。
  12. 根据权利要求11所述的通式(I)所示的化合物或其可药用的盐，其中：
    L 1和L 2相同或不同，且各自独立地选自O原子、S原子、NR 1d和CR 1eR 1f；L 3和L 4各自独立地为CR 1eR 1f；
    R 1d、R 1e和R 1f如权利要求11中所定义。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：各个R 2相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；优选地，R 2为氢原子。
  14. 根据权利要求1至4、7至13中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：各个R 3相同或不同，且各自独立地选自卤素、C 1-6烷基、C 1-6烷氧基、3至8元环烷基、3至8元杂环基和氰基；优选地，R 3为卤素。
  15. 根据权利要求1、5至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R 4为氢原子或3至8元杂环基；其中所述的3至8元杂环基被选自羟基和羧基中的一个或多个相同或不同的取代基取代。
  16. 根据权利要求1、2、5至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R 4为
    Figure PCTCN2022095441-appb-100007
  17. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2022095441-appb-100008
    Figure PCTCN2022095441-appb-100009
    Figure PCTCN2022095441-appb-100010
  18. 一种通式(I-1C)或(I-2C)所示的化合物或其盐：
    Figure PCTCN2022095441-appb-100011
    其中：
    R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C 1-6烷基；R 11为C 1-6烷基；
    环A、G、R 1至R 3、m、n和p如权利要求1中所定义。
  19. 根据权利要求18所述的化合物或其盐，其为如下化合物：
    Figure PCTCN2022095441-appb-100012
  20. 一种制备根据权利要求3所述的通式(IC)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    Figure PCTCN2022095441-appb-100013
    通式(IA)化合物或其盐与通式(IB)化合物或其盐反应，得到通式(IC)的化合物或其可药用的盐；
    其中：
    X为卤素；优选为Cl原子；
    环A、G、R 1至R 3、m、n和p如权利要求3中所定义。
  21. 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，该方法包括以下步骤：
    Figure PCTCN2022095441-appb-100014
    通式(IC)的化合物或其可药用的盐与R 4’-Y化合物反应，然后脱去R 4’上的保护基，得到通式(I)的化合物或其可药用的盐；
    其中：
    Y为卤素；优选为Br原子；
    R 4’为
    Figure PCTCN2022095441-appb-100015
    R和R 11相同或不同，且各自独立地选自烷基、环烷基和杂环基；
    R 4为
    Figure PCTCN2022095441-appb-100016
    环A、G、R 1至R 3、m、n和p如权利要求1中所定义。
  22. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1至17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。
  23. 根据权利要求1至17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22所述的药物组合物在制备用于调节miRNA水平的药物中的用途。
  24. 根据权利要求1至17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22所述的药物组合物在制备用于治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况选自病毒感染、炎症和癌症。
  25. 根据权利要求1至17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22所述的药物组合物在制备用于治疗和/或预防AIDS或AIDS相关的病况或人类免疫缺陷病毒(HIV)药物中的用途。
  26. 根据权利要求24所述的用途，其中所述的炎症选自自身免疫有关的炎性疾病、中枢神经系统(CNS)中的炎性疾病、关节中的炎性疾病、消化道中的炎性疾病、皮肤中的炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
  27. 根据权利要求24所述的用途，其中所述的炎症选自炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、系统性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症；优选地，所述炎症为炎性肠病。
  28. 根据权利要求27所述的用途，其中所述的炎性肠病为溃疡性结肠炎(UC)或克罗恩病(CD)。
  29. 根据权利要求24所述的用途，其中所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞癌、汗腺癌、皮脂腺癌、乳头状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏肿瘤、宫颈癌、子宫癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结肠直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤。
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