WO2022161447A1 - Dicarboxamide compound, preparation method therefor, and pharmaceutical use thereof - Google Patents

Dicarboxamide compound, preparation method therefor, and pharmaceutical use thereof Download PDF

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Publication number
WO2022161447A1
WO2022161447A1 PCT/CN2022/074454 CN2022074454W WO2022161447A1 WO 2022161447 A1 WO2022161447 A1 WO 2022161447A1 CN 2022074454 W CN2022074454 W CN 2022074454W WO 2022161447 A1 WO2022161447 A1 WO 2022161447A1
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cancer
general formula
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/074454
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French (fr)
Chinese (zh)
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杨方龙
杨倩
贺峰
陶维康
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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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Priority to CN202280012569.2A priority Critical patent/CN116783166A/en
Publication of WO2022161447A1 publication Critical patent/WO2022161447A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a dimethylamide compound, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a dimethylamide compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a drug for inhibiting protein kinases.
  • RTKs Receptor tyrosine kinases
  • VEGF/VEGFR signaling is the major rate-limiting step in angiogenesis.
  • Pathological angiogenesis is a hallmark of tumorigenesis. The growth of primary tumors and their subsequent metastasis depend on angiogenesis.
  • VEGF/VEGFR is found in most solid tumors. High expression of VEGFR;
  • VEGF/VEGFR inhibitors According to clinical and preclinical data, there are certain limitations in the treatment methods that simply inhibit the expression of VEGFR. For example, although monotherapy can delay tumor growth, most of them do not lead to tumor regression. , and may induce invasive or metastatic behavior of cancer. Monotherapy with bevacizumab can improve the PFS of cancer patients, but cannot effectively increase the overall survival of patients. Moreover, there are primary and secondary resistance to VEGF/VEGFR therapy. The latter is usually caused by the up-regulation of other important genes/proteins. For example, in patients with renal cancer after VEGFR target therapy, high expression of MET and Axl was found to promote tumor development. Therefore, VEGF/VEGFR therapy usually needs to be combined with other drugs.
  • the TAM subfamily is composed of three tyrosine kinases TYRO3, Axl and Mer.
  • the extracellular ligand-binding domain of TAM family kinases consists of two immunoglobulin-like domains and two fibronectin III domains. It has been confirmed that the natural ligands of TAM are growth arrest-specific protein 6 (GAS6) and protein S (PROS1). GAS6 binds and activates all three TAM kinases, and PROS1 is a ligand for both Mer and TYRO3 kinases.
  • Axl (also known as UFO, ARK, JTK11 and TYRO7) was first discovered as a transforming gene in chronic myeloid leukemia human DNA. GAS6 binding to Axl induces its autophosphorylation and activates the tyrosine kinase Axl. Axl can continue to activate proteins in multiple downstream signaling pathways, including PI3K-AKT, Raf-MAPK, PLC-PKC, etc.
  • Mer also known as MERTK, EYK, RYK, RP38, NYK and TYRO12
  • GAS6 and PROS1 can bind to Mer and induce its phosphorylation and activation of Mer kinase. Similar to Axl, Mer activation can also continue to transmit signals downstream, such as activation of PI3K-AKT and Raf-MAPK pathways.
  • TYRO3 also known as DTK, SKY, RSE, BRT, TIF and ETK2
  • GAS6 and PROS1 are able to bind to TYRO3 and activate the kinase.
  • the downstream signaling pathways activated by TYRO3 are least studied in the TAM family, the present results show that it appears that the PI3K-AKT and Raf-MAPK pathways are activated by TYRO3.
  • TYRO3, AXL and Mer were all found to be overexpressed in tumors.
  • the MET family includes mesenchymal-epithelial transition factor (c-Met), an independent tyrosine kinase receptor expressed on the surface of various epithelial cells; its natural ligand is hepatocyte growth factor/dispersion factor (HGF). /SF). Binding of the natural ligand HGF to c-Met initiates a series of intracellular signaling processes, including embryonic development and wound healing in normal cells.
  • c-Met mesenchymal-epithelial transition factor
  • HGF hepatocyte growth factor/dispersion factor
  • Ring A is selected from the group consisting of 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl;
  • G 1 is N atom or CR 2a ;
  • G 2 is N atom or CR 2b ;
  • G 3 is N atom or CR 3a ;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 , R 2a and R 2b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl , cycloalkyl and heterocyclyl;
  • R 3 and R 3a are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkane base and heterocyclyl;
  • R4 is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • R 5 is selected from alkyl, -(CH 2 ) m Ra , cycloalkyl and heterocyclyl; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents ;
  • R a is cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - substituted with one or more substituents in NR b R c , hydroxy and hydroxyalkyl;
  • R b and R c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;
  • n 0, 1, 2, 3, 4, or 5;
  • n 1, 2, 3, 4, 5 or 6.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof:
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 2a or N atom; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, G 1 is CR 2a ; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; more preferably, G 1 is CH; G2 is CH or N atom ; G3 is CH; most preferably, G1 is CH ; G2 is N atom ; G3 is CH.
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; or G 1 is an N atom; G 2 is CR 2b ; G 3 is CR 3a ; R 2b and R 3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; or G 1 is CR 2a ; G 2 is an N atom; G 3 is CR 3a ; R 2a and R 3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; more preferably, G 1 is CH; G 2 is CH; G 3 is CH.
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; preferably, R 2a , R 2b and R 3a are all hydrogen atoms.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:
  • Ring A, R 1 to R 5 and n are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (II-1)
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof Salt used:
  • Ring A, R 1 to R 5 and n are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1) or general formula (III) or a pharmaceutically acceptable salt thereof is represented by general formula (III-1)
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in general formula (I).
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl; preferably, Ring A is phenyl.
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound shown in 1) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl and 3- to 8-membered cycloalkyl; preferably, Ring A is 6 to 10 membered aryl groups 10-membered aryl or 3- to 8-membered cycloalkyl; more preferably, Ring A is phenyl or cyclohexyl.
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-6 alkyl; preferably, R 4 is methyl.
  • R 5 is C 1-6 alkyl or -(CH 2 ) m R a ;
  • R a is a 3- to 6-membered cycloalkyl; wherein the 3- to 6-membered cycloalkyl is optionally selected from C 1-6 alkyl and -NR b R c substituted by one or more substituents;
  • R b and R c are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group;
  • m is 1, 2 or 3; preferably, R 5 is methyl or
  • the compounds of general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts wherein L is Ring B is a 3- to 6-membered cycloalkyl, p is 0, 1, 2 or 3; preferably, L is Ring B is cyclopropyl, p is 1, 2 or 3; more preferably, L is Ring B is p is 1.
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound shown in 1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1 -6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; preferably, Each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl;
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound represented by 1) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 2 is hydrogen atom.
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 3 is hydrogen atom.
  • the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl; G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; G 1 is CR 2a ; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; R 4 is methyl; R 5 is methyl base or Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; G 1 is CH; G 2 is CH or N atom; G 3 is CH; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and each is independently a hydrogen atom or halogen; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; G 1 is CH; G 2 is CH or N atom; G 3 is CH; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl or Each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl; R 4 is methyl; R 5 is methyl; each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl ; Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl ; each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound of general formula (IA) or a salt thereof:
  • G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (I-1A) or a salt thereof:
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • G 1 , G 2 , G 3 and R 2 to R 4 are as defined in the general formula (I-1). It is an intermediate for preparing the compound represented by the general formula (I-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (II-1A) or a salt thereof:
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • R 2 to R 4 are as defined in the general formula (II-1). It is an intermediate for preparing the compound represented by the general formula (II-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III). Another aspect of the present disclosure relates to a compound of general formula (III-1A) or a salt thereof:
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • R 2 to R 4 are as defined in the general formula (III-1). It is an intermediate for preparing the compound represented by the general formula (III-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IC) or a salt thereof:
  • Y is a halogen; preferably a bromine atom
  • G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (IIC) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIC) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III).
  • Another aspect of the present disclosure relates to a compound of general formula (IAa) or a salt thereof:
  • G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (IIAa) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIAa) or a salt thereof:
  • R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III).
  • 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:
  • the compound of general formula (IA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,
  • X is a halogen; preferably a chlorine atom
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • 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:
  • the compound of general formula (IIA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • 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:
  • the compound of general formula (IIIA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (III) or its pharmaceutically acceptable salt,
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a preparation method for the compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n 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 (II-1), or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in the general formula (II-1).
  • 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:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in the general formula (III-1).
  • 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:
  • a compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
  • Y is a halogen; preferably a bromine atom
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • 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:
  • a compound of general formula (IIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,
  • Y is a halogen; preferably a bromine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • 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:
  • a compound of general formula (IIIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,
  • Y is a halogen; preferably a bromine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • 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:
  • a compound of general formula (IAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • 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:
  • a compound of general formula (IIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • 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:
  • a compound of general formula (IIIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • compositions comprising the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula ( II-1), the compound shown in general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A Use of a compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for the treatment and/or prevention of diseases, disorders and syndromes; specifically, in the preparation of a drug for inhibiting protein kinase Use in medicaments for the treatment and/or prevention of diseases, disorders and syndromes.
  • the diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibro
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A
  • the tumor is preferably cancer, more preferably selected from sarcoma, multiple Myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer , gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bil
  • the present disclosure further relates to a method of inhibiting protein kinases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III), formula (I-1), formula (II-1), the compound represented by the general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of treating and/or preventing diseases, disorders and syndromes, in particular a method of treating and/or preventing diseases, disorders and syndromes being treated and/or prevented by inhibiting protein kinases, which Including the administration of a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) to a patient in need and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibro
  • the present disclosure further relates to a method of treating and/or preventing tumors, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1) , the compounds of general formula (II-1), general formula (III-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.
  • the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer , liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST);
  • the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosar
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A
  • the compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used as a drug for inhibiting protein kinases.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A
  • the diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibro
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A
  • the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloid tumor, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, gastric cancer , esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer
  • the lymphoma described in the present disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (eg, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma);
  • the lung cancer is preferably non-small cell lung cancer (NSCLC) (such as lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC)
  • NSCLC non-small cell lung cancer
  • the renal cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma;
  • the leukemia is preferably chronic leukemia (eg chronic lymphocytic leukemia) or acute leukemia (eg acute myeloid leukemia).
  • the protein kinases described in the present disclosure are preferably receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are TAM, MET, KDR or a combination thereof.
  • RTKs receptor tyrosine kinases
  • the protein kinases described in the present disclosure are receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR, or a combination thereof.
  • RTKs receptor tyrosine kinases
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the 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 vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents 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 can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • 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.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.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 suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 carbon atoms (ie, a C 1-20 alkyl group).
  • the alkyl group is preferably an alkyl group having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie, a C 1-12 alkyl group). ), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group preferably has 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C1-12 alkylene) , more preferably having 1 to 6 carbon atoms (ie C 1-6 alkylene).
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) 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 -), and the like.
  • the alkylene 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 alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group preferably has 2 to 6 carbon atoms (ie C 2-6 alkynyl).
  • Alkynyl may be substituted or unsubstituted, when substituted it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like.
  • the alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 14 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl) , further preferably have 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl), most preferably 5 or 6 carbon atoms (ie 5 to 6 membered cycloalkyl).
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably 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 rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups base.
  • spirocycloalkyl 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 Monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably 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 cycloalkyl groups preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered RMB/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 6/ 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 bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, 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 constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 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 spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the 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.
  • 6 to 14 yuan eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan
  • more preferably 7 to 10 yuan eg 7, 8, 9 or 10 yuan.
  • the spiroheterocyclyl groups are divided into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiro-heterocyclyl groups), preferably mono-spiro-heterocyclyl groups or bis-spiro-heterocyclic groups base.
  • spiroheterocyclyl 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 of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan
  • more preferably 7 to 10 yuan eg 7, 8, 9 or 10 yuan.
  • bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered RMB/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 6/ 3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 20-membered, polycyclic heterocyclic group in which any two rings share two atoms that are 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, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan
  • 7 to 10 yuan eg 7, 8, 9 or 10 yuan
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, For example phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked 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 are 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 (ie 5- to 6-membered heteroaryl), eg furyl, thienyl , pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked 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 , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", “heterocyclylene”, “arylene”, “heteroarylene”.
  • amino protecting group is used to protect the amino group by introducing an easily removed group on the amino group to keep the amino group unchanged when the other parts of the molecule are reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and para methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxy protecting group refers to a hydroxy derivative commonly used to block or protect a hydroxy group while reacting on other functional groups of a compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl base, 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.
  • 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 is as defined above.
  • deuterated alkyl 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.
  • hydroxy refers to -OH.
  • thiol 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.
  • the compounds of the present disclosure include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • “deuterium” or “tritium” is used in place of hydrogen
  • 18F -fluorine label 18F isotope
  • 18F isotope is used in place of fluorine, or11C- , 13C- , or14C -enriched
  • Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • stereoisomer refers to isomers that are structurally identical 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 the compounds of the present disclosure may have additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “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 due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids 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 therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (I) of the present disclosure or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
  • X is a halogen; preferably a chlorine atom
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • the compound represented by the general formula (II) of the present disclosure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • the compound represented by the general formula (III) of the present disclosure or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
  • X is a halogen; preferably a chlorine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (I-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n are as defined in the general formula (I-1).
  • the preparation method of the compound represented by the general formula (II-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in the general formula (II-1).
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
  • X is a halogen; preferably a chlorine atom
  • R w is an amino protecting group, preferably Boc
  • L is alkylene or Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
  • Ring A, R 1 to R 4 and n are as defined in the general formula (III-1).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • Y is a halogen; preferably a bromine atom
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • Y is a halogen; preferably a bromine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • Y is a halogen; preferably a bromine atom
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound of general formula (IAa) or its salt and the compound of general formula (IBb) or its salt undergo amidation reaction under a condensing agent (preferably HATU) and basic conditions to obtain the compound of general formula (I) or its salts.
  • a condensing agent preferably HATU
  • Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound of general formula (IIAa) or its salt is subjected to amidation reaction with the compound of general formula (IBb) or its salt under a condensing agent (preferably HATU) and basic conditions to obtain the compound of general formula (II) or its salts.
  • a condensing agent preferably HATU
  • Ring A, R 1 to R 5 and n are as defined in general formula (II).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • a compound of general formula (IIIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof under a condensing agent (preferably HATU) and basic conditions to obtain a compound of general formula (III) or its salts.
  • a condensing agent preferably HATU
  • Ring A, R 1 to R 5 and n are as defined in general formula (III).
  • the reagents that provide 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-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, lithium hydroxide monohydrate and potassium hydroxide; wherein the reagent providing alkaline conditions in schemes one to six is preferably pyridine; scheme The reagent for providing basic conditions in seven to nine is preferably cesium carbonate; the reagent for providing basic conditions in schemes ten to twelve is preferably N,N-diisopropy
  • the catalysts in the above synthetic schemes seven to nine include but are not limited to bis(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-tris Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphorus)dichlorodi Palladium pentamethylene, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis
  • the amidation reactions in the above synthesis schemes ten to twelve are carried out in the presence of a condensing agent, and the condensing agent is preferably O-(7-azabenzotriazole-1-yl)-N,N,N' , N'-tetramethylurea hexafluorophosphate (HATU).
  • a condensing agent is preferably O-(7-azabenzotriazole-1-yl)-N,N,N' , N'-tetramethylurea hexafluorophosphate (HATU).
  • the deprotection reactions in the above synthetic schemes 4 to 6 are preferably carried out under acidic conditions, and the reagent for providing the acidic conditions is preferably trifluoroacetic acid.
  • 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, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and mixtures thereof.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hex
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (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 determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations were performed using Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • 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 size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC 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 average inhibition rate and IC50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: In the dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • reaction solution was cooled to room temperature, slowly poured into 800 mL of water, extracted with ethyl acetate (300 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the eluent was subjected to silica gel column chromatography. System A was purified to give the title product 2d (840 mg, yield: 20%).
  • the reaction solution was concentrated at room temperature, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, concentrated, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triar-Exrs Prep C18 150*30mm, 5 ⁇ m; mobile phase 1: water (containing 10 mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: acetonitrile: 35%-47%, flow rate: 30 mL/min) to obtain the title product 4 (86 mg, yield 77%) ).
  • Test Example 1 Compounds of the present disclosure have inhibitory effects on Axl, Mer, KDR and MET kinase activities
  • the purpose of this experiment is to test the inhibitory effect of the compounds on the kinase activity of Axl, Mer, KDR and MET, and to evaluate the in vitro activities of the compounds according to the IC 50 size.
  • the compound was dissolved in DMSO to 10 mM, and 5-fold serially diluted to 9 concentrations. Each gradient compound previously diluted in DMSO was diluted again with PBS, and the compound was diluted to the initial concentration of 50 ⁇ M, and the 5-fold gradient was diluted to 9 concentration points. Then 2 ⁇ L of compound was added to 384-well plate (PE, 6005620).
  • Axl (Carna Biosciences, 08-107), Mer (Carna Biosciences, 08-108), KDR (Carna Biosciences, 08-191) and MET (Carna Biosciences, 08-151) proteins were sequentially diluted with enzyme activity buffer To 0.025ng/ ⁇ L, 0.125ng/ ⁇ L, 0.01ng/ ⁇ L and 0.05ng/ ⁇ L, take 4 ⁇ L into 384 wells respectively. Incubate for 15 minutes at room temperature.
  • the enzyme activity buffer to prepare the reaction substrate mixture of ATP and substrate.
  • the ATP concentration was 100 ⁇ M and the substrate concentration was 1 ⁇ M.
  • 4 ⁇ L of the reaction substrate mixture was added to a 384-well plate and reacted at 37°C for 0.5 hours.
  • the detection mixture According to the instructions of the HTRF KinEASE-TK kit, configure the detection mixture. Add 10 ⁇ L of detection mixture to a 384-well plate and incubate at room temperature for 1 hour.
  • the disclosed compound has obvious inhibitory effect on the binding effect of KDR, MET, Axl and Mer, and has a better inhibitory effect than control example A.
  • Test Example 2 Identification of Reactive Metabolites of Compounds of the Disclosure in Human Liver Microsomes
  • test compound solution Take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve, and mix well to obtain a stock solution with a concentration of 30 mM.
  • the stock solution at a concentration of 10 mM was diluted 10-fold with 50% acetonitrile/water (v/v) to give working solution 1 at a concentration of 3.0 mM.
  • the working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain a working solution 2 of 300 ⁇ M, which was stored at 4° C. before use.
  • phosphate buffer solution Preparation of phosphate buffer solution: Weigh appropriate amounts of K 2 HPO 4 and KH 2 PO 4 respectively, dissolve them in 4L of pure water to prepare a buffer solution with a concentration of 100mM, and then adjust the pH to 7.4 with phosphoric acid or sodium hydroxide .
  • liver microsome solution Take an appropriate amount of liver microsome stock solution (concentration of 20 mg/mL) of each species, and dilute to 1.43 mg/mL microsomal solution with phosphate buffer solution (pH 7.4) of concentration 100 mM.
  • NADPH cofactor solution Weigh an appropriate amount of NADPH and magnesium chloride and dissolve in an appropriate amount of phosphate buffer (pH value is 7.4) with a concentration of 100 mM, so that the concentrations of NADPH and magnesium chloride are 10 mM and 30 mM, respectively, for use.
  • GSH glutathione
  • the incubation system is as follows:
  • Test compound concentration 30 ⁇ M NADPH concentration 1.0mM MgCl concentration 3.0mM GSH concentration 5mM Incubation medium 100mM PBS System pH 7.4 Incubation temperature 37°C Incubation time 60min Incubation volume 200 ⁇ L positive control Diclofenac (10 ⁇ M)

Abstract

The present invention relates to a dicarboxamide compound, a preparation method therefor, and a pharmaceutical use thereof. Specifically, the present invention relates to a dicarboxamide compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the compound as a therapeutic agent, especially a use of the compound in preparation of a drug for inhibiting protein kinases. Groups in general formula (I) are as defined in the description.

Description

二甲酰胺类化合物、其制备方法及其在医药上的应用Diformamide compounds, their preparation method and their application in medicine 技术领域technical field
本公开属于医药领域，涉及一种二甲酰胺类化合物、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)所示的二甲酰胺类化合物、其制备方法及含有该类化合物的药物组合物，以及其在制备用于抑制蛋白激酶的药物中的用途。The present disclosure belongs to the field of medicine, and relates to a dimethylamide compound, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to a dimethylamide compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a drug for inhibiting protein kinases.
背景技术Background technique
受体酪氨酸激酶(RTKs)属于细胞膜表面的跨膜蛋白家族，其主要功能是将细胞外信号传导至细胞内并参与调控生存、生长、增殖、分化、黏附和迁移等一系列过程。Receptor tyrosine kinases (RTKs) belong to a family of transmembrane proteins on the surface of cell membranes. Their main function is to transduce extracellular signals into cells and participate in a series of processes such as regulation of survival, growth, proliferation, differentiation, adhesion and migration.
VEGF/VEGFR信号传导是血管生成的主要限速步骤，病理性血管生成是肿瘤发生的标志，原发性肿瘤的生长及其随后的转移取决于血管生成，在大多数实体瘤中均发现VEGF/VEGFR的高表达；VEGF/VEGFR signaling is the major rate-limiting step in angiogenesis. Pathological angiogenesis is a hallmark of tumorigenesis. The growth of primary tumors and their subsequent metastasis depend on angiogenesis. VEGF/VEGFR is found in most solid tumors. High expression of VEGFR;
VEGF/VEGFR抑制剂治疗限制：通过临床和临床前的数据来看，单纯抑制VEGFR表达的治疗方法存在一定的局限性，例如单药治疗虽然可以延迟肿瘤的生长，但大多数不会导致肿瘤消退，并且可能诱发癌症的侵袭性或转移性行为，使用贝伐珠单抗(bevacizumab)进行单药治疗，虽然可以提高肿瘤患者的PFS，但无法有效增加患者的总生存期。而且VEGF/VEGFR疗法存在原发和继发耐药，后者通常是由于其他重要基因/蛋白被上调造成的，如在VEGFR靶点治疗后的肾癌患者中，发现MET和Axl的高表达促进了肿瘤发展。因此VEGF/VEGFR疗法通常需要与其他药物联用。Treatment limitations of VEGF/VEGFR inhibitors: According to clinical and preclinical data, there are certain limitations in the treatment methods that simply inhibit the expression of VEGFR. For example, although monotherapy can delay tumor growth, most of them do not lead to tumor regression. , and may induce invasive or metastatic behavior of cancer. Monotherapy with bevacizumab can improve the PFS of cancer patients, but cannot effectively increase the overall survival of patients. Moreover, there are primary and secondary resistance to VEGF/VEGFR therapy. The latter is usually caused by the up-regulation of other important genes/proteins. For example, in patients with renal cancer after VEGFR target therapy, high expression of MET and Axl was found to promote tumor development. Therefore, VEGF/VEGFR therapy usually needs to be combined with other drugs.
TAM亚家族是由TYRO3、Axl和Mer三种酪氨酸激酶组成。TAM家族激酶的胞外配体结合域由两个免疫球蛋白样结构域及两个纤粘蛋白III结构域组成。目前已经确认TAM的天然配体分别为生长阻滞特异性蛋白6(GAS6)和蛋白S(PROS1)。GAS6能结合并激活全部三种TAM激酶，PROS1则是Mer和TYRO3两种激酶的配体。The TAM subfamily is composed of three tyrosine kinases TYRO3, Axl and Mer. The extracellular ligand-binding domain of TAM family kinases consists of two immunoglobulin-like domains and two fibronectin III domains. It has been confirmed that the natural ligands of TAM are growth arrest-specific protein 6 (GAS6) and protein S (PROS1). GAS6 binds and activates all three TAM kinases, and PROS1 is a ligand for both Mer and TYRO3 kinases.
Axl(也被称为UFO、ARK、JTK11和TYRO7)最早在慢性髓性白血病人的DNA中作为转化基因被发现。GAS6结合Axl之后可以诱导其自磷酸化并激活酪氨酸激酶Axl。Axl能继续活化下游多个信号传导途径中的蛋白包括PI3K-AKT，Raf-MAPK，PLC-PKC等。Axl (also known as UFO, ARK, JTK11 and TYRO7) was first discovered as a transforming gene in chronic myeloid leukemia human DNA. GAS6 binding to Axl induces its autophosphorylation and activates the tyrosine kinase Axl. Axl can continue to activate proteins in multiple downstream signaling pathways, including PI3K-AKT, Raf-MAPK, PLC-PKC, etc.
Mer(也被称为MERTK、EYK、RYK、RP38、NYK和TYRO12)最早作为磷蛋白在类淋巴母细胞表达文库中被发现。GAS6和PROS1均能够与Mer结合并诱导其发生磷酸化并活化Mer激酶。与Axl类似，Mer活化之后也能将信号向下游继续传导，比如活化PI3K-AKT和Raf-MAPK通路。Mer (also known as MERTK, EYK, RYK, RP38, NYK and TYRO12) was first discovered as a phosphoprotein in a lymphoblastoid expression library. Both GAS6 and PROS1 can bind to Mer and induce its phosphorylation and activation of Mer kinase. Similar to Axl, Mer activation can also continue to transmit signals downstream, such as activation of PI3K-AKT and Raf-MAPK pathways.
TYRO3(也被称为DTK、SKY、RSE、BRT、TIF和ETK2)最早由基于PCR 技术的克隆研究中发现。GAS6和PROS1均能够与TYRO3结合并激活该激酶。尽管TYRO3活化的下游信号通路在TAM家族中研究的最少，目前的结果显示似乎PI3K-AKT和Raf-MAPK通路被TYRO3所激活。TYRO3、AXL和Mer在肿瘤中均被发现过表达。TYRO3 (also known as DTK, SKY, RSE, BRT, TIF and ETK2) was first discovered by PCR-based cloning studies. Both GAS6 and PROS1 are able to bind to TYRO3 and activate the kinase. Although the downstream signaling pathways activated by TYRO3 are least studied in the TAM family, the present results show that it appears that the PI3K-AKT and Raf-MAPK pathways are activated by TYRO3. TYRO3, AXL and Mer were all found to be overexpressed in tumors.
MET家族包括了间叶-上皮转化因子(c-Met)，一种独立的表达于多种上皮细胞表面的酪氨酸激酶受体；它的天然配体为肝细胞生长因子/分散因子(HGF/SF)。天然配体HGF结合于c-Met后会开启一系列细胞内的信号传导过程，包括正常细胞的胚胎发育和伤口愈合。然而，在肿瘤细胞中，由于c-Met基因突变、过表达和扩增，引起了HGF/c-Met轴异常活化并激活PI3K/AKT、Ras/MAPK、JAK/STAT、SRC和Wnt/β-连环素信号通路使得肿瘤生长增殖。由于持续活化上述提到的c-Met依赖性信号传导通路使得肿瘤细胞获得了相比正常细胞更多的竞争优势，并且通过接触血液供给和增加脱离组织的能力使得肿瘤发生转移的可能性大大增加。The MET family includes mesenchymal-epithelial transition factor (c-Met), an independent tyrosine kinase receptor expressed on the surface of various epithelial cells; its natural ligand is hepatocyte growth factor/dispersion factor (HGF). /SF). Binding of the natural ligand HGF to c-Met initiates a series of intracellular signaling processes, including embryonic development and wound healing in normal cells. However, in tumor cells, due to c-Met gene mutation, overexpression, and amplification, aberrant activation of the HGF/c-Met axis and activation of PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, and Wnt/β- The catenin signaling pathway enables tumor growth and proliferation. Due to the continuous activation of the above-mentioned c-Met-dependent signaling pathway, tumor cells gain more competitive advantages than normal cells, and the possibility of tumor metastasis is greatly increased by contacting the blood supply and increasing the ability to detach from tissues. .
目前已公开的专利申请有WO2005030140A2、WO2010045095A1、WO2010075376A2、WO2019148044A1、CN102212062A和WO2012006960A1等，这些专利申请中的活性都还有提升空间，相关病患人群中存在重大未满足的医学需求。The currently published patent applications include WO2005030140A2, WO2010045095A1, WO2010075376A2, WO2019148044A1, CN102212062A and WO2012006960A1, etc. The activities in these patent applications still have room for improvement, and there is a major unmet medical need in the relevant patient population.
因此，为治疗KDR(VEGFR2)、TAM和MET激酶介导的肿瘤需要开发一类新的化合物来更好的调控这类靶点。Therefore, it is necessary to develop a new class of compounds to better regulate these targets for the treatment of KDR (VEGFR2), TAM and MET kinase-mediated tumors.
发明内容SUMMARY OF THE INVENTION
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：The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074454-appb-000001
Figure PCTCN2022074454-appb-000001
其中：in:
环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；Ring A is selected from the group consisting of 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl;
G 1为N原子或CR 2a； G 1 is N atom or CR 2a ;
G 2为N原子或CR 2b； G 2 is N atom or CR 2b ;
G 3为N原子或CR 3a； G 3 is N atom or CR 3a ;
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、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、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、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Each R 1 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 2、R 2a和R 2b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基； R 2 , R 2a and R 2b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl , cycloalkyl and heterocyclyl;
R 3和R 3a相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基； R 3 and R 3a are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkane base and heterocyclyl;
R 4选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； R4 is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
R 5选自烷基、-(CH 2) mR a、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、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 5 is selected from alkyl, -(CH 2 ) m Ra , cycloalkyl and heterocyclyl; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents ;
R a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、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR bR c、羟基和羟烷基中的一个或多个取代基所取代； R a is cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - substituted with one or more substituents in NR b R c , hydroxy and hydroxyalkyl;
R b和R c相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； R b and R c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;
n为0、1、2、3、4或5；且n is 0, 1, 2, 3, 4, or 5; and
m为1、2、3、4、5或6。m is 1, 2, 3, 4, 5 or 6.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐为通式(I-1)所示的化合物，或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074454-appb-000002
Figure PCTCN2022074454-appb-000002
其中：in:
L为亚烷基或
Figure PCTCN2022074454-appb-000003
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000003
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、G 1、G 2、G 3、R 1至R 4和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中G 1为CR 2a或N原子；G 2为CR 2b或N原子；G 3为CR 3a；R 2a、R 2b和R 3a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，G 1为CR 2a；G 2为CR 2b或N原子；G 3为CR 3a；R 2a、R 2b和R 3a相同或不同，且各自独立 地选自氢原子、卤素和C 1-6烷基；更优选地，G 1为CH；G 2为CH或N原子；G 3为CH；最优选地，G 1为CH；G 2为N原子；G 3为CH。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 2a or N atom; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, G 1 is CR 2a ; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; more preferably, G 1 is CH; G2 is CH or N atom ; G3 is CH; most preferably, G1 is CH ; G2 is N atom ; G3 is CH.
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中G 1为CR 2a；G 2为CR 2b；G 3为CR 3a；R 2a、R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；或者G 1为N原子；G 2为CR 2b；G 3为CR 3a；R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；或者G 1为CR 2a；G 2为N原子；G 3为CR 3a；R 2a和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; or G 1 is an N atom; G 2 is CR 2b ; G 3 is CR 3a ; R 2b and R 3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; or G 1 is CR 2a ; G 2 is an N atom; G 3 is CR 3a ; R 2a and R 3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中G 1为CR 2a；G 2为CR 2b；G 3为CR 3a；R 2a、R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；更优选地，G 1为CH；G 2为CH；G 3为CH。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; more preferably, G 1 is CH; G 2 is CH; G 3 is CH.
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中R 2a、R 2b和R 3a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 2a、R 2b和R 3a均为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b and R 3a are the same or different, and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; preferably, R 2a , R 2b and R 3a are all hydrogen atoms.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐为通式(II)所示的化合物，或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074454-appb-000004
Figure PCTCN2022074454-appb-000004
其中：in:
环A、R 1至R 5和n如通式(I)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(I-1)或通式(II)所示的化合物或其可药用的盐为通式(II-1)所示的化合物，或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (II-1) The compound shown, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074454-appb-000005
Figure PCTCN2022074454-appb-000005
其中：in:
L为亚烷基或
Figure PCTCN2022074454-appb-000006
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000006
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(I)中所定义。 Ring A, R 1 to R 4 and n are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐为通式(III)所示的化合物，或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof Salt used:
Figure PCTCN2022074454-appb-000007
Figure PCTCN2022074454-appb-000007
其中：in:
环A、R 1至R 5和n如通式(I)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(I-1)或通式(III)所示的化合物或其可药用的盐为通式(III-1)所示的化合物，或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (III) or a pharmaceutically acceptable salt thereof is represented by general formula (III-1) The compound shown, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074454-appb-000008
Figure PCTCN2022074454-appb-000008
其中：in:
L为亚烷基或
Figure PCTCN2022074454-appb-000009
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000009
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(I)中所定义。 Ring A, R 1 to R 4 and n are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中环A为苯基或5至6元杂芳基；优选地，环A为苯基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl; preferably, Ring A is phenyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中环A选自6至10元芳基、5至10元杂芳基和3至8元环烷基；优选地，环A为6至10元芳基或3至8元环烷基；更优选地，环A为苯基或环己基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound shown in 1) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl and 3- to 8-membered cycloalkyl; preferably, Ring A is 6 to 10 membered aryl groups 10-membered aryl or 3- to 8-membered cycloalkyl; more preferably, Ring A is phenyl or cyclohexyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中R 4为C 1-6烷基；优选地，R 4为甲基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-6 alkyl; preferably, R 4 is methyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)和通式(III)所示的化合物或其可药用的盐，其中R 5为C 1-6烷基或-(CH 2) mR a；R a为3至6元环烷基；其中所述的3至6元环烷基任选被选自C 1-6烷基和-NR bR c中的一个或多个取代基所取代；R b和R c相同或不同，且各自独立地为氢原子或C 1-6烷基；m为1、2或3；优 选地，R 5为甲基或
Figure PCTCN2022074454-appb-000010
In some embodiments of the present disclosure, the compounds of general formula (I), general formula (II) and general formula (III) or their pharmaceutically acceptable salts, wherein R 5 is C 1-6 alkyl or -(CH 2 ) m R a ; R a is a 3- to 6-membered cycloalkyl; wherein the 3- to 6-membered cycloalkyl is optionally selected from C 1-6 alkyl and -NR b R c substituted by one or more substituents; R b and R c are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; m is 1, 2 or 3; preferably, R 5 is methyl or
Figure PCTCN2022074454-appb-000010
在本公开一些实施方案中，所述的通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中L为
Figure PCTCN2022074454-appb-000011
环B为3至6元环烷基，p为0、1、2或3；优选地，L为
Figure PCTCN2022074454-appb-000012
环B为环丙基，p为1、2或3；更优选地，L为
Figure PCTCN2022074454-appb-000013
环B为
Figure PCTCN2022074454-appb-000014
p为1。 In some embodiments of the present disclosure, the compounds of general formula (I-1), general formula (II-1) and general formula (III-1) or their pharmaceutically acceptable salts, wherein L is
Figure PCTCN2022074454-appb-000011
Ring B is a 3- to 6-membered cycloalkyl, p is 0, 1, 2 or 3; preferably, L is
Figure PCTCN2022074454-appb-000012
Ring B is cyclopropyl, p is 1, 2 or 3; more preferably, L is
Figure PCTCN2022074454-appb-000013
Ring B is
Figure PCTCN2022074454-appb-000014
p is 1.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)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 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至6元环烷基和3至6元杂环基；优选地，各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，各个R 1相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；进一步优选地，各个R 1相同或不同，且各自独立地为氢原子或卤素；最优选地，各个R 1相同或不同，且各自独立地为氢原子或F。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound shown in 1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1 -6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; preferably, Each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; further preferably, each R 1 is the same or different, and each is independently a hydrogen atom or halogen; most preferably, each R 1 is the same or different, and each is independently a hydrogen atom or F.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中R 2选自氢原子、卤素和C 1-6烷基；优选地，R 2为氢原子。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound represented by 1) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 2 is hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中R 3选自氢原子、卤素和C 1-6烷基；优选地，R 3为氢原子。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 3 is hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可药用的盐，其中n为0、1或2；优选地，n为0或1。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III- 1) The compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 0 or 1.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基；G 1为CR 2a；G 2为CR 2b；G 3为CR 3a；R 2a、R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000015
各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl; G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000015
Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；G 1为CR 2a；G 2为CR 2b或N原子；G 3为CR 3a；R 2a、 R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000016
各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; G 1 is CR 2a ; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; R 4 is methyl; R 5 is methyl base or
Figure PCTCN2022074454-appb-000016
Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；G 1为CH；G 2为CH或N原子；G 3为CH；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000017
各个R 1相同或不同，且各自独立地为氢原子或卤素；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; G 1 is CH; G 2 is CH or N atom; G 3 is CH; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000017
Each R 1 is the same or different, and each is independently a hydrogen atom or halogen; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；G 1为CH；G 2为CH或N原子；G 3为CH；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000018
各个R 1相同或不同，且各自独立地为氢原子或卤素；R 2为氢原子；R 3为氢原子；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; G 1 is CH; G 2 is CH or N atom; G 3 is CH; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000018
Each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中：环A为苯基；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000019
各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000019
Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000020
各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000020
Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 and n is 0 or 1 selected from hydrogen atom, halogen and C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；R 4为甲基；R 5为甲基或
Figure PCTCN2022074454-appb-000021
各个R 1相同或不同，且各自独立地为氢原子或卤素；R 2为氢原子；R 3为氢原子；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl or
Figure PCTCN2022074454-appb-000021
Each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：环A为苯基；R 4为甲基；R 5为甲基；各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl; R 4 is methyl; R 5 is methyl; each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；R 4为甲基；R 5为甲基；各个R 1相同或不同，且各 自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素和C 1-6烷基；R 3选自氢原子、卤素和C 1-6烷基；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl ; Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 3 is selected from hydrogen atom, halogen and C 1-6 alkyl; and n is 0 or 1.
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：环A为苯基或环己基；R 4为甲基；R 5为甲基；各个R 1相同或不同，且各自独立地为氢原子或卤素；R 2为氢原子；R 3为氢原子；且n为0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or cyclohexyl; R 4 is methyl; R 5 is methyl ; each R 1 is the same or different, and is each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; and n is 0 or 1.
表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2022074454-appb-000022
Figure PCTCN2022074454-appb-000022
本公开的另一方面涉及通式(IA)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IA) or a salt thereof:
Figure PCTCN2022074454-appb-000023
Figure PCTCN2022074454-appb-000023
其中：in:
G 1、G 2、G 3和R 2至R 5如通式(I)中所定义。其为制备通式(I)所示化合物的中间体。 G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
本公开的另一方面涉及通式(I-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (I-1A) or a salt thereof:
Figure PCTCN2022074454-appb-000024
Figure PCTCN2022074454-appb-000024
其中：in:
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000025
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000025
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
G 1、G 2、G 3和R 2至R 4如通式(I-1)中所定义。其为制备通式(I-1)所示化合物的中间体。 G 1 , G 2 , G 3 and R 2 to R 4 are as defined in the general formula (I-1). It is an intermediate for preparing the compound represented by the general formula (I-1).
本公开的另一方面涉及通式(IIA)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof:
Figure PCTCN2022074454-appb-000026
Figure PCTCN2022074454-appb-000026
其中：in:
R 2至R 5如通式(II)中所定义。其为制备通式(II)所示化合物的中间体。 R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
本公开的另一方面涉及通式(II-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (II-1A) or a salt thereof:
Figure PCTCN2022074454-appb-000027
Figure PCTCN2022074454-appb-000027
其中：in:
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000028
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000028
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
R 2至R 4如通式(II-1)中所定义。其为制备通式(II-1)所示化合物的中间体。 R 2 to R 4 are as defined in the general formula (II-1). It is an intermediate for preparing the compound represented by the general formula (II-1).
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof:
Figure PCTCN2022074454-appb-000029
Figure PCTCN2022074454-appb-000029
其中：in:
R 2至R 5如通式(III)中所定义。其为制备通式(III)所示化合物的中间体。本公开的另一方面涉及通式(III-1A)所示的化合物或其盐： R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III). Another aspect of the present disclosure relates to a compound of general formula (III-1A) or a salt thereof:
Figure PCTCN2022074454-appb-000030
Figure PCTCN2022074454-appb-000030
其中：in:
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000031
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000031
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
R 2至R 4如通式(III-1)中所定义。其为制备通式(III-1)所示化合物的中间体。 R 2 to R 4 are as defined in the general formula (III-1). It is an intermediate for preparing the compound represented by the general formula (III-1).
本公开的另一方面涉及通式(IC)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IC) or a salt thereof:
Figure PCTCN2022074454-appb-000032
Figure PCTCN2022074454-appb-000032
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
G 1、G 2、G 3和R 2至R 5如通式(I)中所定义。其为制备通式(I)所示化合物的中间体。 G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
本公开的另一方面涉及通式(IIC)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIC) or a salt thereof:
Figure PCTCN2022074454-appb-000033
Figure PCTCN2022074454-appb-000033
其中：in:
R 2至R 5如通式(II)中所定义。其为制备通式(II)所示化合物的中间体。 R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
本公开的另一方面涉及通式(IIIC)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIIC) or a salt thereof:
Figure PCTCN2022074454-appb-000034
Figure PCTCN2022074454-appb-000034
其中：in:
R 2至R 5如通式(III)中所定义。其为制备通式(III)所示化合物的中间体。 R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III).
本公开的另一方面涉及通式(IAa)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IAa) or a salt thereof:
Figure PCTCN2022074454-appb-000035
Figure PCTCN2022074454-appb-000035
其中：in:
G 1、G 2、G 3和R 2至R 5如通式(I)中所定义。其为制备通式(I)所示化合物的中间体。 G 1 , G 2 , G 3 and R 2 to R 5 are as defined in general formula (I). It is an intermediate for preparing the compound represented by the general formula (I).
本公开的另一方面涉及通式(IIAa)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIAa) or a salt thereof:
Figure PCTCN2022074454-appb-000036
Figure PCTCN2022074454-appb-000036
其中：in:
R 2至R 5如通式(II)中所定义。其为制备通式(II)所示化合物的中间体。 R 2 to R 5 are as defined in general formula (II). It is an intermediate for preparing the compound represented by the general formula (II).
本公开的另一方面涉及通式(IIIAa)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IIIAa) or a salt thereof:
Figure PCTCN2022074454-appb-000037
Figure PCTCN2022074454-appb-000037
其中：in:
R 2至R 5如通式(III)中所定义。其为制备通式(III)所示化合物的中间体。 R 2 to R 5 are as defined in general formula (III). It is an intermediate for preparing the compound represented by the general formula (III).
表B本公开的典型中间体化合物包括但不限于：Typical intermediate compounds of the present disclosure include, but are not limited to:
Figure PCTCN2022074454-appb-000038
Figure PCTCN2022074454-appb-000038
Figure PCTCN2022074454-appb-000039
Figure PCTCN2022074454-appb-000039
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：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:
Figure PCTCN2022074454-appb-000040
Figure PCTCN2022074454-appb-000040
通式(IA)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通 式(I)的化合物或其可药用的盐，The compound of general formula (IA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
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：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:
Figure PCTCN2022074454-appb-000041
Figure PCTCN2022074454-appb-000041
通式(IIA)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(II)的化合物或其可药用的盐，The compound of general formula (IIA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
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：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:
Figure PCTCN2022074454-appb-000042
Figure PCTCN2022074454-appb-000042
通式(IIIA)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(III)的化合物或其可药用的盐，The compound of general formula (IIIA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (III) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(I-1)所示的化合物，或其可药用的盐的制备方法，该方法包括：Another aspect of the present disclosure relates to a preparation method for the compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074454-appb-000043
Figure PCTCN2022074454-appb-000043
(a)通式(I-1A)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(I-1Aa)的化合物或其可药用的盐；(a) the compound of general formula (I-1A) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt;
(b)通式(I-1Aa)的化合物或其可药用的盐发生脱保护反应得到通式(I-1)的 化合物或其可药用的盐；(b) the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt undergoes deprotection reaction to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000044
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000044
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、G 1、G 2、G 3、R 1至R 4和n如通式(I-1)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n are as defined in the general formula (I-1).
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：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:
Figure PCTCN2022074454-appb-000045
Figure PCTCN2022074454-appb-000045
(a)通式(II-1A)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(II-1Aa)的化合物或其可药用的盐；(a) the compound of general formula (II-1A) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (II-1Aa) or its pharmaceutically acceptable salt;
(b)通式(II-1Aa)的化合物或其可药用的盐发生脱保护反应得到通式(II-1)的化合物或其可药用的盐；(b) the compound of general formula (II-1Aa) or its pharmaceutically acceptable salt is subjected to deprotection reaction to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000046
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000046
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(II-1)中所定义。 Ring A, R 1 to R 4 and n are as defined in the general formula (II-1).
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：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:
Figure PCTCN2022074454-appb-000047
Figure PCTCN2022074454-appb-000047
(a)通式(III-1A)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(III-1Aa)的化合物或其可药用的盐；(a) the compound of general formula (III-1A) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (III-1Aa) or its pharmaceutically acceptable salt;
(b)通式(III-1Aa)的化合物或其可药用的盐发生脱保护反应得到通式(III-1)的化合物或其可药用的盐；(b) the compound of general formula (III-1Aa) or its pharmaceutically acceptable salt is subjected to deprotection reaction to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000048
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000048
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(III-1)中所定义。 Ring A, R 1 to R 4 and n are as defined in the general formula (III-1).
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：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:
Figure PCTCN2022074454-appb-000049
Figure PCTCN2022074454-appb-000049
通式(IC)的化合物或其盐与通式(ID)的化合物或其盐发生偶联反应，得到通式(I)的化合物或其可药用的盐，A compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
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：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:
Figure PCTCN2022074454-appb-000050
Figure PCTCN2022074454-appb-000050
通式(IIC)的化合物或其盐与通式(ID)的化合物或其盐发生偶联反应，得到通式(II)的化合物或其可药用的盐，A compound of general formula (IIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
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：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:
Figure PCTCN2022074454-appb-000051
Figure PCTCN2022074454-appb-000051
通式(IIIC)的化合物或其盐与通式(ID)的化合物或其盐发生偶联反应，得到通式(III)的化合物或其可药用的盐，A compound of general formula (IIIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
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：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:
Figure PCTCN2022074454-appb-000052
Figure PCTCN2022074454-appb-000052
通式(IAa)的化合物或其盐与通式(IBb)的化合物或其盐发生酰胺化反应，得到通式(I)的化合物或其可药用的盐，A compound of general formula (IAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
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：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:
Figure PCTCN2022074454-appb-000053
Figure PCTCN2022074454-appb-000053
通式(IIAa)的化合物或其盐与通式(IBb)的化合物或其盐发生酰胺化反应，得到通式(II)的化合物或其可药用的盐，A compound of general formula (IIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,
其中：in:
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
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：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:
Figure PCTCN2022074454-appb-000054
Figure PCTCN2022074454-appb-000054
通式(IIIAa)的化合物或其盐与通式(IBb)的化合物或其盐发生酰胺化反应，得到通式(III)的化合物或其可药用的盐，A compound of general formula (IIIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,
其中：in:
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula ( II-1), the compound shown in general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于抑制蛋白激酶的药物中的用途。The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A Use of a compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting protein kinases.
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防疾病、病症和综合征的药物中的用途；具体为在制备用于通过抑制蛋白激酶来治疗和/或预防的疾病、病症和综合征的药物中的用途。其中所述的疾病、病症和综合征优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、银屑病、胃肠道间质瘤(GIST)、动脉粥样硬化和肺纤维化；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A Use of a compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for the treatment and/or prevention of diseases, disorders and syndromes; specifically, in the preparation of a drug for inhibiting protein kinase Use in medicaments for the treatment and/or prevention of diseases, disorders and syndromes. The diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer Or rectal cancer; the fibroma is preferably a neurofibroma.
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途，其中所述的肿瘤优选为癌症，更优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤(GIST)；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1 ) and those in Table A Use of the compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for the treatment and/or prevention of tumors, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple Myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer , gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroma cell tumor, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the throat cancer is preferably nasopharyngeal cancer; the The sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibromatosis.
本公开进一步涉及一种抑制蛋白激酶的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method of inhibiting protein kinases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III), formula (I-1), formula (II-1), the compound represented by the general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
本公开进一步涉及一种治疗和/或预防疾病、病症和综合征的方法，具体为一种治疗和/或预防通过抑制蛋白激酶来治疗和/或预防的疾病、病症和综合征的方法， 其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表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、病症和综合征优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、银屑病、胃肠道间质瘤(GIST)、动脉粥样硬化和肺纤维化；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to a method of treating and/or preventing diseases, disorders and syndromes, in particular a method of treating and/or preventing diseases, disorders and syndromes being treated and/or prevented by inhibiting protein kinases, which Including the administration of a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) to a patient in need and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer Or rectal cancer; the fibroma is preferably a neurofibroma.
本公开进一步涉及一种治疗和/或预防肿瘤的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物。其中所述的肿瘤优选为癌症，更优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤(GIST)；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to a method of treating and/or preventing tumors, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1) , the compounds of general formula (II-1), general formula (III-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them. The tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer , liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); The throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibromas.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表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。The present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A The compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作抑制蛋白激酶的药物。The present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A The compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used as a drug for inhibiting protein kinases.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表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、病症和综合征的药物，具体为用作治疗和/或预防通过抑制蛋白激酶来治疗和/或预防的疾病、病症和综合征的药物。其中所述的疾病、病症和综合征优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质 瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、银屑病、胃肠道间质瘤(GIST)、动脉粥样硬化和肺纤维化；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A The compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of diseases, disorders and syndromes, particularly for use in the treatment and/or prevention by inhibiting protein kinases Medications to treat and/or prevent diseases, disorders and syndromes. The diseases, disorders and syndromes described therein are preferably selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, Alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer , testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal tract Stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer Or rectal cancer; the fibroma is preferably a neurofibroma.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表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/或预防肿瘤的药物，其中所述的肿瘤优选为癌症，更优选选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤(GIST)；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and Table A The compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used as a medicine for the treatment and/or prevention of tumors, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloid tumor, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, gastric cancer , esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma , melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the throat cancer is preferably nasopharyngeal carcinoma; the The sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibromatosis.
本公开中所述的淋巴瘤优选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)；所述的肺癌优选为非小细胞肺癌(NSCLC)(如肺腺癌、肺鳞状细胞癌和大细胞癌等)或小细胞肺癌(SCLC)；所述的肾癌优选选自肾细胞癌、透明细胞瘤和肾嗜酸细胞瘤；所述的白血病优选为慢性白血病(例如慢性淋巴细胞白血病)或急性白血病(例如急性髓性白血病)。The lymphoma described in the present disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (eg, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); the lung cancer is preferably non-small cell lung cancer (NSCLC) (such as lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC) The renal cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma; the leukemia is preferably chronic leukemia (eg chronic lymphocytic leukemia) or acute leukemia (eg acute myeloid leukemia).
本公开中所述的蛋白激酶优选为受体酪氨酸激酶(RTKs)；优选地，受体酪氨酸激酶(RTKs)为TAM、MET、KDR或它们的组合。The protein kinases described in the present disclosure are preferably receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are TAM, MET, KDR or a combination thereof.
本公开中所述的蛋白激酶为受体酪氨酸激酶(RTKs)；优选地，受体酪氨酸激酶(RTKs)为Axl、Mer、TYRO3、MET、KDR或它们的组合。The protein kinases described in the present disclosure are receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR, or a combination thereof.
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。The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
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。As a general guide, the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方 法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.
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。Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，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。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。The pharmaceutical 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 suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
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。The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
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、***的速率、药物的 组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
术语说明Glossary
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
术语“烷基”指饱和的直链或支链脂肪族烃基，其具有1至20个碳原子(即C 1-20烷基)。所述烷基优选具有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)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。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。最优选具有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。 The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 carbon atoms (ie, a C 1-20 alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie, a C 1-12 alkyl group). ), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. Most preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20亚烷基)。所述亚烷基优选具有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)，更优选具有1至6个碳原子(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、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代中的一个或多个。 The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene). The alkylene group preferably has 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C1-12 alkylene) , more preferably having 1 to 6 carbon atoms (ie C 1-6 alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) 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 -), and the like. The alkylene 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 alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其优选选自烷氧基、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。 The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12炔基)。所述炔基优选具有2至6个碳原子(即C 2-6炔基)。炔基可以是取代的或非取代的，当被取代时，其优选选自烷氧基、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。 The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkynyl). The alkynyl group preferably has 2 to 6 carbon atoms (ie C 2-6 alkynyl). Alkynyl may be substituted or unsubstituted, when substituted it is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , one or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、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。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即3至20元环烷基)，优选具有3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)碳原子(即3至14元环烷基)，更优选具有3至8个碳原子(即3至8元环烷基)，进一步优选具有3至6个碳原子(即3至6元环烷基)，最优选具有5或6个碳原子(即5至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。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 14 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl) , further preferably have 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl), most preferably 5 or 6 carbon atoms (ie 5 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.
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)，优选为单螺环烷基或双螺环烷基。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元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably 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 rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups base. 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 Monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:
Figure PCTCN2022074454-appb-000055
Figure PCTCN2022074454-appb-000055
术语“稠环烷基”指5至20元，***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。优选为6至14元，更优选为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，优选为双环或三环稠环烷基，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、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元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple 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 formed rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered RMB/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 6/ 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 bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022074454-appb-000056
Figure PCTCN2022074454-appb-000056
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。优选为6至14元，更优选为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、四环或多环桥环烷基，优选为双环、三环或四环桥环烷基，更优选为双环或三环桥环烷基。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, 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 constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:
Figure PCTCN2022074454-appb-000057
Figure PCTCN2022074454-appb-000057
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 PCTCN2022074454-appb-000058
等；优选
Figure PCTCN2022074454-appb-000059
Figure PCTCN2022074454-appb-000060
The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include
Figure PCTCN2022074454-appb-000058
etc.; preferred
Figure PCTCN2022074454-appb-000059
Figure PCTCN2022074454-appb-000060
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、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。Cycloalkyl may be substituted or unsubstituted, 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其具有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)，其余环原子为碳。优选具有3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)环原子，其中1～4个(例如1、2、3和4个)是杂原子(即3至14元杂环基)；更优选具有3至8个(例如3、4、5、6、7和8个)环原子，其中1-3个(例如1、2和3个)是杂原子(即3至8元杂环基)或6至14个环原子(例如6、7、8、9、10、11、12、13和14个)，其中1-3个(例如1、2和3个)是杂原子(即6至14元杂环基)；更优选具有3至6个环原子，其中1-3个(例如1、2和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至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。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably there are 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) ) is a heteroatom (ie 3 to 14 membered heterocyclyl); more preferably has 3 to 8 (eg 3, 4, 5, 6, 7 and 8) ring atoms, of which 1-3 (eg 1, 2 and 3) are heteroatoms (ie 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14), wherein 1- 3 (eg 1, 2 and 3) are heteroatoms (ie 6 to 14 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 (eg 1, 2 and 3) are Heteroatom (ie 3 to 6 membered heterocyclyl); most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms (ie 5 to 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 spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
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6至14元(例如6、7、8、9、10、11、12、13和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杂环基分为单螺杂环基或多螺杂环基(如双螺杂环基)，优选为单螺杂环基或双螺杂环基。最优选为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：The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the 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 6 to 14 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13 and 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 rings, the spiroheterocyclyl groups are divided into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiro-heterocyclyl groups), preferably mono-spiro-heterocyclyl groups or bis-spiro-heterocyclic groups base. The most preferred is 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 Single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl include:
Figure PCTCN2022074454-appb-000061
Figure PCTCN2022074454-appb-000061
术语“稠杂环基”指5至20元，***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(例如6、7、8、9、10、11、12、13和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、四环等多环稠杂环基，优选为双环或三环稠杂环基，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、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：The term "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 of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13 and 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 polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered RMB/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 6/ 3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Figure PCTCN2022074454-appb-000062
Figure PCTCN2022074454-appb-000062
术语“桥杂环基”指5至20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(例如6、7、8、9、10、11、12、13和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、四环等多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环桥杂环基。桥杂环基的非限制性实例包括：The term "bridged heterocyclyl" refers to a 5- to 20-membered, polycyclic heterocyclic group in which any two rings share two atoms that are 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, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan), more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022074454-appb-000063
Figure PCTCN2022074454-appb-000063
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：The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022074454-appb-000064
等。
Figure PCTCN2022074454-appb-000064
Wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，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。Heterocyclyl 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
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：The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, For example phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
Figure PCTCN2022074454-appb-000065
Figure PCTCN2022074454-appb-000065
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。Aryl 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
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。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元(即5至6元杂芳基)，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、***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：The term "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 (ie 5- to 6-membered heteroaryl), eg furyl, thienyl , pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
Figure PCTCN2022074454-appb-000066
Figure PCTCN2022074454-appb-000066
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。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 , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
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“亚环烷基”、“亚杂环基”、“亚芳基”、“亚杂芳基”。The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".
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，在氨基上引入的易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、乙酰基、苄基、苄氧羰基(Cbz)、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。The term "amino protecting group" is used to protect the amino group by introducing an easily removed group on the amino group to keep the amino group unchanged when the other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and para methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
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。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、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、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。The term "hydroxy protecting group" refers to a hydroxy derivative commonly used to block or protect a hydroxy group while reacting on other functional groups of a compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl base, benzoyl, p-nitrobenzoyl, etc.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
术语“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。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“巯基”指-SH。The term "thiol" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代”指“＝O”。The term "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -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。The term "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.
本公开的化合物包含其同位素衍生物。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。本公开的各种氘化形式的化合物是指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。 The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structures of the present disclosure, "deuterium" or "tritium" is used in place of hydrogen, or 18F -fluorine label ( 18F isotope) is used in place of fluorine, or11C- , 13C- , or14C -enriched Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that are structurally identical 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 the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
本公开所述化合物的化学结构中，键
Figure PCTCN2022074454-appb-000067
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022074454-appb-000068
可以为
Figure PCTCN2022074454-appb-000069
或者同时包含
Figure PCTCN2022074454-appb-000070
Figure PCTCN2022074454-appb-000071
两种构型。 In the chemical structure of the compound described in the present disclosure, the bond
Figure PCTCN2022074454-appb-000067
Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond
Figure PCTCN2022074454-appb-000068
can be
Figure PCTCN2022074454-appb-000069
or both
Figure PCTCN2022074454-appb-000070
Figure PCTCN2022074454-appb-000071
Two configurations.
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:
Figure PCTCN2022074454-appb-000072
Figure PCTCN2022074454-appb-000072
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：When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:
Figure PCTCN2022074454-appb-000073
Figure PCTCN2022074454-appb-000073
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of this disclosure and the naming of compounds does not exclude any tautomers.
“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。 "Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C 1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
“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。"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 due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗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，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, 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 therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by those skilled in the art based on routine experiments.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will understand, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.
本公开化合物的合成方法Synthetic methods of compounds of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物，或其可药用的盐的制备方法，该方法包括：The compound represented by the general formula (I) of the present disclosure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000074
Figure PCTCN2022074454-appb-000074
通式(IA)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下，发生酰化反应，得到通式(I)的化合物或其可药用的盐，The compound of general formula (IA) or its salt and the compound of general formula (IB) or its salt are subjected to acylation reaction under basic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
方案二Option II
本公开通式(II)所示的化合物，或其可药用的盐的制备方法，该方法包括：The compound represented by the general formula (II) of the present disclosure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000075
Figure PCTCN2022074454-appb-000075
通式(IIA)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下，发生酰化反应，得到通式(II)的化合物或其可药用的盐，The compound of general formula (IIA) or its salt and the compound of general formula (IB) or its salt are subjected to acylation reaction under basic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
方案三third solution
本公开通式(III)所示的化合物，或其可药用的盐的制备方法，该方法包括：The compound represented by the general formula (III) of the present disclosure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000076
Figure PCTCN2022074454-appb-000076
通式(IIIA)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下，发生酰化反应，得到通式(III)的化合物或其可药用的盐，The compound of general formula (IIIA) or its salt and the compound of general formula (IB) or its salt, under basic conditions, undergo acylation reaction to obtain the compound of general formula (III) or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
方案四Option 4
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，该方法包括：The preparation method of the compound represented by the general formula (I-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
Figure PCTCN2022074454-appb-000077
Figure PCTCN2022074454-appb-000077
(a)通式(I-1A)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下发生酰化反应，得到通式(I-1Aa)的化合物或其可药用的盐；(a) The compound of general formula (I-1A) or its salt and the compound of general formula (IB) or its salt are subjected to acylation reaction under basic conditions to obtain the compound of general formula (I-1Aa) or its salts. medicinal salt;
(b)通式(I-1Aa)的化合物或其可药用的盐在酸性条件下发生脱保护反应，得到通式(I-1)的化合物或其可药用的盐；(b) the compound of general formula (I-1Aa) or a pharmaceutically acceptable salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (I-1) or a pharmaceutically acceptable salt thereof;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000078
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000078
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、G 1、G 2、G 3、R 1至R 4和n如通式(I-1)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 4 and n are as defined in the general formula (I-1).
方案五Option five
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，该方法包括：The preparation method of the compound represented by the general formula (II-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
Figure PCTCN2022074454-appb-000079
Figure PCTCN2022074454-appb-000079
(a)通式(II-1A)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下发生酰化反应，得到通式(II-1Aa)的化合物或其可药用的盐；(a) The compound of general formula (II-1A) or its salt and the compound of general formula (IB) or its salt are subjected to acylation reaction under basic conditions to obtain the compound of general formula (II-1Aa) or its salts. medicinal salt;
(b)通式(II-1Aa)的化合物或其可药用的盐在酸性条件下发生脱保护反应，得到通式(II-1)的化合物或其可药用的盐；(b) the compound of general formula (II-1Aa) or a pharmaceutically acceptable salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (II-1) or a pharmaceutically acceptable salt thereof;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000080
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000080
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(II-1)中所定义。 Ring A, R 1 to R 4 and n are as defined in the general formula (II-1).
方案六Option 6
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，该方法包括：The preparation method of the compound represented by the general formula (III-1) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises:
Figure PCTCN2022074454-appb-000081
Figure PCTCN2022074454-appb-000081
(a)通式(III-1A)的化合物或其盐与通式(IB)的化合物或其盐，在碱性条件下发生酰化反应，得到通式(III-1Aa)的化合物或其可药用的盐；(a) The compound of general formula (III-1A) or its salt and the compound of general formula (IB) or its salt are subjected to acylation reaction under basic conditions to obtain the compound of general formula (III-1Aa) or its salts. medicinal salt;
(b)通式(III-1Aa)的化合物或其可药用的盐在酸性条件下发生脱保护反应，得到通式(III-1)的化合物或其可药用的盐；(b) the compound of general formula (III-1Aa) or a pharmaceutically acceptable salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (III-1) or a pharmaceutically acceptable salt thereof;
其中：in:
X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
R w为氨基保护基，优选为Boc； R w is an amino protecting group, preferably Boc;
L为亚烷基或
Figure PCTCN2022074454-appb-000082
环B为环烷基或杂环基；p为0、1、2、3、4、5或6； L is alkylene or
Figure PCTCN2022074454-appb-000082
Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;
环A、R 1至R 4和n如通式(III-1)中所定义。 Ring A, R 1 to R 4 and n are as defined in the general formula (III-1).
方案七Option 7
本公开通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000083
Figure PCTCN2022074454-appb-000083
通式(IC)的化合物或其盐与通式(ID)的化合物或其盐，在碱性条件下，在催化剂存在下，发生偶联反应，得到通式(I)的化合物或其可药用的盐，Compounds of general formula (IC) or their salts and compounds of general formula (ID) or their salts undergo a coupling reaction under basic conditions and in the presence of a catalyst to obtain compounds of general formula (I) or their pharmaceutically acceptable compounds. salt used,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
方案八Option 8
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000084
Figure PCTCN2022074454-appb-000084
通式(IIC)的化合物或其盐与通式(ID)的化合物或其盐，在碱性条件下，在催化剂存在下，发生偶联反应，得到通式(II)的化合物或其可药用的盐，The compound of general formula (IIC) or its salt and the compound of general formula (ID) or its salt undergo a coupling reaction under basic conditions and in the presence of a catalyst to obtain the compound of general formula (II) or its pharmaceutically acceptable compound. salt used,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
方案九Option Nine
本公开通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000085
Figure PCTCN2022074454-appb-000085
通式(IIIC)的化合物或其盐与通式(ID)的化合物或其盐，在碱性条件下，在催化剂存在下，发生偶联反应，得到通式(III)的化合物或其可药用的盐，The compound of general formula (IIIC) or its salt and the compound of general formula (ID) or its salt undergo a coupling reaction under basic conditions and in the presence of a catalyst to obtain the compound of general formula (III) or its pharmaceutically acceptable compound. salt used,
其中：in:
Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
方案十Option ten
本公开通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000086
Figure PCTCN2022074454-appb-000086
通式(IAa)的化合物或其盐与通式(IBb)的化合物或其盐在缩合剂(优选为HATU)和碱性条件下发生酰胺化反应，得到通式(I)的化合物或其可药用的盐，The compound of general formula (IAa) or its salt and the compound of general formula (IBb) or its salt undergo amidation reaction under a condensing agent (preferably HATU) and basic conditions to obtain the compound of general formula (I) or its salts. medicinal salt,
其中：in:
环A、G 1、G 2、G 3、R 1至R 5和n如通式(I)中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in general formula (I).
方案十一Plan Eleven
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000087
Figure PCTCN2022074454-appb-000087
通式(IIAa)的化合物或其盐与通式(IBb)的化合物或其盐在缩合剂(优选为HATU)和碱性条件下发生酰胺化反应，得到通式(II)的化合物或其可药用的盐，The compound of general formula (IIAa) or its salt is subjected to amidation reaction with the compound of general formula (IBb) or its salt under a condensing agent (preferably HATU) and basic conditions to obtain the compound of general formula (II) or its salts. medicinal salt,
其中：in:
环A、R 1至R 5和n如通式(II)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (II).
方案十二Plan 12
本公开通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074454-appb-000088
Figure PCTCN2022074454-appb-000088
通式(IIIAa)的化合物或其盐与通式(IBb)的化合物或其盐在缩合剂(优选为HATU)和碱性条件下发生酰胺化反应，得到通式(III)的化合物或其可药用的盐，A compound of general formula (IIIAa) or a salt thereof is subjected to amidation reaction with a compound of general formula (IBb) or a salt thereof under a condensing agent (preferably HATU) and basic conditions to obtain a compound of general formula (III) or its salts. medicinal salt,
其中：in:
环A、R 1至R 5和n如通式(III)中所定义。 Ring A, R 1 to R 5 and n are as defined in general formula (III).
以上合成方案中提供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、氢氧化钠、氢氧化锂、氢氧化锂一水合物和氢氧化钾；其中方案一至六中提供碱性条件的试剂优选为吡啶；方案七至九中提供碱性条件的试剂优选为碳酸铯；方案十至十二中提供碱性条件的试剂优选为N,N-二异丙基乙胺。The reagents that provide 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-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, lithium hydroxide monohydrate and potassium hydroxide; wherein the reagent providing alkaline conditions in schemes one to six is preferably pyridine; scheme The reagent for providing basic conditions in seven to nine is preferably cesium carbonate; the reagent for providing basic conditions in schemes ten to twelve is preferably N,N-diisopropylethylamine.
以上合成方案七至九中的催化剂包括但不限于双(二亚芐基丙酮)钯、双(二亚芐基丙酮)钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽、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(二苄基磷)二氯二戊铁钯、[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，优选为双(二亚芐基丙酮)钯或双(二亚芐基丙酮)钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽。The catalysts in the above synthetic schemes seven to nine include but are not limited to bis(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-tris Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphorus)dichlorodi Palladium pentamethylene, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex, tris(dibenzylideneacetone)dipalladium, preferably bis(dibenzylideneacetone)palladium or bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphine-9 , 9-dimethylxanthene.
以上合成方案十至十二中的酰胺化反应在缩合剂存在下进行，所述的缩合剂优选为O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)。The amidation reactions in the above synthesis schemes ten to twelve are carried out in the presence of a condensing agent, and the condensing agent is preferably O-(7-azabenzotriazole-1-yl)-N,N,N' , N'-tetramethylurea hexafluorophosphate (HATU).
以上合成方案四至六中的脱保护反应优选在酸性条件下进行，提供酸性条件的试剂优选为三氟乙酸。The deprotection reactions in the above synthetic schemes 4 to 6 are preferably carried out under acidic conditions, and the reagent for providing the acidic conditions is preferably trifluoroacetic acid.
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。The reaction 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, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and mixtures thereof.
具体实施方式Detailed ways
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(d)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M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)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (d) are given in units of 10-6 (ppm). NMR was measured by Bruker AVANCE NEO 500M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (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)。The determination of MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (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).
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。High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor 2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。HPLC preparations were performed using Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average inhibition rate and IC50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。There is no special description in the examples, and the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S 908860 microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯 甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: In the dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
实施例1Example 1
N-(4-氟苯基)-N'-(5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)环丙烷-1,1-二甲酰胺1N-(4-Fluorophenyl)-N'-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cycle Propane-1,1-dicarboxamide 1
Figure PCTCN2022074454-appb-000089
Figure PCTCN2022074454-appb-000089
第一步first step
4-((6-氨基吡啶-3-基)氧基)-7-甲氧基-N-甲基喹啉-6-甲酰胺1b4-((6-Aminopyridin-3-yl)oxy)-7-methoxy-N-methylquinoline-6-carboxamide 1b
化合物4-氯-7-甲氧基-N-甲基喹啉-6-甲酰胺1a(501mg，1.99mmol，采用专利申请“WO2019148043A1中说明书第168页的实施例中间体29”公开的方法制备而得)溶于二甲亚砜(5mL)中，加入6-氨基吡啶-3-酚(220mg,1.99mmol)和氢氧化钾溶液(2M，0.1mL)，加热到85℃反应2小时。冷却至室温，反应液减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化残余物，得到标题产物1b(400mg，产率：62％)。Compound 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide 1a (501 mg, 1.99 mmol, prepared by the method disclosed in Example Intermediate 29 on page 168 of the specification in the patent application "WO2019148043A1" obtained) was dissolved in dimethyl sulfoxide (5 mL), 6-aminopyridin-3-ol (220 mg, 1.99 mmol) and potassium hydroxide solution (2 M, 0.1 mL) were added, and the mixture was heated to 85° C. to react for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1b (400 mg, yield: 62%).
MS m/z(ESI):325.1[M+1]MS m/z(ESI): 325.1[M+1]
第二步second step
N-(4-氟苯基)-N'-(5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)环丙烷-1,1-二甲酰胺1N-(4-Fluorophenyl)-N'-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cycle Propane-1,1-dicarboxamide 1
将化合物1b(170mg，524.15μmol)，化合物1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰氯1c(130mg，537.98μmol，采用专利申请“EP3750893A1中说明书第14页的实施例公用中间体”公开的方法制备而得)溶于吡啶(10mL)，搅拌12小时。反应液减压浓缩后，用高效液相色谱法(Gilson281，色谱柱：SharpSil-T C18150*30mm,5μm；流动相1：水(含10mmol/L的碳酸氢铵)；流动相2：乙腈；15分钟梯度：乙腈38％-90％，流速：30mL/min)纯化残余物，得标题产物1(98mg，产率：35.0％)。Compound 1b (170 mg, 524.15 μmol), compound 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride 1c (130 mg, 537.98 μmol) were prepared using the methods described on page 14 of the specification in the patent application “EP3750893A1. Prepared by the method disclosed in "Example Common Intermediate") was dissolved in pyridine (10 mL) and stirred for 12 hours. After the reaction solution was concentrated under reduced pressure, high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18150*30mm, 5μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 15 min gradient: acetonitrile 38%-90%, flow rate: 30 mL/min), the residue was purified to give the title product 1 (98 mg, yield: 35.0%).
MS m/z(ESI):530.2[M+1]MS m/z(ESI): 530.2[M+1]
1H NMR(500MHz,DMSO-d 6)δ11.18(s,1H),9.76(s,1H),8.68(d,J＝5.3Hz,1H),8.63(s,1H),8.40-8.35(m,2H),8.23(d,J＝9.0Hz,1H),7.85(dd,J＝9.0,2.9Hz,1H), 7.65-7.59(m,2H),7.54(s,1H),7.23-7.14(m,2H),6.56(d,J＝5.3Hz,1H),4.03(s,3H),2.85(d,J＝4.6Hz,3H),1.65-1.53(m,4H)。 1 H NMR (500MHz, DMSO-d 6 ) δ 11.18(s, 1H), 9.76(s, 1H), 8.68(d, J=5.3Hz, 1H), 8.63(s, 1H), 8.40-8.35( m, 2H), 8.23(d, J=9.0Hz, 1H), 7.85(dd, J=9.0, 2.9Hz, 1H), 7.65-7.59(m, 2H), 7.54(s, 1H), 7.23-7.14 (m, 2H), 6.56 (d, J=5.3 Hz, 1H), 4.03 (s, 3H), 2.85 (d, J=4.6 Hz, 3H), 1.65-1.53 (m, 4H).
实施例2Example 2
N-(4-氟苯基)-N'-[5-[[7-甲氧基-6-(甲基氨基甲酰基)-喹啉-4-基]氧基]吡嗪-2-基]环丙烷-1,1-二甲酰胺2N-(4-Fluorophenyl)-N'-[5-[[7-methoxy-6-(methylcarbamoyl)-quinolin-4-yl]oxy]pyrazin-2-yl ]cyclopropane-1,1-dicarboxamide 2
Figure PCTCN2022074454-appb-000090
Figure PCTCN2022074454-appb-000090
第一步first step
N-(4-氟苯基)环丙烷-1,1-二甲酰胺2aN-(4-Fluorophenyl)cyclopropane-1,1-dicarboxamide 2a
将1c(2g，8.27mmol)溶于四氢呋喃(20mL)，冰浴下，将25-28％的氨水(30mL)滴入反应瓶中，升至室温，搅拌1小时。用二氯甲烷萃取(100mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物2a(1.8g，产率：97.8％)。1c (2 g, 8.27 mmol) was dissolved in tetrahydrofuran (20 mL), 25-28% ammonia water (30 mL) was dropped into the reaction flask under ice bath, warmed to room temperature, and stirred for 1 hour. Extracted with dichloromethane (100 mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 2a (1.8 g, yield : 97.8%).
MS m/z(ESI):223.1[M+1]。MS m/z(ESI): 223.1[M+1].
第二步second step
4-羟基-7-甲氧基-N-甲基喹啉-6-甲酰胺2c4-Hydroxy-7-methoxy-N-methylquinoline-6-carboxamide 2c
将化合物7-甲氧基-4-氧代-1,4-二氢喹啉-6-羧酸甲酯2b(10g，42.87mmol，上海韶远试剂有限公司)溶于30％甲胺的乙醇溶液中(200mL，上海泰坦科技股份有限公司)，室温搅拌16小时，反应液减压浓缩后得粗品标题产物2c(9.7g，产率：97.4％)，产物不经纯化直接用于下一步。Compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester 2b (10 g, 42.87 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in 30% methylamine in ethanol The solution (200 mL, Shanghai Titan Technology Co., Ltd.) was stirred at room temperature for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title product 2c (9.7 g, yield: 97.4%), which was used in the next step without purification.
MS m/z(ESI):233.1[M+1]。MS m/z (ESI): 233.1 [M+1].
第三步third step
4-((5-溴吡嗪-2-基)氧基)-7-甲氧基-N-甲基喹啉-6-甲酰胺2d4-((5-Bromopyrazin-2-yl)oxy)-7-methoxy-N-methylquinoline-6-carboxamide 2d
将化合物2c(2.5g，10.76mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入碳酸铯(8.7g，26.9mmol，上海韶远试剂有限公司)，搅拌，80℃反应1小时，将2,5-二溴吡嗪(2.5g，10.76mmol，上海韶远试剂有限公司)溶于N,N-二甲基甲酰胺(2mL)，在80℃条件下滴加入反应瓶中，继续反应1小时。将反应液冷却至室温，缓慢倒入800mL水中，加入乙酸乙酯萃取(300mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物2d(840mg，产率：20％)。Compound 2c (2.5g, 10.76mmol) was dissolved in N,N-dimethylformamide (100mL), cesium carbonate (8.7g, 26.9mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was added, stirred, and reacted at 80°C for 1 hours, 2,5-dibromopyrazine (2.5g, 10.76mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N,N-dimethylformamide (2mL), and added dropwise to the reaction flask at 80°C , and continue to react for 1 hour. The reaction solution was cooled to room temperature, slowly poured into 800 mL of water, extracted with ethyl acetate (300 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the eluent was subjected to silica gel column chromatography. System A was purified to give the title product 2d (840 mg, yield: 20%).
MS m/z(ESI):391.0[M+1]。MS m/z (ESI): 391.0 [M+1].
第四步the fourth step
N-(4-氟苯基)-N'-[5-[[7-甲氧基-6-(甲基氨基甲酰基)-喹啉-4-基]氧基]吡嗪-2-基]环丙烷-1,1-二甲酰胺2N-(4-Fluorophenyl)-N'-[5-[[7-methoxy-6-(methylcarbamoyl)-quinolin-4-yl]oxy]pyrazin-2-yl ]cyclopropane-1,1-dicarboxamide 2
将化合物2d(810mg，2.08mmol)溶于甲苯(150mL)中，加入化合物2a(925mg，4.16mmol)，碳酸铯(2.0g，6.24mmol，上海韶远试剂有限公司)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(721mg，1.24mmol，上海韶远试剂有限公司)，通入氮气两次，排出空气，加入双(二亚芐基丙酮)钯(571mg，0.62mmol，北京百灵威科技有限公司)，通入氮气三次，排出空气，加入预先热好的90℃油浴锅中，搅拌16小时。冷至室温，反应液减压浓缩后用高效液相色谱法(Gilson281，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相1：水(含10mmol/L的碳酸氢铵)；流动相2：乙腈；20分钟梯度：25％-45％，流速：30mL/min)纯化得标题产物2(410mg，产率：37.1％)。MS m/z(ESI):531.2[M+1]。Compound 2d (810 mg, 2.08 mmol) was dissolved in toluene (150 mL), compound 2a (925 mg, 4.16 mmol), cesium carbonate (2.0 g, 6.24 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdi Phenylphosphine-9,9-dimethylxanthene (721 mg, 1.24 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), passed nitrogen twice, exhausted the air, added bis(dibenzylideneacetone)palladium (571 mg, 0.62 mmol, Beijing Bailingwei Technology Co., Ltd.), passed nitrogen three times, exhausted the air, added it to a preheated 90°C oil bath, and stirred for 16 hours. Cooled to room temperature, the reaction solution was concentrated under reduced pressure and then used high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18 150*30mm, 5μm; mobile phase 1: water (containing 10mmol/L of ammonium bicarbonate); mobile phase 2: acetonitrile; 20 min gradient: 25%-45%, flow rate: 30 mL/min) was purified to give the title product 2 (410 mg, yield: 37.1%). MS m/z (ESI): 531.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ11.39(d,1H),9.80(s,1H),9.01(s,1H),8.80(d,1H),8.60(s,1H),8.48(s,1H),8.40–8.35(m,1H),7.60-7.65(m,2H),7.57(s,1H),7.18(t,2H),7.04(d,1H),4.04(s,3H),2.83(d,3H),1.60-1.64(m,4H)。 1 H NMR (500MHz, DMSO-d 6 )δ11.39(d,1H), 9.80(s,1H), 9.01(s,1H), 8.80(d,1H), 8.60(s,1H), 8.48( s, 1H), 8.40-8.35(m, 1H), 7.60-7.65(m, 2H), 7.57(s, 1H), 7.18(t, 2H), 7.04(d, 1H), 4.04(s, 3H) , 2.83 (d, 3H), 1.60-1.64 (m, 4H).
实施例3Example 3
N-环己基-N-(5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)环丙烷-1,1-二甲酰胺3N-Cyclohexyl-N-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1- Dicarboxamide 3
Figure PCTCN2022074454-appb-000091
Figure PCTCN2022074454-appb-000091
Figure PCTCN2022074454-appb-000092
Figure PCTCN2022074454-appb-000092
第一步first step
1-((5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)氨甲酰基)环丙烷-1-羧酸甲酯3b1-((5-((7-Methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid methyl ester 3b
将化合物1b(200mg,0.62mmol)，1,1-环丙基二甲酸单甲酯3a(106mg,0.74mmol)溶于N,N-二甲基甲酰胺(5mL)，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(282mg，0.74mmol，上海韶远试剂有限公司)，N,N-二异丙基乙胺(240mg，1.86mmol，阿达玛斯试剂有限公司)，室温搅拌4小时。减压浓缩除去溶剂，所得残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物3b(180mg，产率：64.8％)。Compound 1b (200 mg, 0.62 mmol), 1,1-cyclopropyldicarboxylate monomethyl ester 3a (106 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), O-(7- Azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (282mg, 0.74mmol, Shanghai Shaoyuan Reagent Co., Ltd.), N,N-di Isopropylethylamine (240 mg, 1.86 mmol, Adamas Reagent Co., Ltd.) was stirred at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3b (180 mg, yield: 64.8%).
MS m/z(ESI):451.1[M+1]。MS m/z(ESI): 451.1 [M+1].
第二步second step
1-((5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)氨甲酰基)环丙烷-1-羧酸3c1-((5-((7-Methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid 3c
化合物3b(80mg，0.18mmol)溶于6.6mL甲醇、四氢呋喃和水(V/V/V＝5:5:1)的混合溶剂中，加入氢氧化锂一水合物(37mg，0.88mmol)，室温搅拌2小时。减压浓缩除去大部分溶剂，加入1M盐酸至反应液pH为3～4，有固体析出，过滤，收集滤饼，真空干燥，得到标题产物3c(77mg，产率：99％)。Compound 3b (80 mg, 0.18 mmol) was dissolved in 6.6 mL of a mixed solvent of methanol, tetrahydrofuran and water (V/V/V=5:5:1), lithium hydroxide monohydrate (37 mg, 0.88 mmol) was added, and the room temperature Stir for 2 hours. Concentrate under reduced pressure to remove most of the solvent, add 1M hydrochloric acid until the pH of the reaction solution is 3-4, a solid is precipitated, filter, collect the filter cake, and dry in vacuo to obtain the title product 3c (77 mg, yield: 99%).
MS m/z(ESI):437.1[M+1]。MS m/z (ESI): 437.1 [M+1].
第三步third step
N-环己基-N-(5-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)环丙烷-1,1-二甲酰胺3N-Cyclohexyl-N-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1,1- Dicarboxamide 3
化合物3c(77mg,0.18mmol)，环己胺(21mg，0.21mmol，阿达玛斯试剂有限公司)溶于N,N-二甲基甲酰胺(3mL)，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(81mg，0.21mmol，上海韶远试剂有限公司)，N,N-二异丙基乙胺(182mg,1.41mmol)，室温搅拌2小时。过滤，减压浓缩除去溶剂，所得残余物用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T，30*150mm,5μm；流动相1：水(含10mmol/L的碳酸氢铵)；流动相2：乙腈；12分钟梯度：乙腈：35％-50％，流速：30mL/min)纯化，得到标题产物3(11mg，产率：12.0％)。Compound 3c (77 mg, 0.18 mmol), cyclohexylamine (21 mg, 0.21 mmol, Adamas Reagent Co., Ltd.) was dissolved in N,N-dimethylformamide (3 mL), and O-(7-azabenzone) was added Triazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (81mg, 0.21mmol, Shanghai Shaoyuan Reagent Co., Ltd.), N,N-diisopropylethyl acetate Amine (182 mg, 1.41 mmol) was stirred at room temperature for 2 hours. Filtration, concentration under reduced pressure to remove the solvent, and the obtained residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T, 30*150mm, 5μm; mobile phase 1: water (containing 10mmol/L of ammonium bicarbonate)) ; mobile phase 2: acetonitrile; 12 min gradient: acetonitrile: 35%-50%, flow rate: 30 mL/min) purification gave the title product 3 (11 mg, yield: 12.0%).
MS m/z(ESI):518.2[M+1]。MS m/z(ESI): 518.2[M+1].
1H NMR(500MHz,DMSO-d 6):10.82(s,1H),8.67(d,1H)，8.61(s,1H)，8.30-8.44(m,2H)，8.18(d,1H),7.82(dd,1H),7.60(d,1H),7.52(s,1H),6.55(d,1H),4.02(s,3H)，3.58-3.69(m,1H),2.84(d,3H),1.62-1.79(m,4H),1.55-1.61(m,1H),1.39-1.54(d,4H),1.21-1.26(m,5H)。 1 H NMR (500 MHz, DMSO-d 6 ): 10.82(s,1H), 8.67(d,1H), 8.61(s,1H), 8.30-8.44(m,2H), 8.18(d,1H), 7.82 (dd, 1H), 7.60(d, 1H), 7.52(s, 1H), 6.55(d, 1H), 4.02(s, 3H), 3.58-3.69(m, 1H), 2.84(d, 3H), 1.62-1.79 (m, 4H), 1.55-1.61 (m, 1H), 1.39-1.54 (d, 4H), 1.21-1.26 (m, 5H).
实施例4Example 4
N-(5-((7-((1-氨基环丙基)甲氧基)-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺4N-(5-((7-((1-Aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)-N -(4-Fluorophenyl)cyclopropane-1,1-dicarboxamide 4
Figure PCTCN2022074454-appb-000093
Figure PCTCN2022074454-appb-000093
第一步first step
(1-((叔丁氧基羰基)氨基)环丙基)甲基甲磺酸酯4b(1-((tert-butoxycarbonyl)amino)cyclopropyl)methylmethanesulfonate 4b
化合物(1-(羟甲基)环丙基)氨基甲酸叔丁酯4a(1.8g，9.6mmol)溶于二氯甲烷(15mL)，加入三乙胺(2.91g，28.75mmol)。0℃下滴加甲磺酰氯(1.31g，11.49mmol)，室温反应0.5小时。用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，浓缩得到标题产物4b粗品(2.5g，产率：98％)。Compound (tert-butyl 1-(hydroxymethyl)cyclopropyl)carbamate 4a (1.8 g, 9.6 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (2.91 g, 28.75 mmol) was added. Methanesulfonyl chloride (1.31 g, 11.49 mmol) was added dropwise at 0°C, and the mixture was reacted at room temperature for 0.5 hours. Extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain crude title product 4b (2.5 g, yield: 98%).
第二步second step
4-氯-7-羟基-N-甲基喹啉-6-甲酰胺4c4-Chloro-7-hydroxy-N-methylquinoline-6-carboxamide 4c
化合物1a(1g，3.98mmol)溶于二氯甲烷(50mL)，0℃下滴加三溴化硼二氯甲烷溶液(1M，39.89mL)。升至室温反应5小时。加入10mL甲醇淬灭反应，用饱和碳酸氢钠溶液将溶液pH调节至弱酸性。减压浓缩后残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物4c(944mg，产率：99％)。Compound 1a (1 g, 3.98 mmol) was dissolved in dichloromethane (50 mL), and a solution of boron tribromide in dichloromethane (1 M, 39.89 mL) was added dropwise at 0°C. Raised to room temperature for 5 hours. The reaction was quenched by adding 10 mL of methanol, and the pH of the solution was adjusted to weakly acidic with saturated sodium bicarbonate solution. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to give the title product 4c (944 mg, yield: 99%).
MS m/z(ESI):237.1[M+1]。MS m/z (ESI): 237.1 [M+1].
第三步third step
(1-(((4-氯-6-(甲基氨基甲酰基)喹啉-7-基)氧基)甲基)环丙基)氨基甲酸叔丁酯4dtert-Butyl (1-(((4-chloro-6-(methylcarbamoyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 4d
将化合物4c(900mg，3.80mmol)和化合物4b(2.0g，7.53mmol)溶于N,N-二甲基甲酰胺(10mL)，加入无水碳酸钾(2.6g，18.81mmol)和碘化钾(1.8g，10.84mmol)。85℃搅拌16小时。冷却至室温，反应液减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物4d(600mg，产率：38.8％)。Compound 4c (900 mg, 3.80 mmol) and compound 4b (2.0 g, 7.53 mmol) were dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (2.6 g, 18.81 mmol) and potassium iodide (1.8 g, 10.84 mmol). Stir at 85°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4d (600 mg, yield: 38.8%).
MS m/z(ESI):406.2[M+1]。MS m/z(ESI): 406.2[M+1].
第四步the fourth step
(1-(((4-((6-氨基吡啶-3-基)氧基)-6-(甲基氨基甲酰基)喹啉-7-基)氧基)甲基)环丙基氨基甲酸叔丁酯4e(1-(((4-((6-Aminopyridin-3-yl)oxy)-6-(methylcarbamoyl)quinolin-7-yl)oxy)methyl)cyclopropylcarbamic acid tert-butyl ester 4e
化合物4d(600mg，1.47mmol)溶于二甲基亚砜(10mL)，加入6-氨基吡啶-3-酚(162mg，1.47mmol)，加入氢氧化钾溶液(1M，3mL)，加热到85℃反应2小时。冷却至室温，反应也减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物4e(300mg，产率：42％)。Compound 4d (600 mg, 1.47 mmol) was dissolved in dimethyl sulfoxide (10 mL), 6-aminopyridin-3-ol (162 mg, 1.47 mmol) was added, potassium hydroxide solution (1 M, 3 mL) was added, and the mixture was heated to 85°C React for 2 hours. After cooling to room temperature, the reaction was also concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 4e (300 mg, yield: 42%).
MS m/z(ESI):480.1[M+1]。MS m/z (ESI): 480.1 [M+1].
第五步the fifth step
(1-(((4-((6-(1-((4-氟苯基)氨基甲酰基)环丙烷-1-甲酰胺基)吡啶-3-基)氧基)-6-(甲基氨基甲酰基)喹啉-7-基)氧基)甲基)环丙基)氨基甲酸叔丁酯4f(1-(((4-((6-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)pyridin-3-yl)oxy)-6-(methyl) carbamoyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate tert-butyl ester 4f
化合物4e(130mg，271.10μmol)和化合物1c(130mg，537.97μmol)溶于吡啶(10mL)，室温搅拌16小时。反应液减压浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物4f(130mg，产率：70％)。Compound 4e (130 mg, 271.10 μmol) and compound 1c (130 mg, 537.97 μmol) were dissolved in pyridine (10 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4f (130 mg, yield: 70%).
MS m/z(ESI):685.3[M+1]。MS m/z (ESI): 685.3 [M+1].
第六步Step 6
N-(5-((7-((1-氨基环丙基)甲氧基)-6-(甲基氨基甲酰基)喹啉-4-基)氧基)吡啶-2-基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺4N-(5-((7-((1-Aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyridin-2-yl)-N -(4-Fluorophenyl)cyclopropane-1,1-dicarboxamide 4
化合物4f(130mg，189.86μmol)溶于二氯甲烷(5mL)，0℃下滴加三氟乙酸(1mL)，室温反应1小时。室温浓缩反应液，用饱和碳酸氢钠溶液调节反应液pH为8，浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triar-Exrs Prep C18 150*30mm,5μm；流动相1：水(含10mmol/L的碳酸氢铵)；流动相2：乙腈；15分钟梯度：乙腈：35％-47％，流速：30mL/min)纯化得标题产物4(86mg，产率 77％)。Compound 4f (130 mg, 189.86 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise at 0° C., and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated at room temperature, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, concentrated, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triar-Exrs Prep C18 150*30mm, 5 μm; mobile phase 1: water (containing 10 mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: acetonitrile: 35%-47%, flow rate: 30 mL/min) to obtain the title product 4 (86 mg, yield 77%) ).
MS m/z(ESI):585.2[M+1]。MS m/z (ESI): 585.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ11.18(s,1H),9.76(s,1H),8.77-8.58(m,3H),8.38(d,1H),8.22(d,1H),7.85(dd,1H),7.67-7.59(m,2H),7.51(s,1H),7.17(t,2H),6.55(d,1H),4.17(s,2H),2.87(d,3H),2.15(s,2H),1.58(dt,4H),0.67(dt,2H),0.65-0.59(m,2H)。 1 H NMR (500MHz, DMSO-d 6 )δ11.18(s,1H), 9.76(s,1H), 8.77-8.58(m,3H), 8.38(d,1H), 8.22(d,1H), 7.85(dd,1H),7.67-7.59(m,2H),7.51(s,1H),7.17(t,2H),6.55(d,1H),4.17(s,2H),2.87(d,3H) , 2.15(s, 2H), 1.58(dt, 4H), 0.67(dt, 2H), 0.65-0.59(m, 2H).
对照例AComparative Example A
N-(4-氟苯基)-N-(2-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)嘧啶-5-基)环丙烷-1,1-二甲酰胺AN-(4-Fluorophenyl)-N-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyrimidin-5-yl)cyclopropane -1,1-Dicarboxamide A
Figure PCTCN2022074454-appb-000094
Figure PCTCN2022074454-appb-000094
第一步first step
7-甲氧基-N-甲基-4-((5-硝基嘧啶-2-基)氧基)喹啉-6-甲酰胺A27-Methoxy-N-methyl-4-((5-nitropyrimidin-2-yl)oxy)quinoline-6-carboxamide A2
将化合物2c(1g，4.31mmol)分散于N,N-二甲基甲酰胺(10mL)中，加入2-氯-5硝基嘧啶A1(690mg，4.33mmol，上海毕得医药科技股份有限公司)，三乙胺(0.48g，4.74mmol)，室温反应5分钟，减压浓缩除去溶剂，所得残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物A2(200mg，产率：13.1％)。Compound 2c (1 g, 4.31 mmol) was dispersed in N,N-dimethylformamide (10 mL), and 2-chloro-5-nitropyrimidine A1 (690 mg, 4.33 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was added. , triethylamine (0.48 g, 4.74 mmol), reacted at room temperature for 5 minutes, concentrated under reduced pressure to remove the solvent, the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product A2 (200 mg, yield: 13.1%) ).
MS m/z(ESI):356.1[M+1]。MS m/z (ESI): 356.1 [M+1].
第二步second step
4-((5-氨基嘧啶-2-基)氧基)-7-甲氧基-N-甲基-喹啉-6-甲酰胺A34-((5-Aminopyrimidin-2-yl)oxy)-7-methoxy-N-methyl-quinoline-6-carboxamide A3
将化合物A2(180mg，0.51mmol)溶于25mL乙醇和水(V/V＝4:1)的混合溶剂中，加入170mg铁粉，再加入170mg氯化铵。加热至90℃反应2小时，减压浓缩除去溶剂，所得残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物A3(160mg，产率：97.1％)。Compound A2 (180 mg, 0.51 mmol) was dissolved in 25 mL of a mixed solvent of ethanol and water (V/V=4:1), 170 mg of iron powder was added, and 170 mg of ammonium chloride was added. The reaction was heated to 90°C for 2 hours, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product A3 (160 mg, yield: 97.1%).
MS m/z(ESI):326.2[M+1]。MS m/z(ESI): 326.2[M+1].
第三步third step
N-(4-氟苯基)-N-(2-((7-甲氧基-6-(甲基氨基甲酰基)喹啉-4-基)氧基)嘧啶-5-基)环丙烷-1,1-二甲酰胺AN-(4-Fluorophenyl)-N-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)pyrimidin-5-yl)cyclopropane -1,1-Dicarboxamide A
将化合物A3(100mg，0.31mmol)和化合物1c(90mg，0.37mmol)溶于吡啶(10mL)中，室温搅拌反应16小时。反应液减压浓缩后用高效液相色谱法(色谱柱：SharpSil-T C18 150*30mm，5μm；流动相1：水(含10mmol/L的碳酸氢铵)；流动相2：乙腈；22分钟，乙腈：36％-46％，流速：30mL/min)纯化得到标题产物A(60mg，产率：36.8％)。Compound A3 (100 mg, 0.31 mmol) and compound 1c (90 mg, 0.37 mmol) were dissolved in pyridine (10 mL), and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and used high performance liquid chromatography (chromatographic column: SharpSil-T C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 22 minutes , acetonitrile: 36%-46%, flow rate: 30 mL/min) and purified to give the title product A (60 mg, yield: 36.8%).
MS m/z(ESI):531.9[M+1]。MS m/z (ESI): 531.9 [M+1].
1H NMR(500MHz,DMSO-d 6)δ10.44(s,1H),10.10(s,1H),8.91(s,2H),8.87-8.89(d,1H),8.34-8.37(dd,1H),8.28(s,1H)7.62-7.65(dd,2H),7.59(s,1H),7.26-7.27(d,1H),7.13-7.16(t,2H),4.03(s,3H),2.80-2.81(d,3H),1.47(s,4H)。 1 H NMR (500MHz, DMSO-d 6 )δ10.44(s,1H), 10.10(s,1H), 8.91(s,2H), 8.87-8.89(d,1H), 8.34-8.37(dd,1H) ),8.28(s,1H)7.62-7.65(dd,2H),7.59(s,1H),7.26-7.27(d,1H),7.13-7.16(t,2H),4.03(s,3H),2.80 -2.81(d, 3H), 1.47(s, 4H).
生物学评价Biological evaluation
测试例1、本公开化合物对Axl、Mer、KDR和MET激酶活性具有抑制作用Test Example 1. Compounds of the present disclosure have inhibitory effects on Axl, Mer, KDR and MET kinase activities
本实验的目的是为了测试化合物对Axl、Mer、KDR和MET的激酶活性抑制作用，根据IC 50大小评价化合物的体外活性。 The purpose of this experiment is to test the inhibitory effect of the compounds on the kinase activity of Axl, Mer, KDR and MET, and to evaluate the in vitro activities of the compounds according to the IC 50 size.
本公开化合物对Axl、Mer、KDR和MET激酶活性抑制效果通过以下的方法进行测试。The inhibitory effects of the compounds of the present disclosure on Axl, Mer, KDR and MET kinase activities were tested by the following methods.
一、实验材料及仪器1. Experimental materials and instruments
实验仪器laboratory apparatus
Figure PCTCN2022074454-appb-000095
Figure PCTCN2022074454-appb-000095
实验材料Experimental Materials
试剂名称Reagent name 供货公司supply company 货号article number
HTRF KinEASE-TK试剂盒HTRF KinEASE-TK Kit CisbioCisbio 62TK0PEC62TK0PEC
ATPATP SigmaSigma A7699A7699
METMET Carna BiosciencesCarna Biosciences 08-15108-151
KDR(VEGFR2)KDR(VEGFR2) Carna BiosciencesCarna Biosciences 08-19108-191
AxlAxl Carna BiosciencesCarna Biosciences 08-10708-107
MerMer Carna BiosciencesCarna Biosciences 08-10808-108
DTTDTT SigmaSigma D0632D0632
MnCl2MnCl2 SigmaSigma M1787M1787
MgCl2MgCl2 SigmaSigma M1028M1028
Triton x-100Triton x-100 sigmasigma 9002-93-19002-93-1
HTRF KinEASE-TK试剂盒HTRF KinEASE-TK Kit CisbioCisbio 62TK0PEC62TK0PEC
二、实验步骤2. Experimental steps
1.利用DMSO溶解化合物至10mM，5倍依次梯度稀释9个浓度。用PBS再次稀释之前DMSO稀释的各梯度化合物，将化合物稀释为首浓度50μM，5倍梯度稀释9个浓度点。再取2μL化合物加入384孔板中(PE，6005620)。1. The compound was dissolved in DMSO to 10 mM, and 5-fold serially diluted to 9 concentrations. Each gradient compound previously diluted in DMSO was diluted again with PBS, and the compound was diluted to the initial concentration of 50 μM, and the 5-fold gradient was diluted to 9 concentration points. Then 2 μL of compound was added to 384-well plate (PE, 6005620).
2.根据HTRF KinEASE-TK试剂盒(Cisbio，62TK0PEC)说明书，配置酶活反应缓冲液。2. According to the instructions of the HTRF KinEASE-TK kit (Cisbio, 62TKOPEC), configure the enzyme activity reaction buffer.
3.利用酶活缓冲液将Axl(Carna Biosciences，08-107)，Mer(Carna Biosciences，08-108)，KDR(Carna Biosciences，08-191)和MET(Carna Biosciences，08-151)蛋白依次稀释到0.025ng/μL，0.125ng/μL，0.01ng/μL和0.05ng/μL，分别取4μL加入384孔中。室温孵育15分钟。3. Axl (Carna Biosciences, 08-107), Mer (Carna Biosciences, 08-108), KDR (Carna Biosciences, 08-191) and MET (Carna Biosciences, 08-151) proteins were sequentially diluted with enzyme activity buffer To 0.025ng/μL, 0.125ng/μL, 0.01ng/μL and 0.05ng/μL, take 4μL into 384 wells respectively. Incubate for 15 minutes at room temperature.
4.根据HTRF KinEASE-TK试剂盒说明书，利用酶活缓冲液配置ATP和底物的反应底物混合液。其中ATP浓度为100μM，底物浓度为1μM。取4μL反应底物混合液加入384孔板中，37℃反应0.5小时。4. According to the instructions of the HTRF KinEASE-TK kit, use the enzyme activity buffer to prepare the reaction substrate mixture of ATP and substrate. The ATP concentration was 100 μM and the substrate concentration was 1 μM. 4 μL of the reaction substrate mixture was added to a 384-well plate and reacted at 37°C for 0.5 hours.
5.根据HTRF KinEASE-TK试剂盒说明书，配置检测混合液。取10μL检测混合液加入384孔板中，室温孵育1小时。5. According to the instructions of the HTRF KinEASE-TK kit, configure the detection mixture. Add 10 μL of detection mixture to a 384-well plate and incubate at room temperature for 1 hour.
6.利用Envision酶标仪中的HTRF模块读取在665nm和620nm激发的荧光信号值,并计算比值Ratio＝(665nm/620nm)×10 4。 6. Use the HTRF module in the Envision microplate reader to read the fluorescence signal values excited at 665nm and 620nm, and calculate the ratio Ratio=(665nm/620nm)×10 4 .
7.使用graphpad prism5.0软件的log(抑制剂)vs.响应-变量斜率，根据化合物浓度的对数值和相应的比值计算得到抑制率，绘制量效曲线并计算IC 50值。 7. Using the log(inhibitor) vs. response-variable slope of graphpad prism5.0 software, the inhibition rate was calculated according to the logarithm of the compound concentration and the corresponding ratio, the dose-response curve was drawn and the IC 50 value was calculated.
本公开中化合物对Axl、Mer、KDR和MET激酶活性抑制通过以上的试验进行测定，测得的IC 50值见表1。 The inhibition of Axl, Mer, KDR and MET kinase activity by the compounds of the present disclosure was determined by the above assays, and the measured IC50 values are shown in Table 1.
表1本公开中化合物对Axl、Mer、KDR和MET激酶活性抑制作用IC 50值 Table 1 IC 50 values for the inhibition of Axl, Mer, KDR and MET kinase activity by compounds in the present disclosure
实施例编号Example number KDR/IC 50(nM) KDR/ IC50 (nM) MET/IC 50(nM) MET/ IC50 (nM) Axl/IC 50(nM) Axl/ IC50 (nM) Mer/IC 50(nM) Mer/IC 50 (nM)
11 1.321.32 9.89.8 5.85.8 0.80.8
22 3.513.51 1.491.49 10.310.3 0.780.78
33 6.296.29 -- -- --
44 12.512.5 -- -- --
对照例AComparative Example A >10000>10000 2020 151151 179179
结论：本公开化合物对KDR、MET、Axl、Mer的结合作用均具有明显的抑制作用，且比对照例A相比具有更好的抑制作用。Conclusion: The disclosed compound has obvious inhibitory effect on the binding effect of KDR, MET, Axl and Mer, and has a better inhibitory effect than control example A.
测试例2：本公开化合物在人肝微粒体中反应性代谢产物鉴定Test Example 2: Identification of Reactive Metabolites of Compounds of the Disclosure in Human Liver Microsomes
本公开化合物在人肝微粒体中反应性代谢产物鉴定采用如下实验方法：The following experimental methods were used to identify the reactive metabolites of the compounds of the present disclosure in human liver microsomes:
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(购买自上海生工)1. Phosphate buffer (purchased from Shanghai Shenggong)
2、NADPH(ACROS，A2646-71-1)2. NADPH (ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，产品目录号452161，批次号905002)3. Human liver microsomes (Corning Gentest, catalog number 452161, batch number 905002)
4、Thermo UHPLC-Q-Exactive Orbitrap质谱仪(Thermo Fisher Scientific)4. Thermo UHPLC-Q-Exactive Orbitrap Mass Spectrometer (Thermo Fisher Scientific)
5、Acquity BEH C 18柱，2.1×100mm，1.7μm(美国Waters公司) 5. Acquity BEH C 18 column, 2.1×100mm, 1.7μm (Waters, USA)
6、阳性对照化合物(双氯芬酸，Diclofenac)。6. Positive control compound (diclofenac, Diclofenac).
二、实验药品2. Experimental drugs
实施例2化合物、化合物XL-092(见WO2019148044A1第162页实施例8化合物)，其结构如下：The compound of Example 2, compound XL-092 (see the compound of Example 8 on page 162 of WO2019148044A1), has the following structure:
Figure PCTCN2022074454-appb-000096
Figure PCTCN2022074454-appb-000096
三、实验步骤3. Experimental steps
1、受试化合物溶液配制：取受试化合物适量，精密称定，加入适量的DMSO溶解后混合均匀，即得浓度为30mM的储备溶液。将浓度为10mM的储备液用50％乙腈/水(v/v)稀释10倍，得到浓度为3.0mM的工作溶液1。将浓度为3.0mM的工作溶液1用PBS稀释10倍，得到300μM的工作溶液2，使用前于4℃保存。1. Preparation of the test compound solution: Take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve, and mix well to obtain a stock solution with a concentration of 30 mM. The stock solution at a concentration of 10 mM was diluted 10-fold with 50% acetonitrile/water (v/v) to give working solution 1 at a concentration of 3.0 mM. The working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain a working solution 2 of 300 μM, which was stored at 4° C. before use.
2、磷酸缓冲液配制：分别称取K 2HPO 4和KH 2PO 4适量，溶于4L的纯水中,配成浓度为100mM的缓冲溶液，然后用磷酸或者氢氧化钠调整pH值为7.4。 2. Preparation of phosphate buffer solution: Weigh appropriate amounts of K 2 HPO 4 and KH 2 PO 4 respectively, dissolve them in 4L of pure water to prepare a buffer solution with a concentration of 100mM, and then adjust the pH to 7.4 with phosphoric acid or sodium hydroxide .
3、肝微粒体溶液配制：分别取各个种属的肝微粒体储存液(浓度为20mg/mL)适量，用浓度为100mM的磷酸缓冲液(pH 7.4)稀释到1.43mg/mL微粒体溶液。3. Preparation of liver microsome solution: Take an appropriate amount of liver microsome stock solution (concentration of 20 mg/mL) of each species, and dilute to 1.43 mg/mL microsomal solution with phosphate buffer solution (pH 7.4) of concentration 100 mM.
4、NADPH辅因子溶液的配制：称取NADPH和氯化镁适量，溶于适量的浓度为100mM的磷酸缓冲液(pH值为7.4)中，使得NADPH和氯化镁的浓度分别为10mM和30mM，备用。4. Preparation of NADPH cofactor solution: Weigh an appropriate amount of NADPH and magnesium chloride and dissolve in an appropriate amount of phosphate buffer (pH value is 7.4) with a concentration of 100 mM, so that the concentrations of NADPH and magnesium chloride are 10 mM and 30 mM, respectively, for use.
5、谷胱甘肽(GSH)溶液的配制：称取GSH适量，溶于适量的浓度为100mM的磷酸缓冲液(pH值为7.4)中，使得GSH的浓度为50mM，备用。5. Preparation of glutathione (GSH) solution: Weigh an appropriate amount of GSH and dissolve it in an appropriate amount of 100 mM phosphate buffer (pH value is 7.4), so that the concentration of GSH is 50 mM, for later use.
6、孵育体系如下所示：6. The incubation system is as follows:
肝微粒体蛋白浓度Liver microsomal protein concentration 1mg/mL1mg/mL
种属species 人people
受试化合物浓度Test compound concentration 30μM30μM
NADPH浓度NADPH concentration 1.0mM1.0mM
MgCl 2浓度 MgCl concentration 3.0mM3.0mM
GSH浓度GSH concentration 5mM5mM
孵育介质Incubation medium 100mM PBS100mM PBS
体系pHSystem pH 7.47.4
孵育温度Incubation temperature 37℃37℃
孵育时间Incubation time 60min60min
孵育体积Incubation volume 200μL200μL
阳性对照positive control 双氯芬酸(10μM)Diclofenac (10μM)
精密移取20μL浓度为300μM的工作液2，加入到1.5mL离心管中，再加入140μL浓度为1.43mg/mL的肝微粒体溶液，使得孵育体系中肝微粒体蛋白浓度为1mg/mL。再加入20μL浓度为10mM的NADPH溶液和20μL浓度为50mM的GSH溶液后，放入37℃恒温孵育箱中震荡孵育，并开始计时。孵育开始60min后，从孵育箱中取出孵育样品，加入1000μL冰冷乙腈溶液，终止反应并在室温下放置10min后，12000rpm离心10min。移取全部上清液于离心管中，37℃真空浓缩至干。残留物用200μL 25％乙腈/水溶液复溶，12000rpm离心10min，移取上清液至96孔板中，吸取5μL进行LC/MS分析。对于空白样品，加入20μL PBS代替工作液2。对于NCF样品，加入20μL PBS代替GSH溶液。阳性对照双氯芬酸(10μM)同受试化合物。采集数据经Xcalibur软件处理分析，根据精确分子量，二级质谱碎片分析本公开化合物是否会发生代谢活化产生反应性代谢产物。Precisely pipet 20 μL of working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 140 μL of liver microsomal solution with a concentration of 1.43 mg/mL, so that the concentration of liver microsomal protein in the incubation system is 1 mg/mL. After adding 20 μL of NADPH solution with a concentration of 10 mM and 20 μL of GSH solution with a concentration of 50 mM, put it into a 37°C constant temperature incubator for shaking incubation, and start timing. After 60 min of incubation, the incubation sample was taken out from the incubator, 1000 μL of ice-cold acetonitrile solution was added, the reaction was terminated, and after being placed at room temperature for 10 min, centrifuged at 12000 rpm for 10 min. All supernatants were pipetted into centrifuge tubes and concentrated to dryness under vacuum at 37°C. The residue was reconstituted with 200 μL of 25% acetonitrile/water solution, centrifuged at 12,000 rpm for 10 min, the supernatant was transferred to a 96-well plate, and 5 μL was drawn for LC/MS analysis. For blank samples, add 20 μL of PBS in place of Working Solution 2. For NCF samples, add 20 μL of PBS instead of GSH solution. The positive control diclofenac (10 μM) was the same as the test compound. The collected data is processed and analyzed by Xcalibur software, and whether the compound of the present disclosure will undergo metabolic activation to produce reactive metabolites is analyzed according to the precise molecular weight and secondary mass spectrometry fragments.
表2本公开化合物在人肝微粒体中反应性代谢产物鉴定Table 2 Identification of reactive metabolites of the disclosed compounds in human liver microsomes
化合物compound 结果result
实施例2Example 2 阴性feminine
XL-092XL-092 阳性positive
结论：实验中未检测到与本公开实施例2化合物相关的GSH结合物，但检测到与化合物XL-092相关的GSH结合物，由此可知，本公开的化合物较化合物XL-092表现出更好的安全性。Conclusion: GSH conjugates related to the compound of Example 2 of the present disclosure were not detected in the experiment, but GSH conjugates related to compound XL-092 were detected. It can be seen that the compounds of the present disclosure showed better performance than compound XL-092. good security.

Claims (22)

  1. 一种通式(I)所示的化合物或其可药用的盐：A compound of general formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074454-appb-100001
    Figure PCTCN2022074454-appb-100001
    其中：in:
    环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；Ring A is selected from the group consisting of 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl;
    G 1为N原子或CR 2a； G 1 is N atom or CR 2a ;
    G 2为N原子或CR 2b； G 2 is N atom or CR 2b ;
    G 3为N原子或CR 3a； G 3 is N atom or CR 3a ;
    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、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、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、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 2、R 2a和R 2b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基； R 2 , R 2a and R 2b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl , cycloalkyl and heterocyclyl;
    R 3和R 3a相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基； R 3 and R 3a are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkane base and heterocyclyl;
    R 4选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； R 4 is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
    R 5选自烷基、-(CH 2) mR a、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、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 5 is selected from alkyl, -(CH 2 ) m Ra , cycloalkyl and heterocyclyl; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl , alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents ;
    R a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、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR bR c、羟基和羟烷基中的一个或多个取代基所取代； R a is cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - substituted with one or more substituents in NR b R c , hydroxy and hydroxyalkyl;
    R b和R c相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； R b and R c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;
    n为0、1、2、3、4或5；且n is 0, 1, 2, 3, 4, or 5; and
    m为1、2、3、4、5或6。m is 1, 2, 3, 4, 5 or 6.
  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G 1为CR 2a；G 2为CR 2b或N原子；G 3为CR 3a；R 2a、R 2b和R 3a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，G 1为CR 2a；G 2为CR 2b；G 3为CR 3a；R 2a、R 2b和R 3a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。 The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 2a ; G 2 is CR 2b or N atom; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups; preferably, G 1 is CR 2a ; G 2 is CR 2b ; G 3 is CR 3a ; R 2a , R 2b and R 3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
  3. 根据权利要求1或2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，The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022074454-appb-100002
    Figure PCTCN2022074454-appb-100002
    其中：in:
    环A、R 1至R 5和n如权利要求1中所定义。 Ring A, R 1 to R 5 and n are as defined in claim 1 .
  4. 根据权利要求1至3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为苯基或环己基。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is phenyl or cyclohexyl.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 4为C 1-6烷基；优选地，R 4为甲基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 is a C 1-6 alkyl group; preferably, R 4 is a methyl group.
  6. 根据权利要求1至5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 5为C 1-6烷基或-(CH 2) mR a；R a为3至6元环烷基，其中所述的3至6元环烷基任选被选自C 1-6烷基和-NR bR c中的一个或多个取代基所取代；R b和R c相同或不同，且各自独立地为氢原子或C 1-6烷基；m为1、2或3；优选地，R 5为甲基或
    Figure PCTCN2022074454-appb-100003
    The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 5 is C 1-6 alkyl or -(CH 2 ) m R a ; R a is 3- to 6-membered cycloalkyl, wherein said 3- to 6-membered cycloalkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and -NR b R c ; R b and R c are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; m is 1, 2 or 3; preferably, R 5 is a methyl group or
    Figure PCTCN2022074454-appb-100003
  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，其中各个R 1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烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至6元环烷基和3至6元杂环基；优选地，各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, 3 to 6 A membered cycloalkyl group and a 3- to 6-membered heterocyclic group; preferably, each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group.
  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R 2选自氢原子、卤素和C 1-6烷基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
  9. 根据权利要求1至8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 3选自氢原子、卤素和C 1-6烷基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 3 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
  10. 根据权利要求1至9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n为0或1。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein n is 0 or 1.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下化合物：The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from the following compounds:
    Figure PCTCN2022074454-appb-100004
    Figure PCTCN2022074454-appb-100004
  12. 一种通式(IA)所示的化合物或其盐：A compound of general formula (IA) or a salt thereof:
    Figure PCTCN2022074454-appb-100005
    Figure PCTCN2022074454-appb-100005
    其中：in:
    G 1、G 2、G 3和R 2至R 5如权利要求1中所定义。 G 1 , G 2 , G 3 and R 2 to R 5 are as defined in claim 1 .
  13. 化合物，其选自如下结构：A compound selected from the following structures:
    Figure PCTCN2022074454-appb-100006
    Figure PCTCN2022074454-appb-100006
  14. 一种通式(IC)所示的化合物或其盐：A compound of general formula (IC) or a salt thereof:
    Figure PCTCN2022074454-appb-100007
    Figure PCTCN2022074454-appb-100007
    其中：in:
    Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
    G 1、G 2、G 3和R 2至R 5如权利要求1中所定义。 G 1 , G 2 , G 3 and R 2 to R 5 are as defined in claim 1 .
  15. 根据权利要求14所述的通式(IC)所示的化合物或其盐，其选自以下化合物：The compound represented by general formula (IC) according to claim 14 or its salt, which is selected from the following compounds:
    Figure PCTCN2022074454-appb-100008
    Figure PCTCN2022074454-appb-100008
  16. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：A method for preparing a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising:
    Figure PCTCN2022074454-appb-100009
    Figure PCTCN2022074454-appb-100009
    通式(IA)的化合物或其盐与通式(IB)的化合物或其盐发生酰化反应，得到通式(I)的化合物或其可药用的盐，The compound of general formula (IA) or its salt is subjected to acylation reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,
    其中：in:
    X为卤素；优选为氯原子；X is a halogen; preferably a chlorine atom;
    环A、G 1、G 2、G 3、R 1至R 5和n如权利要求1中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in claim 1 .
  17. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：A method for preparing a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising:
    Figure PCTCN2022074454-appb-100010
    Figure PCTCN2022074454-appb-100010
    通式(IC)的化合物或其盐与通式(ID)的化合物或其盐发生偶联反应，得到通式(I)的化合物或其可药用的盐，A compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
    其中：in:
    Y为卤素；优选为溴原子；Y is a halogen; preferably a bromine atom;
    环A、G 1、G 2、G 3、R 1至R 5和n如权利要求1中所定义。 Rings A, G 1 , G 2 , G 3 , R 1 to R 5 and n are as defined in claim 1 .
  18. 一种药物组合物，所述药物组合物含有根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, the pharmaceutical composition contains a compound of the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts thereof. acceptable carrier, diluent or excipient.
  19. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于抑制蛋白激酶的药物中的用途；优选地，其中所述的蛋白激酶为受体酪氨酸激酶(RTKs)。The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for inhibiting protein kinases use; preferably, the protein kinases are receptor tyrosine kinases (RTKs).
  20. 根据权利要求19所述的用途，其中所述的受体酪氨酸激酶(RTKs)为Axl、Mer、TYRO3、MET、KDR或它们的组合。The use according to claim 19, wherein the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or a combination thereof.
  21. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防疾病、病症和综 合征的药物中的用途；其中所述的疾病、病症和综合征选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌、银屑病、胃肠道间质瘤、动脉粥样硬化和肺纤维化；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 is prepared for the treatment and/or prevention of diseases , conditions and syndromes in the medicament; wherein said diseases, conditions and syndromes are selected from the group consisting of sarcomas, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibroids, lipomas, teratomas Tumor, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor, atherosclerosis and pulmonary fibrosis; wherein said throat cancer is preferably nasopharyngeal carcinoma; said sarcoma is preferably osteosarcoma or chondrosarcoma; said The colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably a neurofibroma.
  22. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和或预防肿瘤的药物中的用途；其中所述的肿瘤选自肉瘤、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、结直肠癌、小肠癌、胃癌、食道癌、胰腺癌、乳腺癌、子宫内膜癌、卵巢癌、输卵管癌、***、肾癌、膀胱癌、***癌、睾丸癌、肝癌、胆管癌、神经胶质瘤、神经母细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤；其中所述的咽喉癌优选为鼻咽癌；所述的肉瘤优选为骨肉瘤或软骨肉瘤；所述的结直肠癌优选为结肠癌或直肠癌；所述的纤维瘤优选为神经纤维瘤。The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 is used in the preparation of the treatment and or prevention of tumors. Use in medicine; wherein the tumor is selected from sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, stomach cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor; of which The throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibromas.
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