WO2023143330A1 - Tripterygium wilfordii diterpene epoxide having function of killing myc positive cell, preparation method therefor, and application thereof - Google Patents

Tripterygium wilfordii diterpene epoxide having function of killing myc positive cell, preparation method therefor, and application thereof Download PDF

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WO2023143330A1
WO2023143330A1 PCT/CN2023/072990 CN2023072990W WO2023143330A1 WO 2023143330 A1 WO2023143330 A1 WO 2023143330A1 CN 2023072990 W CN2023072990 W CN 2023072990W WO 2023143330 A1 WO2023143330 A1 WO 2023143330A1
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alkyl
amino
alkylamino
heteroaryl
heterocyclic group
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PCT/CN2023/072990
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French (fr)
Chinese (zh)
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徐荣臻
吴水高
干小仙
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杭州卫本医药科技有限公司
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Publication of WO2023143330A1 publication Critical patent/WO2023143330A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms

Definitions

  • the present invention relates to the field of medicine.
  • the present invention relates to compounds used as anticancer and/or immune disease medicines, in particular to diterpene epoxy compounds of Tripterygium wilfordii.
  • the present invention relates to tripterygium wilfordii diterpenoid epoxy compounds capable of killing MYC-positive tumor cells and/or MYC-positive immune cells, methods for preparing these compounds and uses thereof.
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Cancer is a malignant disease that affects human health. There is a great medical need for the treatment of various types of cancer. Research has shown that cancer development is a complex event involving multiple factors and multiple steps.
  • the MYC gene was first reported in 1982.
  • the MYC gene can not only directly initiate tumorigenesis, but also promote tumor progression (Morelli E, et al. Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92.Blood.2018; 132 (10):1050-1063), known as the super cancer driver gene. Cancers driven by the MYC oncogene account for 50% or more of all tumors. In hematopoietic tissues, MYC-positive tumors are as high as 70%, including the most common leukemia (Bahr C, et al.
  • pancreatic cancer In solid tissues, more than 30% of MYC-positive tumors, including pancreatic cancer (Farrell AS, et al. MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemotherapy. Nat Commun. 2017; 8 (1 ):1728), brain cancer (Wang X, et al.MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. Cancer Res.2017; 77(18):4947-4960), non-small cell lung cancer (NSCLC) (Topper MJ, et al.
  • NSCLC non-small cell lung cancer
  • Tripterygium wilfordii (diterpene epoxide) is a large class of compounds with anti-tumor, anti-inflammatory, immunosuppressive, anti-fertility and other activities in the plant Tripterygium wilfordii (TW), such as triptolide ( triptolide), triptolide, triptolide, tripchlorolide, 16-hydroxytriptolide, triptolide, triptriolide, 12-epitriptriolide, triptophenolide, neo triptophenolide, triptonolide, Triptetraolide, neotriptetraolide, dichlorotriptetraolide, triptolide diol ketone (tripdiotolnide), etc.
  • triptolide triptolide
  • triptolide triptolide
  • triptolide triptolide
  • triptolide tripchlorolide
  • 16-hydroxytriptolide triptolide
  • tripterygium oxyditerpenoids can be divided into tripterygium triepoxyditerpenoids (structural formula I) and tripterygium diepoxyditerpenoids (structural formula II).
  • Tripterygium triepoxyditerpenoids such as triptolide, tripchlorolide, triptonide, tripdiolide, and triptolide have been reported in the literature.
  • Lactone (triptolidenol) and 16-hydroxytriptolide (16-hydroxytriptolide) have anti-tumor, anti-inflammatory, immunosuppressive and anti-fertility activities simultaneously, and triptolide diterpenoids such as triptolide triol ( triptriolide) and 12-epitripterygium wilfordii.III.A comparison of the antiinflammatory and immunos uppressive activities of 7 diterpene lactone epoxy compounds in vivo. Zhongguo Yi Xue Ke Xue Yuan Xue Bao.1991; 13(6):391-7.).
  • the present inventors unexpectedly found that some triepoxy (structural formula I) or diepoxy (structural formula II) diterpenoids of Tripterygium wilfordii can selectively kill immune cells such as tumor cells with high expression of MYC, T lymphocytes and B lymphocytes. Further studies have found that these compounds can selectively reduce the level of MYC protein in cells, induce apoptosis and exert anti-tumor and immunosuppressive effects.
  • the present invention provides tripterygium terpenoids with the general formula (I) and its derivatives, or its derivatives, pharmaceutically acceptable Salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, and provide the general formula of the diepoxytripterygium diterpenoids characterized by killing MYC-positive tumor cells and MYC-positive immune cells
  • the compound of (II), or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug isomer, solvate, hydrate, adduct, complex or prodrug:
  • the present invention also provides processes for preparing the compounds described herein.
  • the present invention also provides a pharmaceutical composition, comprising the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, and optionally A pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
  • the compounds of the present invention, or their derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs can be used to treat proliferative diseases.
  • the present invention also provides the compounds of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs used in the preparation of proliferative Use in medicine for disease or autoimmune disease.
  • the present invention further provides the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, for the treatment of proliferative diseases or their own immune disease.
  • the present invention further provides a method for treating proliferative diseases or autoimmune diseases, comprising administering a therapeutically effective amount of the compound, or its derivatives, pharmaceutically acceptable salts, and isomers to a subject in need , solvate, hydrate, adduct, complex or prodrug.
  • the compounds of the present invention or their derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs can be used to treat abnormally high expression of MYC protein diseases, such as proliferative diseases with abnormally high expression of MYC protein.
  • proliferative disease refers to a disease associated with some degree of abnormal cell proliferation, whether malignant or benign.
  • the proliferative disease is a tumor.
  • the tumor is a solid tumor or a non-solid tumor.
  • the tumor is a hematological tumor (eg, leukemia, myeloma, and lymphoma).
  • proliferative disorder is not mutually exclusive when referred to in the present invention.
  • the proliferative disease described herein is a MYC positive proliferative disease, eg a MYC positive tumor, such as a MYC positive solid tumor and/or a MYC positive hematologic tumor.
  • the tumor described herein is a MYC positive tumor.
  • Exemplary tumors include, but are not limited to, breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, lung cancer, small cell lung cancer, Non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, multiple myeloma, lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoid T-cell tumor, B cell lymphoma), leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML)), sarcoma, cervical cancer, liver cancer, thyroid Carcinoma, colorectal cancer, esophageal cancer, genitourinary tract cancer, chol
  • the tumor is preferably selected from MYC-positive leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, brain cancer, tumor, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.
  • the compounds of the present invention can be used to treat autoimmune diseases.
  • the present invention also provides the compounds of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs used for the treatment of autoimmune Use in medicine for diseases.
  • the present invention further provides the compound, or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, for treating autoimmune diseases.
  • the present invention further provides a method for treating autoimmune diseases, comprising administering a therapeutically effective amount of the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, Hydrates, adducts, complexes or prodrugs.
  • the autoimmune disease may be an autoimmune disease related to abnormal function of immune cells such as T cells or B cells, such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, kidney disease and the like.
  • the autoimmune disease is preferably selected from MYC-positive T cells or B Autoimmune diseases related to abnormal function of immune cells such as cells, such as rheumatoid arthritis associated with MYC-positive T cells or B cells, systemic lupus erythematosus, psoriasis, kidney disease, etc., such as MYC-positive rheumatoid arthritis Inflammation, systemic lupus erythematosus, psoriasis, kidney disease.
  • MYC-positive rheumatoid arthritis Inflammation, systemic lupus erythematosus, psoriasis, kidney disease etc.
  • the present invention will illustrate the beneficial effects of the present invention through examples. Those skilled in the art will recognize that these examples are illustrative and not restrictive. These examples do not limit the scope of the invention in any way.
  • the experimental methods described in the following examples are conventional methods unless otherwise specified; all reagents and materials
  • FIG. 1 Effects of compounds WBC213, 220, 223, 266 and WB005 of the present invention on MYC protein of tumor cells.
  • the present invention provides a compound of formula (I), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • the present invention provides a compound of formula (II), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
  • R2 at each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 al
  • R3 in each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 al
  • R2 and R3 are connected together with the attached carbon atoms to form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system with 5-14 ring atoms, 0, 1, 2 of the ring atoms , 3 or 4 are heteroatoms selected from N, O, S, the rest are carbon atoms, and the ring system is optionally replaced by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino , carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted;
  • R 1 and R 2 are connected together with the attached carbon atoms to form a 3-18 membered heterocyclic group
  • R2 and R3 together with the carbon atoms to which they are attached, are joined to form a 3-18 membered heterocyclyl.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • R 1 and R 2 together with the carbon atoms to which they are attached form a 3-7 membered heterocyclyl.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • R 2 and R 3 together with the carbon atoms to which they are attached form a 3-7 membered heterocyclic group.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • R2 at each occurrence is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN , S(O)NH 2 , S(O) 2 NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl.
  • R 2 at each occurrence is independently selected from hydroxyl, amino, azido, -NH-OH, -NH-NH 2 , -SCN, S(O)NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 is independently C 1 -C 6 alkyl at each occurrence thereof.
  • R3 at each occurrence is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN , S(O)NH 2 , S(O) 2 NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl.
  • R 3 at each occurrence thereof is independently selected from hydroxyl, amino, azido, -NH-OH, -NH-NH 2 , -SCN, S(O)NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 is independently C 1 -C 6 alkyl at each occurrence thereof.
  • the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-2), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • W at each occurrence thereof is independently selected from hydrogen, amino, C 1 -C 6 alkylamino.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q in each occurrence thereof, is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 halo Substituted alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 - C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5
  • W at each occurrence thereof is independently selected from hydrogen, amino, C 1 -C 6 alkylamino.
  • the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • R 1 , R 2 and R 3 are as described and defined in formula (II).
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-2), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • R 1 , R 2 and R 3 are as described and defined in formula (II).
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the compound of formula (II) is a compound of structural formula (II) is a compound of structural formula (I1-4), or Its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-5), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-6), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkane Base (C
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-7), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-8), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
  • W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
  • Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6
  • R 2 and R 3 are as described and defined in formula (II).
  • W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, or C1-C6. As used herein, a specified range refers to each member of the stated range as a separate species of alkyl group.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean each of these as independently type description.
  • C1-C4 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as a separate species.
  • C0-Cn alkyl group is used herein in combination with another group, such as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl (C3-C7 cycloalkyl), the indicated
  • the group in this case cycloalkyl, is either directly bonded by a single covalent bond (C0 alkyl) or linked by an alkyl chain (in this case 1, 2, 3 or 4 carbon atoms).
  • Alkyl groups may also be attached via other groups such as heteroatoms, as in -O-CO-C4alkyl (C3-C7cycloalkyl).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.
  • alkyl groups are optionally substituted as described above.
  • Alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain.
  • Non-limiting examples are C2-C8 alkenyl (alkenyl of 2, 3, 4, 5, 6, 7, and 8 carbon atoms), C2-C6 alkenyl, and C2-C4 alkenyl.
  • a specified range refers to each member of the stated range as a separate species of alkenyl group, as described above for the alkyl moiety.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, isobutenyl.
  • an alkenyl group is optionally substituted as described above.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds which may occur at any stable point along the chain, for example C2-C8 alkynyl (2, 3, 4, 5, 6, 7, and 8 carbon atoms alkynyl) or C2-C6 alkynyl.
  • a specified range refers to each member of the stated range as a separate species of alkynyl group, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl , 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • an alkynyl group is optionally substituted as described above.
  • Alkoxy is an alkyl group as described above covalently bonded through an oxygen bridge (-O-).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentyloxy Oxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methylpentyloxy .
  • an "alkylthio" or “thioalkyl” group is an alkyl group as described above with the indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-).
  • alkoxy groups are optionally substituted as described above.
  • Alkenyloxy is such an alkenyl group that is covalently bonded to the group it replaces through an oxygen bridge (-O-).
  • an alkanoyl group is optionally substituted as described above.
  • Alkyl ester is an alkyl group as described herein covalently bonded through an ester bond.
  • a “carbocyclic group,”"carbocyclicring” or “cycloalkyl” is a saturated or partially unsaturated (ie, non-aromatic) group that contains all carbon ring atoms.
  • Carbocyclic groups generally contain 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.
  • a cycloalkyl substituent may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom which may have two substituents may have a cycloalkyl group attached as a spiro group.
  • carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings.
  • carbocycles are optionally substituted as described above.
  • cycloalkyl is partially unsaturated (i.e., non-aromatic) containing all carbon ring atoms. group.
  • a "carbocycle-oxy group” is a monocyclic carbocycle or a mono- or bi-ring carbocycle group as described above attached to the group it replaces via an oxygen-O-linker.
  • Haloalkyl refers to branched and straight chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
  • Haloalkoxy refers to a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Hydroalkyl is an alkyl group as previously described substituted with at least one hydroxy substituent.
  • Aminoalkyl is an alkyl group as previously described substituted with at least one amino substituent.
  • Alkylamino is an amino substituent substituted with at least one alkyl group as previously described.
  • Halogen independently refers to any one of fluorine, chlorine, bromine and iodine.
  • Aryl refers to an aromatic group containing only carbon in an aromatic ring or ring.
  • the aryl group contains 1 to 3 separate or fused rings and has 6 to 18 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17 or 18) ring atoms, with no heteroatoms as ring members.
  • such aryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitutions may include fusion to a 5 to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, 3, 4-methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a side ring is a phenyl group substituted by a phenyl group. In one embodiment, aryl groups are optionally substituted as described above.
  • Aryl includes bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • Typical aryl groups include, but are not limited to, those formed from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydro Groups derived from naphthyl and the like.
  • the aryl group is phenyl, biphenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, 2.3-dihydrobenzofuranyl and the like.
  • heterocycle refers to rings having 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ) saturated or partially unsaturated (that is, having one or more double and/or triple bonds within the ring without aromaticity) carbon ring atom groups of ) ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen, phosphorus and sulfur heteroatoms, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently by one or more of the aforementioned substituents.
  • 3 to 18 e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18
  • saturated or partially unsaturated that is, having one or more double and/or triple bonds within the ring without aromaticity
  • the heterocycle can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclic [4,5], [5,5], [5,6] or [6,6 ]Tie.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • heterocycles include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperidonyl, morpholino Linyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidine base, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrole Linyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, di Thianyl, dithiolan
  • the heterocyclic groups herein are optionally substituted independently with one or more substituents described herein.
  • Heterocyclyl includes “heterocycloalkyl”.
  • Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment, nitrogen is a heteroatom.
  • Monocyclic heterocycloalkyl groups typically have 3 to about 8 ring atoms, or 4 to 6 ring atoms.
  • Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl.
  • Heterocyclyl may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
  • heterocyclic epoxy group is a monocyclic or bicyclic heterocyclic group as previously described attached to the group it replaces via an oxy-O-linker.
  • Heteroaryl means a stable monocyclic aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, the remaining ring atoms being carbon, or at least one of the 5- to 10-membered (5, 6, 7, 8, 9, 10 stable bicyclic or tricyclic ring systems of aromatic rings.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have 5 to 8 ring atoms (5, 6, 7, 8).
  • the bicyclic heteroaryl group is 9- to 10-membered heteroaryl groups, ie groups containing 9 or 10 ring atoms in which one 5- to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring.
  • the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in a heteroaryl group does not exceed two.
  • the total number of S and O atoms in the aromatic heterocycle does not exceed one.
  • heteroaryl groups include, but are not limited to, pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl , pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, tetrahydro Isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridine Base, purinyl, oxy
  • Heteroaryl groups are optionally substituted independently with one or more substituents described herein.
  • Heteroaryloxy is said heteroaryl group bonded to the group it replaces via an oxygen-O-linker.
  • Heteroaryl may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
  • the present invention also covers bicyclic, tricyclic, tetracyclic, pentacyclic and other polycyclic rings formed by one or more monocyclic rings selected from "cycloalkyl", “aryl” and “heteroaryl” in a manner permitted by valence. system.
  • groups described herein may be substituted or unsubstituted.
  • groups described herein include both the group referred to alone and the group linked to other groups.
  • "alkyl” described herein may be substituted or unsubstituted.
  • the "alkyl” mentioned herein includes not only the alkyl group mentioned alone, but also the alkyl group connected with other groups, such as hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, alkyl in C 1 -C 6 alkylamino. This applies to any other group described herein.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid salt, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate "mesylate", Esylate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule, such as acetate, succinate or other counterion.
  • the counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • pharmaceutically acceptable salts can have more than one charged atom in their structure. multiple charged Examples of atoms that are part of a pharmaceutically acceptable salt can have multiple counterions.
  • a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., such organic acids as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid , pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc.
  • an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by oxidation with an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide such as It can be prepared by treating free acids with inorganic or organic bases such as compounds.
  • suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and those derived from sodium , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium inorganic salts.
  • pharmaceutically acceptable indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
  • the compounds of the present application may exist in various isomers and stereoisomeric forms.
  • stereoisomer refers to compounds having the same chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
  • Stepoisomers may include “diastereomers” and “enantiomers”.
  • Diastereoisomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other.
  • Enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • R” and “S” represent the configuration of substituents around one or more chiral atoms.
  • Compounds of the present application may be prepared as individual isomers by chiral synthesis or resolution from isomeric mixtures.
  • the disclosed compounds may possess one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. When the absolute stereochemistry of a stereocenter is not determined, the stereochemical configuration can be assigned as (*) at the indicated center.
  • the compounds described herein exist in optically active or racemic form. It is to be understood that the compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms or combinations thereof which possess the therapeutically useful properties described herein.
  • the compounds described herein contain one or more chiral centers. These compounds may be prepared by any means including stereoselective synthesis, enantioselective synthesis or separation of mixtures of enantiomers or diastereomers. Resolution of a compound and its isomers can be achieved by any means including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.
  • derivative refers to a compound obtained by derivatizing the compound of the present invention at any position within the range allowed by the valence.
  • solvate refers to a crystalline form of molecules, atoms and/or ions that also includes solvent molecules that penetrate into the crystal structure, the solvent molecules of a solvate may be in a regular arrangement and/or a disordered arrangement.
  • the solvates of the present invention are preferably solvent hydrates.
  • metabolite refers to the active form obtained after metabolism of the compound of the present invention or its derivative under physiological conditions.
  • prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are active in their unreacted form. Prodrugs can generally be prepared using known methods, for example 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Edited by Manfred E. Wolff, 5th edition) and J. Rautio's Prodrugs and Targeted Delivery (2011) 31- 60 (Wiley-VCH, Methods and Principles in Medicinal Chemistry Vol. 47) and those methods described in G. Thomas's Fundamentals of Medicinal Chemistry (2003) 195-200 (Wiley).
  • complex refers to a product in which the compound of the present invention is further combined with other small molecules or biomacromolecules by non-chemical bonds or non-covalent intermolecular forces.
  • the present invention also provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
  • the pharmaceutically acceptable carrier in the present invention refers to the pharmaceutically acceptable carrier well known to those skilled in the art.
  • the pharmaceutically acceptable carrier in the present invention includes but not limited to: fillers, wetting agents, binders, disintegrants, Lubricants, adhesives, glidants, taste masking agents, surfactants, preservatives, etc.
  • Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, and the like.
  • Wetting agents and binders include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, and the like.
  • Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, and the like.
  • Lubricants include, but are not limited to, magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and the like.
  • Binders include, but are not limited to, gum arabic, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dextrose, dextrin, dextrose, ethylcellulose, gelatin, liquid dextrose, guar Gum, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Magnesium Aluminum Silicate, Maltodextrin, Methylcellulose, Polymethacrylate, Polyvinylpyrrolidone, Pregelatinized Starch , sodium alginate, sorbitol, starch, syrup and yellow Achillea gum.
  • Glidants include, but are not limited to, colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc.
  • Taste-masking agents include, but are not limited to, aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin.
  • Surfactants include, but are not limited to, Tween-80, poloxamers.
  • Preservatives include, but are not limited to, paraben, sodium benzoate, potassium sorbate, and the like.
  • compositions containing the active ingredients in various proportions are known, or will be apparent to those skilled in the art in light of this disclosure. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995).
  • the method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents and the like.
  • the pharmaceutical compositions of the present invention are manufactured by known methods, including conventional mixing, dissolving or freeze-drying methods.
  • the proportion of active ingredient may vary from about 0.01% to about 99% by weight of a given unit dosage form.
  • the amount of active ingredient is such that an effective dosage level will be obtained.
  • Tablets, capsules, etc. of the present invention may contain: binders, such as tragacanth, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as cornstarch, potato Starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, oil of wintergreen, or cherry flavor.
  • a liquid carrier such as vegetable oil or polyethylene glycol.
  • any material may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form.
  • tablets or capsules may be coated with gelatin, wax, shellac or sugar or the like.
  • a syrup may contain the active ingredient, sucrose or fructose as a sweetening agent, methyl or propyl paraben as a preservative, a dye and flavoring such as cherry flavor or orange flavor.
  • any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and nontoxic in the amounts employed.
  • the active ingredient can be incorporated into sustained release formulations and sustained release devices.
  • the active ingredient can also be administered intravenously or intraperitoneally by infusion or injection.
  • Aqueous solutions of the active ingredient or its salts can be prepared, optionally mixed with nontoxic surfactants.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the dosage form of the pharmaceutical composition suitable for injection or infusion may comprise a sterile aqueous solution containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solution or dispersion. or dispersion or sterile powder.
  • the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (e.g., glycerol, acrylic acid, glycols, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants.
  • Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption (eg, aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional required ingredient present in sterile-filtered solution.
  • Useful solid carriers include comminuted solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like).
  • Useful liquid carriers include water, ethanol or glycol or water-ethanol/glycol mixtures, in which the pharmaceutical compositions of this invention can be dissolved or dispersed in effective amounts, optionally with the aid of nontoxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.
  • Thickening agents can also be used with liquid carriers to form spreadable pastes, gels, and ointments , soap, etc., directly on the user's skin.
  • the therapeutically effective amount of the active ingredient depends not only on the particular salt chosen, but also on the mode of administration, the nature of the disease to be treated and the age and state of the patient, and ultimately at the discretion of the attending physician or clinician.
  • unit dosage form which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies.
  • the unit dosage form can be a capsule or a tablet.
  • the amount of a unit dose of active ingredient may be varied or adjusted from about 0.01 to about 1000 milligrams or more depending on the particular treatment involved.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.
  • a compound described herein, or a pharmaceutically acceptable salt thereof may also be administered in combination with one or more additional therapeutic agents useful in the treatment of cancer.
  • additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, Cisplatin etc.
  • the present invention also includes compounds obtained by combining any group defined at any variable group of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvents compounds, hydrates, adducts, complexes or prodrugs.
  • the present invention also includes the following exemplary compounds.
  • Embodiment 1 the synthesis of compound WBC208
  • Embodiment 2 the synthesis of compound WBC209
  • Embodiment 3 the synthesis of compound WBC210
  • Embodiment 4 the synthesis of compound WBC211
  • Embodiment 5 the synthesis of compound WBC212
  • Embodiment 6 the synthesis of compound WBC220
  • Embodiment 7 the synthesis of compound WBC221
  • Embodiment 8 the synthesis of compound WBC222
  • the organic layer was washed successively with 5% aqueous sodium bicarbonate solution 4 times, 5% aqueous sodium bisulfate solution 3 times, and aqueous NaCl solution 2 times.
  • the organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave 151 mg of WB001B-2.
  • Embodiment 9 the synthesis of compound WBC223
  • the organic layer was washed successively with 5% aqueous sodium bicarbonate solution 4 times, 5% aqueous sodium bisulfate solution 3 times, and aqueous NaCl solution 2 times.
  • the organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave 154mg of WB001G-2.
  • Embodiment 10 the synthesis of compound WBC213
  • Embodiment 11 the synthesis of compound WBC204
  • Triptolide (250.0 mg, 0.694 mmol) was dissolved in a solution of dichloromethane (5.0 ml). Start stirring with nitrogen protection, add succinic anhydride (694.5mg, 6.94mmol) and triethylamine (0.5ml), stir for 5min, add DMAP (847.8mg, 6.94mmol), and stir at 25°C for 2h after the addition. After the reaction was completed, it was quenched by adding saturated sodium bisulfate and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound II (280.0 mg, 87.8%) was obtained as a white solid after separation and purification by chromatographic column.
  • reaction solution was diluted with EA, washed three times with 5% sodium bicarbonate solution, once with 5% sodium bisulfate solution, once with brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 176 mg of solid.
  • the solid was dissolved in 22.5ml of acetonitrile and 2.5ml of water, 0.4ml of trifluoroacetic acid was added, and the temperature was raised to 80°C for 48h.
  • the reaction solution was diluted with DCM, washed twice with water and once with brine, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • WBC213 160mg, 0.447mmol
  • Example 21 Determination of the Anti-MYC Positive Tumor Cells and Immune Cell Activity of Compounds of the Invention in Vitro
  • MYC-positive tumor cell lines purchased from the Chinese Academy of Sciences Cell Bank: leukemia cell lines: human Molm-13 (acute myeloid leukemia), THP-1 (acute myeloid leukemia), Kasumi-1 (acute myeloid leukemia); H9 ( Acute lymphoblastic leukemia, T lymphocytes) and Jurkat (acute lymphoblastic leukemia, T lymphocytes); RPMI-8228 (myeloma cells, B lymphocytes) and U266 (myeloma cells, B lymphocytes); Mia-paca2 ( pancreatic cancer cells).
  • leukemia cell lines human Molm-13 (acute myeloid leukemia), THP-1 (acute myeloid leukemia), Kasumi-1 (acute myeloid leukemia); H9 ( Acute lymphoblastic leukemia, T lymphocytes) and Jurkat (acute lymphoblastic leukemia, T lymphocytes); RPMI-8228 (myeloma cells, B
  • HEK293 human embryonic kidney cells
  • L02 normal liver cells
  • Main reagents compounds of the present invention.
  • Main instruments CO2 cell incubator (Heraeus, Germany), microplate reader (Bio-Rad, USA)
  • Well-grown cells were taken and inoculated into the wells of a 96-well cell culture plate, 5000 per well.
  • the culture medium is 1640 cell culture medium containing 10% fetal bovine serum.
  • different concentrations of compounds (0-1000 nM) were added, mixed evenly, and placed in a carbon dioxide (5% CO 2 ) cell incubator at 37° C. for 72 hours.
  • Cell viability was then determined by the MTT assay. In this experiment, the cell viability of the control group (without compound treatment) was set as 100%, and the cell viability (%) and the 72-hour half-inhibitory concentration of the cells (72-hour IC 50 value) were calculated after the compound was acted on.
  • Example 22 Compounds WBC213, WBC220, WBC223, WB005 and WBC266 of the present invention selectively inhibit MYC protein experiment
  • the present invention uses cell culture technology and immunoblotting technology to detect the influence of WBC213, WBC220, WBC223, WB005 and WBC266 on the MYC protein of cells with high MYC expression.
  • MYC highly expressed leukemia cell line Molm-13 (human acute myeloid leukemia).
  • Reagents Compounds WBC213, WBC220, WBC223, WB005 and WBC266
  • Well-grown leukemia cells were inoculated into wells of a 6-well cell culture plate at a density of 1 ⁇ 10 6 /ml.
  • the culture medium is 1640 cell culture medium containing 10% fetal bovine serum.
  • the experimental results are shown in Figure 1 below.
  • the compound WBC213 of the present invention down-regulates the MYC protein level of tumor cells in a dose-dependent manner.
  • WBC213 at a concentration of 20nM can significantly down-regulate the level of Molm-13MYC in tumor cells, but has no significant effect on the nuclear protein XPB.
  • WBC213 up-regulated the nuclear protein p53 in a dose-dependent manner (Fig. 1a).
  • WBC220, WB005, WBC223 and WBC266 also down-regulated MYC protein levels in tumor cells in a dose-dependent manner (Fig. 1b, c, d and e). This result shows that the compound of the present invention can target and inhibit cell MYC protein, and can be used for diseases related to abnormal high expression of MYC.

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Abstract

The present invention relates to the field of medicines. The present invention relates to a compound used as an anti-cancer and/or immune disease drug, and specifically relates to a tripterygium wilfordii diterpene epoxide. In particular, the present invention relates to a tripterygium wilfordii diterpene epoxide having the function of killing MYC positive tumor cells and/or MYC positive immune cells, a method for preparing these compounds, and a use of these compounds.

Description

具有杀伤MYC阳性细胞功能雷公藤二萜类环氧化合物、及其制备方法和应用Tripterygium wilfordii diterpenoid epoxy compound with the function of killing MYC positive cells, its preparation method and application 技术领域technical field
本发明涉及医药领域。本发明涉及用作抗癌和/或免疫性疾病药物的化合物，具体涉及雷公藤二萜类环氧化合物(diterpene epoxide)。特别地，本发明涉及具有杀伤MYC阳性肿瘤细胞和/或MYC阳性免疫细胞功能的雷公藤二萜类环氧化合物、制备这些化合物的方法和用途。本发明还提供了包含本发明所述化合物或其药学上可接受盐和可药用载体的药物组合物。The present invention relates to the field of medicine. The present invention relates to compounds used as anticancer and/or immune disease medicines, in particular to diterpene epoxy compounds of Tripterygium wilfordii. In particular, the present invention relates to tripterygium wilfordii diterpenoid epoxy compounds capable of killing MYC-positive tumor cells and/or MYC-positive immune cells, methods for preparing these compounds and uses thereof. The present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
背景技术Background technique
癌症是一种影响人类健康的恶性疾病。存在着巨大的医疗需求，以用于治疗各种类型的癌症。研究表明，癌症的发生是一个复杂的事件，涉及多个因素和多个步骤。Cancer is a malignant disease that affects human health. There is a great medical need for the treatment of various types of cancer. Research has shown that cancer development is a complex event involving multiple factors and multiple steps.
MYC基因在1982年首次被报道。MYC基因不仅能直接启动肿瘤发生，而且还促进肿瘤进展(Morelli E,et al.Therapeutic vulnerability of multiple myeloma to MIR17PTi,a first-in-class inhibitor of pri-miR-17-92.Blood.2018；132(10):1050-1063)，被称为超级癌症驱动基因。MYC癌基因驱动的癌症占全部肿瘤的50％或更多。在造血组织中，MYC阳性肿瘤更是高达70％以上，包括最常见的白血病(Bahr C,et al.Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies.Nature.2018；553(7689):515-520)、淋巴瘤(Reddy A,et al.Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.Cell.2017；171(2):481-494.e15)和多发性骨髓瘤(Nakamura K,et al.Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment.Cancer Cell.2018；33(4):634-648.e5)。在实体组织中，MYC阳性肿瘤也在30％以上，包括胰腺癌(Farrell AS,et al.MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance.Nat Commun.2017；8(1):1728)、脑癌(Wang X,et al.MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells.Cancer Res.2017；77(18):4947-4960)、非小细胞肺癌(NSCLC)(Topper MJ,et al.Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.Cell.2017；171(6):1284-1300.e21)和小细胞肺癌(SCLC)(Christensen CL,et al.Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.Cancer Cell.2014； 26(6):909-922)、肝癌(Dang H,et al.Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma.Cancer Cell.2017；32(1):101-114.e8)、前列腺癌(Welti J,et al.Targeting bromodomain and extra-terminal(BET)family proteins in castration resistant prostate cancer(CRPC).Clin Cancer Res.2018；24(13):3149-3162)等等。更糟糕的是，MYC驱动的肿瘤恶性程度高、侵袭性强、生存期短，对目前常规治疗效果差(Chipumuro E,et al.CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.Cell.2014；159(5):1126-1139)。而且，MYC基因还能调控免疫反应。The MYC gene was first reported in 1982. The MYC gene can not only directly initiate tumorigenesis, but also promote tumor progression (Morelli E, et al. Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92.Blood.2018; 132 (10):1050-1063), known as the super cancer driver gene. Cancers driven by the MYC oncogene account for 50% or more of all tumors. In hematopoietic tissues, MYC-positive tumors are as high as 70%, including the most common leukemia (Bahr C, et al. Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. Nature. 2018; 553(7689): 515- 520), lymphoma (Reddy A, et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017; 171(2):481-494.e15) and multiple myeloma (Nakamura K, et al. Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment. Cancer Cell. 2018; 33(4):634-648.e5). In solid tissues, more than 30% of MYC-positive tumors, including pancreatic cancer (Farrell AS, et al. MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemotherapy. Nat Commun. 2017; 8 (1 ):1728), brain cancer (Wang X, et al.MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. Cancer Res.2017; 77(18):4947-4960), non-small cell lung cancer (NSCLC) (Topper MJ, et al. Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell. 2017; 171(6): 1284-1300.e21) and small cell lung cancer (SCLC) (Christensen CL, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014; 26(6):909-922), liver cancer (Dang H, et al. Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma. Cancer Cell.2017; 32(1):101-114.e8), Prostate cancer (Welti J, et al. Targeting bromodomain and extra-terminal (BET) family proteins in castration resistant prostate cancer (CRPC). Clin Cancer Res. 2018; 24(13): 3149-3162) and so on. To make matters worse, MYC-driven tumors are highly malignant, aggressive, and short-lived, and have poor response to current conventional treatments (Chipumuro E, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014;159(5):1126-1139). Moreover, the MYC gene also regulates the immune response.
尽管研究人员在研发靶向治疗MYC基因的药物和技术上付出了巨大的努力，但迄今为止仍未能成功发现可用于靶向治疗MYC基因、进而治疗癌症和/或调节免疫系统的药物。Although researchers have made great efforts to develop drugs and technologies that target the MYC gene, so far they have not been able to find drugs that can be used to target the MYC gene, thereby treating cancer and/or regulating the immune system.
雷公藤环氧二萜类化合物(diterpene epoxide)是植物雷公藤(Tripterygium wilfordii)(TW)中具有抗肿瘤、抗炎、免疫抑制、抗生育等活性的一大类化合物，如雷公藤甲素(triptolide)、雷公藤乙素(tripdiolide)、雷公藤内酯酮(triptonide)、雷公藤氯内酯醇(tripchlorolide)、16-羟基雷公藤甲素(16-hydroxytriptolide)、雷醇内酯(triptolidenol)、雷公藤内酯三醇(triptriolide)、12-表雷公藤内酯三醇(12-epitriptriolide)、雷酚内酯(triptophenolide)、雷酚新内酯(neo triptophenolide)、雷酚酮内酯(triptonolide)、雷公藤内酯四醇(triptetraolide)、新雷公藤内酯四醇(neotriptetraolide)、双氯雷公藤内酯四醇(dichlorotriptetraolide)、雷公藤内酯二醇酮(tripdiotolnide)等。

Tripterygium wilfordii (diterpene epoxide) is a large class of compounds with anti-tumor, anti-inflammatory, immunosuppressive, anti-fertility and other activities in the plant Tripterygium wilfordii (TW), such as triptolide ( triptolide), triptolide, triptolide, tripchlorolide, 16-hydroxytriptolide, triptolide, triptriolide, 12-epitriptriolide, triptophenolide, neo triptophenolide, triptonolide, Triptetraolide, neotriptetraolide, dichlorotriptetraolide, triptolide diol ketone (tripdiotolnide), etc.

代表性雷公藤二萜类化合物结构(diterpenoids of Tripterygium wilfordii)Representative diterpenoids of Tripterygium wilfordii
根据环氧基团数量，雷公藤环氧二萜类化合物可以分为雷公藤三环氧二萜类化合物(结构式I)和雷公藤二环氧二萜类化合物(结构式II)两类。已有文献报道雷公藤三环氧二萜类化合物如雷公藤甲素(triptolide)、雷公藤氯内酯醇(tripchlorolide)、雷公藤内酯酮(triptonide)、雷公藤乙素(tripdiolide)、雷醇内酯(triptolidenol)和16-羟基雷公藤甲素(16-hydroxytriptolide)同时拥有抗肿瘤、抗炎、免疫抑制和抗生育活性，而雷公藤二环氧二萜类化合物如雷公藤内酯三醇(triptriolide)和12-表雷公藤内酯三醇(12-epitriptriolide)仅有抗炎活性(J Zheng.Screening of active anti-inflammatory,immunosuppressive and antifertility components of Tripterygium wilfordii.III.A comparison of the antiinflammatory and immunosuppressive activities of 7 diterpene lactone epoxide compounds in vivo.Zhongguo Yi Xue Ke Xue Yuan Xue Bao.1991；13(6):391-7.)。According to the number of epoxy groups, tripterygium oxyditerpenoids can be divided into tripterygium triepoxyditerpenoids (structural formula I) and tripterygium diepoxyditerpenoids (structural formula II). Tripterygium triepoxyditerpenoids such as triptolide, tripchlorolide, triptonide, tripdiolide, and triptolide have been reported in the literature. Lactone (triptolidenol) and 16-hydroxytriptolide (16-hydroxytriptolide) have anti-tumor, anti-inflammatory, immunosuppressive and anti-fertility activities simultaneously, and triptolide diterpenoids such as triptolide triol ( triptriolide) and 12-epitripterygium wilfordii.III.A comparison of the antiinflammatory and immunos uppressive activities of 7 diterpene lactone epoxy compounds in vivo. Zhongguo Yi Xue Ke Xue Yuan Xue Bao.1991; 13(6):391-7.).
迄今为止，雷公藤环氧二萜类化合物是否能靶向性地治疗疾病仍然是未知的，因为雷公藤环氧二萜类化合物的作用机制仍然是未知的。此外，一些雷公藤环氧二萜类化合物毒性太大，药代动力学性质不佳。例如，雷公藤甲素口服和静脉注射后的药代动力学特征均提示，雷公藤甲素消除半衰期短，在体内经历快速吸收、分布、代谢和消除，血药浓度和各组织药物浓度随时间变化波动大，不具备理想的药动学性质，预期不具有临床价值。So far, it is still unknown whether the epoxy diterpenoids of tripterygium wilfordii can target diseases, because the mechanism of action of the epoxy diterpenoids of tripterygium wilfordii is still unknown. In addition, some epoxyditerpenoids of tripterygium wilfordii are too toxic and have poor pharmacokinetic properties. For example, the pharmacokinetic characteristics of triptolide after oral administration and intravenous injection all suggest that triptolide has a short elimination half-life, undergoes rapid absorption, distribution, metabolism and elimination in the body, and the blood drug concentration and drug concentration in various tissues change with time. The changes fluctuate greatly, do not have ideal pharmacokinetic properties, and are not expected to have clinical value.
本发明人意外发现，一些三环氧(结构式I)或二环氧(结构式II)雷公藤二萜类化合物能选择性杀伤MYC高表达肿瘤细胞、T淋巴细胞和B淋巴免疫细胞等免疫细胞。进一步研究发现，这类化合物能选择性降低细胞内MYC蛋白水平，诱导细胞凋亡发挥抗肿瘤和免疫抑制效果。The present inventors unexpectedly found that some triepoxy (structural formula I) or diepoxy (structural formula II) diterpenoids of Tripterygium wilfordii can selectively kill immune cells such as tumor cells with high expression of MYC, T lymphocytes and B lymphocytes. Further studies have found that these compounds can selectively reduce the level of MYC protein in cells, induce apoptosis and exert anti-tumor and immunosuppressive effects.
发明简述Brief description of the invention
本发明提供特征为具有杀伤MYC阳性肿瘤细胞和MYC阳性免疫细胞作用的三环氧雷公藤二萜类化合物通式为(I)的化合物及其衍生物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，以及提供特征为具有杀伤MYC阳性肿瘤细胞和MYC阳性免疫细胞作用的二环氧雷公藤二萜类化合物通式为(II)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
The present invention provides tripterygium terpenoids with the general formula (I) and its derivatives, or its derivatives, pharmaceutically acceptable Salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, and provide the general formula of the diepoxytripterygium diterpenoids characterized by killing MYC-positive tumor cells and MYC-positive immune cells The compound of (II), or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
本发明还提供制备本发明所述化合物的方法。The present invention also provides processes for preparing the compounds described herein.
本发明还提供一种药物组合物，包含所述化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，以及任选地药学上可接受载体。本发明所述药物组合物可以是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。The present invention also provides a pharmaceutical composition, comprising the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, and optionally A pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
本发明所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药可用于治疗增殖性疾病。本发明还提供了本发明所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药在制备用于治疗增殖性疾病或自身免疫性疾病的药物中的用途。本发明进一步提供了所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，用于治疗增殖性疾病或自身免疫性疾病。本发明进一步提供了治疗增殖性疾病或自身免疫性疾病的方法，包括向有需要的受试者施用治疗有效量的所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药。 The compounds of the present invention, or their derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs can be used to treat proliferative diseases. The present invention also provides the compounds of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs used in the preparation of proliferative Use in medicine for disease or autoimmune disease. The present invention further provides the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, for the treatment of proliferative diseases or their own immune disease. The present invention further provides a method for treating proliferative diseases or autoimmune diseases, comprising administering a therapeutically effective amount of the compound, or its derivatives, pharmaceutically acceptable salts, and isomers to a subject in need , solvate, hydrate, adduct, complex or prodrug.
本发明所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药可用于治疗还可用于治疗MYC蛋白异常高表达的疾病，例如MYC蛋白异常高表达的增殖性疾病。The compounds of the present invention, or their derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs can be used to treat abnormally high expression of MYC protein diseases, such as proliferative diseases with abnormally high expression of MYC protein.
术语“增殖性疾病”或“细胞增殖性疾病”是指与某种程度的异常细胞增殖相关的疾病，无论是恶性的还是良性的。在一些实施方案中，增殖性疾病是肿瘤。在一些方面，肿瘤是实体瘤或非实体瘤。在一些方面，肿瘤是血液肿瘤(例如白血病、骨髓瘤以及淋巴瘤)。术语“增殖性障碍”、“细胞增殖性障碍”、“癌症”、“癌性”和“肿瘤”在本发明中提及时并不相互排斥。在一种实施方式中，本文所述增殖性疾病是MYC阳性增殖性疾病，例如MYC阳性肿瘤，比如MYC阳性实体瘤和/或MYC阳性血液肿瘤。在一种实施方式中，本文所述肿瘤是MYC阳性肿瘤。示例性肿瘤包括但不限于乳腺癌、结肠癌、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头颈癌、黑素瘤、结直肠癌、胃癌、鳞癌、肺癌，小细胞肺癌、非小细胞肺癌、睾丸癌、梅克尔细胞癌、胶质母细胞瘤、神经细胞瘤、多发性骨髓瘤、淋巴瘤(霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴T细胞瘤、淋巴B细胞瘤)、白血病(急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML))、肉瘤、宫颈癌，肝癌、甲状腺癌、大肠癌、食管癌、泌尿生殖道癌、胆管细胞癌、肺癌、直肠癌、骨肉瘤、神经胶质瘤、鼻咽癌、喉癌、黑色素瘤、人宫颈癌、脑瘤、中耳肿瘤等；优选的，前述肿瘤是MYC阳性的。所述肿瘤优选地选自MYC阳性的白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、脑瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤、前列腺癌等。The term "proliferative disease" or "cell proliferative disease" refers to a disease associated with some degree of abnormal cell proliferation, whether malignant or benign. In some embodiments, the proliferative disease is a tumor. In some aspects, the tumor is a solid tumor or a non-solid tumor. In some aspects, the tumor is a hematological tumor (eg, leukemia, myeloma, and lymphoma). The terms "proliferative disorder", "cell proliferative disorder", "cancer", "cancerous" and "tumor" are not mutually exclusive when referred to in the present invention. In one embodiment, the proliferative disease described herein is a MYC positive proliferative disease, eg a MYC positive tumor, such as a MYC positive solid tumor and/or a MYC positive hematologic tumor. In one embodiment, the tumor described herein is a MYC positive tumor. Exemplary tumors include, but are not limited to, breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, lung cancer, small cell lung cancer, Non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, multiple myeloma, lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoid T-cell tumor, B cell lymphoma), leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML)), sarcoma, cervical cancer, liver cancer, thyroid Carcinoma, colorectal cancer, esophageal cancer, genitourinary tract cancer, cholangiocarcinoma, lung cancer, rectal cancer, osteosarcoma, glioma, nasopharyngeal cancer, laryngeal cancer, melanoma, human cervical cancer, brain tumor, middle ear tumor etc.; preferably, the aforementioned tumor is MYC positive. The tumor is preferably selected from MYC-positive leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, brain cancer, tumor, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.
本发明所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药可用于治疗自身免疫性疾病。本发明还提供了本发明所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药在制备用于治疗自身免疫性疾病的药物中的用途。本发明进一步提供了所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，用于治疗自身免疫性疾病。本发明进一步提供了治疗自身免疫性疾病的方法，包括向有需要的受试者施用治疗有效量的所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药。所述自身免疫性疾病可以是T细胞或B细胞等免疫细胞功能异常相关的自身免疫性疾病，例如类风湿性关节炎、系统性红斑狼疮、银屑病、肾病等。所述自身免疫性疾病优选选自MYC阳性的T细胞或B 细胞等免疫细胞功能异常相关的自身免疫性疾病，如与MYC阳性T细胞或B细胞相关的类风湿性关节炎、系统性红斑狼疮、银屑病、肾病等，例如MYC阳性的类风湿性关节炎、系统性红斑狼疮、银屑病、肾病。以下，本发明将通过实施例来说明本发明的有益效果。本领域技术人员将认识到这些示例是说明性的而非限制性的。这些示例不会以任何方式限制本发明的范围。以下实施例中所描述的实验方法，除另有说明外，均为常规方法；除非另有说明，试剂和材料均为市售品。The compounds of the present invention, or their derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs can be used to treat autoimmune diseases. The present invention also provides the compounds of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs used for the treatment of autoimmune Use in medicine for diseases. The present invention further provides the compound, or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, for treating autoimmune diseases. The present invention further provides a method for treating autoimmune diseases, comprising administering a therapeutically effective amount of the compound, or its derivatives, pharmaceutically acceptable salts, isomers, solvates, Hydrates, adducts, complexes or prodrugs. The autoimmune disease may be an autoimmune disease related to abnormal function of immune cells such as T cells or B cells, such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, kidney disease and the like. The autoimmune disease is preferably selected from MYC-positive T cells or B Autoimmune diseases related to abnormal function of immune cells such as cells, such as rheumatoid arthritis associated with MYC-positive T cells or B cells, systemic lupus erythematosus, psoriasis, kidney disease, etc., such as MYC-positive rheumatoid arthritis Inflammation, systemic lupus erythematosus, psoriasis, kidney disease. Hereinafter, the present invention will illustrate the beneficial effects of the present invention through examples. Those skilled in the art will recognize that these examples are illustrative and not restrictive. These examples do not limit the scope of the invention in any way. The experimental methods described in the following examples are conventional methods unless otherwise specified; all reagents and materials are commercially available unless otherwise specified.
附图说明Description of drawings
图1：本发明化合物WBC213、220、223、266和WB005对肿瘤细胞MYC蛋白影响。Figure 1: Effects of compounds WBC213, 220, 223, 266 and WB005 of the present invention on MYC protein of tumor cells.
具体实施方式Detailed ways
在一个方面，本发明提供式(I)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药∶
In one aspect, the present invention provides a compound of formula (I), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
其中：in:
R1独立地选自羟基、羰基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、 -O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。R 1 is independently selected from hydroxyl, carbonyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, -O(C=O)(C 1 -C 6 Alkyl) R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C=O )OR', -O(C=O)R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkane Group (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), - C 0 -C 5 alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl Aryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl- O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
在一种优选实施方式中，所述R1独立地选自羰基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，所述R1独立地选自羰基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选实施方式中，所述R1独立地选自羰基、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基-O-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, said R 1 is independently selected from carbonyl, -O(C=O)(C 1 -C 6 alkyl) R', -O(C=O)(C 1 -C 6 Alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O)R', wherein R' is in Each occurrence thereof is independently selected from C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 - C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkane Base (3-12 membered heterocyclic group), -C 0 -C 5 alkyl group (3-12 membered heterocyclic group), wherein the alkyl, alkylamino, cycloalkyl, and heterocyclic group are optionally 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, said R 1 is independently selected from carbonyl, -O(C=O)(C 1 -C 6 alkyl) R', -O(C=O)(C 1 -C 6 alkane radical)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O)R', wherein R' is in its Each occurrence is independently selected from C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclic Cyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group) , -C 0 -C 5 alkyl (3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, heterocyclic group is optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, said R 1 is independently selected from carbonyl, -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O )R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, -C 0 -C 5 alkyl (C 3 -C 7 cycloalkane group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, heterocyclic group is optionally replaced by 1, 2, 3 or 4 hydroxyl groups , amino, carbonyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution. In yet another preferred embodiment, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一个方面，本发明提供式(II)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药∶
In one aspect, the present invention provides a compound of formula (II), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
其中：in:
R1在其每一次出现时独立地选自羟基、羰基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。R at each occurrence thereof is independently selected from hydroxyl, carbonyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, -O(C=O) (C 1 -C 6 alkyl) R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkane group) (C=O)OR', -O(C=O)R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), - OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 heterocyclyl), -C 0 -C 5 alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 Alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein The alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro , cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
R2在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、氨基C1-C6烷基、C1-C6烷基氨基、-OC(O)OR11、-OC(O)R11、-SO2R11、-OSO2R11、-SO2NR11R12、-S(O)R11,-S(O)NR11R12，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基，R12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基； R2 at each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, R 12 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxy, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl , C 1 -C 6 Haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl;
R3在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、氨基C1-C6烷基、C1-C6烷基氨基、-OC(O)OR11、-OC(O)R11、-SO2R11、-OSO2R11、-SO2NR11R12、-S(O)R11,-S(O)NR11R12，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基，R12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基； R3 in each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, R 12 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxy, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl , C 1 -C 6 Haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl;
或者，R2和R3连同所连接的碳原子一起连接形成且具有5-14环原子的单环、双环或三环的饱和或不饱和环系统，所述环原子中的0、1、2、3或4个是选自N、O、S的杂原子、其余为碳原子，并且所述环系统任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Alternatively, R2 and R3 are connected together with the attached carbon atoms to form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system with 5-14 ring atoms, 0, 1, 2 of the ring atoms , 3 or 4 are heteroatoms selected from N, O, S, the rest are carbon atoms, and the ring system is optionally replaced by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino , carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted;
或者，R1和R2连同所连接的碳原子一起连接形成3-18元杂环基；Alternatively, R 1 and R 2 are connected together with the attached carbon atoms to form a 3-18 membered heterocyclic group;
或者，R2和R3连同所连接的碳原子一起连接形成3-18元杂环基。Alternatively, R2 and R3 , together with the carbon atoms to which they are attached, are joined to form a 3-18 membered heterocyclyl.
在一种优选的实施方式中，所述R1独立地选自羟基、羰基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)、-O-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，所述R1独立地选自羟基、羰基、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)、-O-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、 氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选实施方式中，所述R1独立地选自羰基、-O(C＝O)(C1-C6烷基)(C＝O)OR’、和-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、氨基C1-C6烷基、羟基C1-C6烷基、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基-O-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, said R 1 is independently selected from hydroxyl, carbonyl, -O(C=O)(C 1 -C 6 alkyl)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O)R', wherein R', at each occurrence thereof, is independently selected from C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di -C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), - C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 - C 5 alkyl (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), wherein the alkyl, alkylamino, cycloalkyl, heterocyclic group are any optionally substituted by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl . In a further preferred embodiment, said R 1 is independently selected from hydroxyl, carbonyl, -O(C=O)(C 1 -C 6 alkyl)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O)R', wherein R' Each occurrence thereof is independently selected from C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl -O- (3-12 membered heterocyclyl), -C 0 -C 5 alkyl -( C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group) ), wherein the alkyl, alkylamino, cycloalkyl, heterocyclyl is optionally replaced by 1, 2, 3 or 4 hydroxyl, Amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, said R 1 is independently selected from carbonyl, -O(C=O)(C 1 -C 6 alkyl)(C=O)OR', and -O(C=O )R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, -C 0 -C 5 alkane (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclyl), wherein the alkyl, cycloalkyl, heterocyclyl are optionally 1, 2, 3 or 4 hydroxyl, amino, carbonyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitutions. In yet another preferred embodiment, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一种优选的实施方式中，R1和R2连同所连接的碳原子一起连接形成3-7元杂环基。优选地，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, R 1 and R 2 together with the carbon atoms to which they are attached form a 3-7 membered heterocyclyl. Preferably, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一种优选的实施方式中，R2和R3连同所连接的碳原子一起连接形成3-7元杂环基。优选地，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, R 2 and R 3 together with the carbon atoms to which they are attached form a 3-7 membered heterocyclic group. Preferably, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一种优选的实施方式中，R2在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、C1-C6烷基氨基、-OSO2R11，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基。在进一步优选的实施方式中，R2在其每一次出现时独立地选自羟基、氨基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、C1-C6烷基氨基、-OSO2R11，其中R11在其每一次出现时独立地是C1-C6烷基。In a preferred embodiment, R2 at each occurrence is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN , S(O)NH 2 , S(O) 2 NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl. In a further preferred embodiment, R 2 at each occurrence is independently selected from hydroxyl, amino, azido, -NH-OH, -NH-NH 2 , -SCN, S(O)NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 is independently C 1 -C 6 alkyl at each occurrence thereof.
在一种优选的实施方式中，R3在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、C1-C6烷基氨基、-OSO2R11，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基。在进一步优选的实施方式中，R3在其每一次出现时独立地选自羟基、氨基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、C1-C6烷基氨基、-OSO2R11，其中R11在其每一次出现时独立地是C1-C6烷基。In a preferred embodiment, R3 at each occurrence is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN , S(O)NH 2 , S(O) 2 NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl. In a further preferred embodiment, R 3 at each occurrence thereof is independently selected from hydroxyl, amino, azido, -NH-OH, -NH-NH 2 , -SCN, S(O)NH 2 , C 1 -C 6 alkylamino, -OSO 2 R 11 , wherein R 11 is independently C 1 -C 6 alkyl at each occurrence thereof.
在一个方面，所述式(I)的化合物为结构式(I)的化合物为结构式(I-1)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane group, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷 基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, Q is independently selected at each occurrence of C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O- (3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), wherein the alkyl, alkylamino, ring Alkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution. In a further preferred embodiment, Q is independently selected from C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkane amino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkyl- O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl(3-12 membered heterocyclyl), wherein the alkyl, alkylamino, cycloalkyl, heterocyclyl is optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 Alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution. In yet another preferred embodiment, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一个方面，所述式(I)的化合物为结构式(I)的化合物为结构式(I-2)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-2), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、 氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, Amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, C 1 -C 6 alkylamino.
在一种优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, Q is independently selected at each occurrence of C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O- (3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), wherein the alkyl, alkylamino, ring Alkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution. In a further preferred embodiment, Q is independently selected from C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, -C 0 -C 5 alkyl (C 3 -C 7 ring Alkyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl Base-(C=O)O-(3-12 membered heterocyclic group),-C 0 -C 5 alkyl(3-12 membered heterocyclic group), wherein the alkyl, alkylamino, cycloalkyl , heterocyclyl is optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkane base substitution. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution. In yet another preferred embodiment, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一个方面，所述式(I)的化合物为结构式(I)的化合物为结构式(I-3)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (I) is a compound of the structural formula (I), a compound of the structural formula (I-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤 代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q, in each occurrence thereof, is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 halo Substituted alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 - C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 Alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), - OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3- 12-membered heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl) , -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, Haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, - COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, C 1 -C 6 alkylamino.
在一种优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自C1-C6烷基、羟基C1-C6烷基、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，所述杂环基包含一个或多个硫、氧或氮杂原子。In a preferred embodiment, Q is independently selected at each occurrence of C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O- (3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), wherein the alkyl, alkylamino, ring Alkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution. In a further preferred embodiment, Q is independently selected from C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, -C 0 -C 5 alkyl (C 3 -C 7 ring Alkyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl Base-(C=O)O-(3-12 membered heterocyclic group),-C 0 -C 5 alkyl(3-12 membered heterocyclic group), wherein the alkyl, alkylamino, cycloalkyl , heterocyclyl is optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkane base substitution. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution. In yet another preferred embodiment, the heterocyclyl group contains one or more sulfur, oxygen or nitrogen heteroatoms.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-1)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中R1、R2和R3如式(II)中描述和定义的。wherein R 1 , R 2 and R 3 are as described and defined in formula (II).
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-2)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-2), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中R1、R2和R3如式(II)中描述和定义的。wherein R 1 , R 2 and R 3 are as described and defined in formula (II).
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-3)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中： in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane Base, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution;
R2和R3如式(II)中描述和定义的。R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O- (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic group are optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-4)的化合物、或 其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of formula (II) is a compound of structural formula (II) is a compound of structural formula (I1-4), or Its derivatives, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane Base, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution;
R2和R3如式(II)中描述和定义的。R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5 烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 Alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-( 3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl and heterocyclic group are optionally replaced by 1, 2, 3 Or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-5)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-5), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane Base, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution;
R2和R3如式(II)中描述和定义的。 R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O- (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic group are optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-6)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-6), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5 烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkane Base (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O- (3-12 membered Heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), - OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl , alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, carbonyl, mercapto, -COOH, Amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted;
R2和R3如式(II)中描述和定义的。R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O- (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic group are optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-7)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-7), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane Base, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution;
R2和R3如式(II)中描述和定义的。R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5 烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 Alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-( 3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl and heterocyclic group are optionally replaced by 1, 2, 3 Or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
在一个方面，所述式(II)的化合物为结构式(II)的化合物为结构式(I1-8)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
In one aspect, the compound of the formula (II) is a compound of the structural formula (II) is a compound of the structural formula (I1-8), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate , adducts, complexes or prodrugs:
其中：in:
W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane Base, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution;
R2和R3如式(II)中描述和定义的。 R 2 and R 3 are as described and defined in formula (II).
在一种优选实施方式中，W在其每一次出现时独立地选自氢、氨基、或C1-C6烷基氨基。In a preferred embodiment, W at each occurrence thereof is independently selected from hydrogen, amino, or C 1 -C 6 alkylamino.
在一种优选的实施方式中，所述Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、烷基氨基、环烷基、杂环基任选地被1、2、3或4个羟基、氰基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在进一步优选实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、C0-C5烷基(C3-C7环烷基)、C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基-(3-12元杂环基)，其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。在还有一种优选地实施方式中，Q在其每一次出现时独立地选自氢、C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-C0-C5烷基(C3-C7环烷基)、其中所述烷基、环烷基、杂环基任选地被1、2、3或4个羟基、氨基、羰基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。In a preferred embodiment, said Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl , alkylamino, cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, cyano, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 Alkylamino, or C 1 -C 6 alkyl substituted. In a further preferred embodiment, Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O- (3-12 membered heterocyclic group), -OC 0 -C 5 alkyl-(3-12 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic group are optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted. In yet another preferred embodiment, Q is independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, - C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), wherein said alkyl, Cycloalkyl, heterocyclyl optionally replaced by 1, 2, 3 or 4 hydroxyl, amino, carbonyl, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 - C 6 alkyl substitution.
“烷基”为支链或直链饱和脂族烃基团。在一个实施方案中，烷基含1至约12个碳原子，更通常1至约6个碳原子或1至约4个碳原子。在一个实施方案中，烷基含1至约8个碳原子。在某些实施方案中，烷基为C1-C2、C1-C3或C1-C6。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的烷基基团。例如，如本文所用，术语C1-C6烷基指具有1、2、3、4、5或6个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。例如，如本文所用，术语C1-C4烷基指具有1、2、3或4个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。当C0-Cn烷基在本文中结合另一基团使用时，例如(C3-C7环烷基)C0-C4烷基或-C0-C4烷基(C3-C7环烷基)，所指示的基团——在此情况下环烷基，或通过单一共价键(C0烷基)直接键合或通过烷基链(在此情况下1、2、3或4个碳原子)连接。烷基也可经由其它基团如杂原子连接，如在-O-C0-C4烷基(C3-C7环烷基)中。烷基的实例包括但不限于甲基、乙基、正-丙基、异丙基、正-丁基、异丁基、仲-丁基、叔-丁基、正-戊基、异戊基、叔-戊基、新戊基、正-己基、2-甲基戊烷、3-甲基戊烷、2,2-二甲基丁烷和2,3-二甲基丁烷。在一个实施方案中，烷基基团任选地被如上所述取代。 "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, or C1-C6. As used herein, a specified range refers to each member of the stated range as a separate species of alkyl group. For example, as used herein, the term C1-C6 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean each of these as independently type description. For example, as used herein, the term C1-C4 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as a separate species. When a C0-Cn alkyl group is used herein in combination with another group, such as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl (C3-C7 cycloalkyl), the indicated The group, in this case cycloalkyl, is either directly bonded by a single covalent bond (C0 alkyl) or linked by an alkyl chain (in this case 1, 2, 3 or 4 carbon atoms). Alkyl groups may also be attached via other groups such as heteroatoms, as in -O-CO-C4alkyl (C3-C7cycloalkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In one embodiment, alkyl groups are optionally substituted as described above.
“烯基”为具有一个或多个碳-碳双键的支链或直链脂族烃基团，所述双键可发生在沿链的稳定点处。非限制性实例有C2-C8烯基(2、3、4、5、6、7、和8个碳原子的烯基)、C2-C6烯基和C2-C4烯基。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的烯基基团，如上面针对烷基部分所述。烯基的实例包括但不限于乙烯基、丙烯基、烯丙基、丁烯基、异丁烯基。在一个实施方案中，烯基基团任选地被如上所述取代。"Alkenyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain. Non-limiting examples are C2-C8 alkenyl (alkenyl of 2, 3, 4, 5, 6, 7, and 8 carbon atoms), C2-C6 alkenyl, and C2-C4 alkenyl. As used herein, a specified range refers to each member of the stated range as a separate species of alkenyl group, as described above for the alkyl moiety. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, isobutenyl. In one embodiment, an alkenyl group is optionally substituted as described above.
“炔基”为具有一个或多个碳-碳三键的支链或直链脂族烃基团，所述三键可发生在沿链的任何稳定点处，例如C2-C8炔基(2、3、4、5、6、7、和8个碳原子的炔基)或C2-C6炔基。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的炔基基团，如上面针对烷基部分所述。炔基的实例包括但不限于乙炔基、丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基和5-己炔基。在一个实施方案中，炔基基团任选地被如上所述取代。"Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds which may occur at any stable point along the chain, for example C2-C8 alkynyl (2, 3, 4, 5, 6, 7, and 8 carbon atoms alkynyl) or C2-C6 alkynyl. As used herein, a specified range refers to each member of the stated range as a separate species of alkynyl group, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl , 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, an alkynyl group is optionally substituted as described above.
“烷氧基”为通过氧桥(-O-)共价键合的如上所述烷基基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正-丙氧基、异-丙氧基、正-丁氧基、2-丁氧基、叔-丁氧基、正-戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正-己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。类似地，“烷硫基”或“硫代烷基”基团为通过硫桥(-S-)共价键合的具有指定数量的碳原子的如上所述烷基基团。在一个实施方案中，烷氧基基团任选地被如上所述取代。"Alkoxy" is an alkyl group as described above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentyloxy Oxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methylpentyloxy . Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group as described above with the indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, alkoxy groups are optionally substituted as described above.
“烯氧基”为通过氧桥(-O-)共价键合到其取代的基团的所述烯基基团。"Alkenyloxy" is such an alkenyl group that is covalently bonded to the group it replaces through an oxygen bridge (-O-).
“烷酰基”为通过羰基(C＝O)桥共价键合的如上所述烷基基团。羰基碳包括在碳数中，即C2烷酰基为CH3(C＝O)-基团。在一个实施方案中，烷酰基基团任选地被如上所述取代。"Alkanoyl" is an alkyl group as described above covalently bonded through a carbonyl (C=O) bridge. The carbonyl carbon is included in the carbon number, ie a C 2 alkanoyl is a CH 3 (C=O)- group. In one embodiment, an alkanoyl group is optionally substituted as described above.
“烷基酯”为通过酯键共价键合的如本文所述烷基基团。酯键可在任一方向上，例如式-O(C＝O)烷基的基团或式-(C＝O)O烷基的基团。"Alkyl ester" is an alkyl group as described herein covalently bonded through an ester bond. The ester linkage can be in either direction, eg a group of formula -O(C=O)alkyl or a group of formula -(C=O)Oalkyl.
“碳环基团”“碳环环”或“环烷基”为包含所有碳环原子的饱和或部分不饱和(即，非芳族)基团。碳环基团通常含3至7个碳原子的1个环或各含3至7个碳原子的2个稠环。环烷基取代基可以是自取代的氮或碳原子的侧基，或者可具有两个取代基的取代碳原子可具有环烷基基团，其作为螺环基团连接。碳环的实例包括环己烯基、环己基、环戊烯基、环戊基、环丁烯基、环丁基和环丙基环。在一个实施方案中，碳环任选地被如上所述取代。在一个实施方案中，环烷基为含所有碳环原子的部分不饱和(即非芳族) 基团。A "carbocyclic group,""carbocyclicring" or "cycloalkyl" is a saturated or partially unsaturated (ie, non-aromatic) group that contains all carbon ring atoms. Carbocyclic groups generally contain 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. A cycloalkyl substituent may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom which may have two substituents may have a cycloalkyl group attached as a spiro group. Examples of carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings. In one embodiment, carbocycles are optionally substituted as described above. In one embodiment, cycloalkyl is partially unsaturated (i.e., non-aromatic) containing all carbon ring atoms. group.
“碳环-氧基基团”为经由氧-O-连接基连接到其取代的基团的如上所述单环碳环或者单-或二-环碳环基团。A "carbocycle-oxy group" is a monocyclic carbocycle or a mono- or bi-ring carbocycle group as described above attached to the group it replaces via an oxygen-O-linker.
“卤代烷基”指被1个或多个卤素原子、至多最大许可数量的卤素原子所取代的支链和直链烷基基团。卤代烷基的实例包括但不限于三氟甲基、单氟甲基、二氟甲基、2-氟乙基和五氟乙基。"Haloalkyl" refers to branched and straight chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
“卤代烷氧基”指通过氧桥(醇原子团的氧)连接的如本文所述卤代烷基基团。"Haloalkoxy" refers to a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).
“羟烷基”为被至少一个羟基取代基所取代的如前所述烷基基团。"Hydroxyalkyl" is an alkyl group as previously described substituted with at least one hydroxy substituent.
“氨基烷基”为被至少一个氨基取代基所取代的如前所述烷基基团。"Aminoalkyl" is an alkyl group as previously described substituted with at least one amino substituent.
“烷基氨基”为被至少一个如前所述烷基基团所取代的氨基取代基。"Alkylamino" is an amino substituent substituted with at least one alkyl group as previously described.
“卤素”独立地指氟、氯、溴和碘中的任何一者。"Halogen" independently refers to any one of fluorine, chlorine, bromine and iodine.
“芳基”指在芳族环或环中仅含碳的芳族基团。在一个实施方案中，芳基基团含1至3个单独的或稠合的环并且具有6至18个(例如，6、7、8、9、10、11、12、13、14、15、16、17或18个)环原子，无杂原子作为环成员。在指出时，这样的芳基基团可还被碳或非碳原子或基团所取代。此类取代可包括稠合到5至7-元饱和环基团，所述饱和环基团任选地含1或2个独立地选自N、O和S的杂原子，以形成例如3,4-亚甲基二氧苯基基团。芳基基团包括例如苯基和萘基，包括1-萘基和2-萘基。在一个实施方案中，芳基基团是侧基。侧环实例为被苯基基团所取代的苯基基团。在一个实施方案中，芳基基团任选地被如上所述取代。芳基包括双环基团，其包含与饱和、部分不饱和的环或芳族碳环或杂环稠合的芳族环。典型的芳基基团包括但不限于由苯(苯基)、取代的苯、萘、蒽、茚基、茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等等衍生的基团。优选地，芳基为苯基、联苯基、萘基、5,6,7,8-四氢萘基、2.3-二氢苯并呋喃基等。"Aryl" refers to an aromatic group containing only carbon in an aromatic ring or ring. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and has 6 to 18 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17 or 18) ring atoms, with no heteroatoms as ring members. Where indicated, such aryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitutions may include fusion to a 5 to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, 3, 4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a side ring is a phenyl group substituted by a phenyl group. In one embodiment, aryl groups are optionally substituted as described above. Aryl includes bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, those formed from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydro Groups derived from naphthyl and the like. Preferably, the aryl group is phenyl, biphenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, 2.3-dihydrobenzofuranyl and the like.
如本文所用，术语“杂环”指具有3至18个(例如，3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个)个环原子的饱和或部分不饱和(即，在环内具有一个或多个双键和/或三键而无芳香性)碳环原子团，其中至少一个环原子为选自氮、氧、磷和硫的杂原子，其余的环原子为C，其中一个或多个环原子任选地被一个或多个上述取代基独立地取代。杂环可为具有3至7个环成员(2至6个碳原子和1至4个选自N、O、P和S的杂原子)的单环或具有6至10个环元(4至9个碳原子和1至6个选自N、O、P和S的杂原子)的双环，例如：双环[4,5]、[5,5]、[5,6]或[6,6]系。在一个实施方案中，唯一的杂原子为氮。在一个实施方案中，唯一的杂原子为氧。在一个实施方案中， 唯一的杂原子为硫。杂环描述在Paquette,Leo A.；“Principles of Modern Heterocyclic Chemistry”(W.A.Benjamin,New York,1968)特别是第1、3、4、6、7和9章；“The Chemistry of Heterocyclic Compounds,A series of Monographs”(John Wiley & Sons,New York,1950至现在)特别是第13、14、16、19和28章；和J.Am.Chem.Soc.(1960)82:5566中。杂环的实例包括但不限于吡咯烷基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、哌啶酮基、吗啉基、硫代吗啉基、氧硫杂环己烷基(thioxanyl)、哌嗪基、高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、氧氮杂环基(oxazepinyl)、二氮杂环基(diazepinyl)、硫氮杂环基(thiazepinyl)、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧杂环戊基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、二氢异喹啉基、四氢异喹啉基、吡唑烷基咪唑啉基、咪唑烷基、2-氧杂-5-氮杂双环[2.2.2]辛烷、3-氧杂-8-氮杂双环[3.2.1]辛烷、8-氧杂-3-氮杂双环[3.2.1]辛烷、6-氧杂-3-氮杂双环[3.1.1]庚烷、2-氧杂5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[4.1.0]庚烷基、氮杂双环[2.2.2]己烷基、3H-吲哚基、喹嗪基、N-吡啶基脲和吡咯并嘧啶。螺部分也包括在本定义的范围内。其中1或2个环碳原子被氧代基(＝O)部分所取代的杂环基团的实例有嘧啶酮基和1,1-二氧代基-硫代吗啉基。本文中的杂环基团任选地被一个或多个本文所述的取代基独立地取代。“杂环基”包括“杂环烷基”。“杂环烷基”为饱和环基团。其可具有例如1、2、3或4个独立地选自N、S和O的杂原子，其余环原子为碳。在一个典型的实施方案中，氮为杂原子。单环杂环烷基基团通常具有3至约8个环原子或4至6个环原子。杂环烷基基团的实例包括吗啉基、哌嗪基、哌啶基和吡咯啉基。“杂环基”可以含有1、2、3、4、或5个选自N、O和S的杂原子。As used herein, the term "heterocycle" refers to rings having 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ) saturated or partially unsaturated (that is, having one or more double and/or triple bonds within the ring without aromaticity) carbon ring atom groups of ) ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen, phosphorus and sulfur heteroatoms, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently by one or more of the aforementioned substituents. The heterocycle can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclic [4,5], [5,5], [5,6] or [6,6 ]Tie. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, The only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968) especially chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950-present), especially Chapters 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocycles include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperidonyl, morpholino Linyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidine base, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrole Linyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, di Thianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, dihydroisoquinolyl, tetrahydroisoquinolyl, pyrazolidinyl imidazolinyl, imidazolidine Base, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2 .1] octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0 ]hexyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexyl, 3H-indolyl, quinozinyl, N-pyridylurea and pyrrolopyrimidine . Spiro moieties are also included within the scope of this definition. Examples of heterocyclic groups in which 1 or 2 ring carbon atoms are replaced by an oxo (=O) moiety are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups herein are optionally substituted independently with one or more substituents described herein. "Heterocyclyl" includes "heterocycloalkyl". "Heterocycloalkyl" is a saturated ring group. It may have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically have 3 to about 8 ring atoms, or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl. "Heterocyclyl" may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
“杂环氧基团”为经由氧-O-连接基连接到其取代的基团的如前所述单环杂环或双环杂环基团。A "heterocyclic epoxy group" is a monocyclic or bicyclic heterocyclic group as previously described attached to the group it replaces via an oxy-O-linker.
“杂芳基”指含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的稳定单环芳族环，或者含至少一个其中含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的5-至10-元(5、6、7、8、9、10元)芳族环的稳定双环或三环系。在一个实施方案中，唯一的杂原子为氮。在一个实施方案中，唯一的杂原子为氧。在一个实施方案中，唯一的杂原子为硫。单环杂芳基基团通常具有5至8个环原子(5、6、7、8个)。在一些实施方案中，双环杂芳基基团为 9-至10-元杂芳基基团，即含9或10个环原子的基团，其中一个5-至7-元芳族环稠合到第二个芳族或非芳族环。当杂芳基基团中S和O原子的总数超过1时，这些杂原子不彼此相邻。在一个实施方案中，杂芳基基团中S和O原子的总数不超过2。在另一个实施方案中，芳族杂环中S和O原子的总数不超过1。杂芳基基团的实例包括但不限于吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、四氢呋喃基和呋喃并吡啶基。杂芳基基团任选地被一个或多个本文所述取代基独立地取代。“杂芳氧基”为经由氧-O-连接基键合到其取代的基团的所述杂芳基基团。“杂芳基”可以含有1、2、3、4、或5个选自N、O和S的杂原子。"Heteroaryl" means a stable monocyclic aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, the remaining ring atoms being carbon, or at least one of the 5- to 10-membered (5, 6, 7, 8, 9, 10 stable bicyclic or tricyclic ring systems of aromatic rings. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 8 ring atoms (5, 6, 7, 8). In some embodiments, the bicyclic heteroaryl group is 9- to 10-membered heteroaryl groups, ie groups containing 9 or 10 ring atoms in which one 5- to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in a heteroaryl group does not exceed two. In another embodiment, the total number of S and O atoms in the aromatic heterocycle does not exceed one. Examples of heteroaryl groups include, but are not limited to, pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl , pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, tetrahydro Isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridine Base, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, Quinazolinyl, quinoxalinyl, naphthyridyl, tetrahydrofuranyl and furopyridyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. "Heteroaryloxy" is said heteroaryl group bonded to the group it replaces via an oxygen-O-linker. "Heteroaryl" may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
本发明还涵盖由一个或多个选自“环烷基”、“芳基”和“杂芳基”单环以化合价允许的方式形成的二环、三环、四环、五环等多环系统。The present invention also covers bicyclic, tricyclic, tetracyclic, pentacyclic and other polycyclic rings formed by one or more monocyclic rings selected from "cycloalkyl", "aryl" and "heteroaryl" in a manner permitted by valence. system.
本文所述各种基团可以是取代或未取代的。当描述取代时，本文所述基团既包括单独提及的基团，也包括与其他基团相连的基团。例如，本文所述“烷基”可以是取代或未取代的。当描述取代时，本文所述“烷基”既包括单独提及的烷基，也包括与其他基团相连的烷基，例如也包括羟基C1-C6烷基、氨基C1-C6烷基、C1-C6烷基氨基中的烷基。这适用于本文所述任何其他基团。Various groups described herein may be substituted or unsubstituted. When substitution is described, groups described herein include both the group referred to alone and the group linked to other groups. For example, "alkyl" described herein may be substituted or unsubstituted. When describing substitution, the "alkyl" mentioned herein includes not only the alkyl group mentioned alone, but also the alkyl group connected with other groups, such as hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, alkyl in C 1 -C 6 alkylamino. This applies to any other group described herein.
术语“药学上可接受的盐”是指本发明化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐“甲磺酸盐(mesylate)”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即1,1'-亚甲基-双-(2-羟基-3-萘甲酸)盐)、碱金属(例如，钠和钾)盐、碱土金属(例如，镁)盐和铵盐。药学上可接受的盐可涉及包含另一种分子，诸如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是使母体化合物上的电荷稳定化的任何有机或无机部分。此外，药学上可接受的盐在其结构中可以具有多于一个带电荷的原子。多个带电荷 的原子是药学上可接受的盐的一部分的例子可以具有多个抗衡离子。因此，药学上可接受的盐可具有一个或多个带电荷的原子和/或一个或多个抗衡离子。The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid salt, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate "mesylate", Esylate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt), alkali metal ( For example, sodium and potassium), alkaline earth metal (eg, magnesium) and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as acetate, succinate or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts can have more than one charged atom in their structure. multiple charged Examples of atoms that are part of a pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
如果本发明的化合物是碱，则期望的药学上可接受的盐可以通过本领域可用的任何合适的方法制备，例如用无机酸或有机酸处理游离碱来制备，该无机酸诸如为盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等，该有机酸诸如为乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳族酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙磺酸、等等。If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., such organic acids as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid , pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc.
如果本发明的化合物是酸，则期望的药学上可接受的盐可以通过任何合适的方法制备，例如用诸如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等无机或有机碱处理游离酸来制备。合适盐的示例性实例包括但不限于衍生自氨基酸如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环胺如哌啶、吗啉和哌嗪的有机盐，以及衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by oxidation with an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide such as It can be prepared by treating free acids with inorganic or organic bases such as compounds. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and those derived from sodium , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium inorganic salts.
术语“药学上可接受的”表明该物质或组合物必须在化学和/或毒理学上与包含制剂的其他成分和/或用其治疗的哺乳动物相容。The term "pharmaceutically acceptable" indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
本申请化合物可以各种异构体、立体异构形式存在。术语“立体异构体”是指具有相同化学构成和连接性的化合物，但是其原子在空间中的不同取向不能通过围绕单键旋转而相互转化。“立体异构体”可以包括“非对映异构体”和“对映异构体”。“非对映异构体”是指具有两个或更多个手性中心且其分子彼此不是镜像的立体异构体。“对映异构体”是指化合物的两个立体异构体，它们是彼此不可重叠的镜像。“R”和“S”代表围绕一个或多个手性原子的取代基构型。本申请的化合物可以通过手性合成或从异构体混合物拆分来制备为单独的异构体。所公开的化合物可以具有一个或多个立体中心，并且每个立体中心可以独立地以R或S构型存在。当立体中心的绝对立体化学未确定时，立体化学构型可在指定中心指定为(*)。在一个实施方案中，本文所述的化合物以旋光或外消旋形式存在。应当理解，本文所述的化合物包括具有本文所述的治疗有用特性的外消旋、旋光、区域异构和立体异构形式或其组合。The compounds of the present application may exist in various isomers and stereoisomeric forms. The term "stereoisomer" refers to compounds having the same chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds. "Stereoisomers" may include "diastereomers" and "enantiomers". "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. "R" and "S" represent the configuration of substituents around one or more chiral atoms. Compounds of the present application may be prepared as individual isomers by chiral synthesis or resolution from isomeric mixtures. The disclosed compounds may possess one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. When the absolute stereochemistry of a stereocenter is not determined, the stereochemical configuration can be assigned as (*) at the indicated center. In one embodiment, the compounds described herein exist in optically active or racemic form. It is to be understood that the compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms or combinations thereof which possess the therapeutically useful properties described herein.
在一个实施方案中，本申请所述的化合物含有一个或多个手性中心。这些化合物可通过任何方式制备，包括立体选择性合成、对映选择性合成或对映异构体或非对映异构体的混合物的分离。化合物及其异构体的拆分可通过任何方式实现，包括但不限于化学过程、酶促过程、分步结晶、蒸馏和色谱法。 In one embodiment, the compounds described herein contain one or more chiral centers. These compounds may be prepared by any means including stereoselective synthesis, enantioselective synthesis or separation of mixtures of enantiomers or diastereomers. Resolution of a compound and its isomers can be achieved by any means including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.
术语“衍生物”是指在化合价允许的范围内在任意位置对本发明化合物衍生化所得化合物。The term "derivative" refers to a compound obtained by derivatizing the compound of the present invention at any position within the range allowed by the valence.
术语“溶剂合物”是指还包括渗入到晶体结构中的溶剂分子的分子、原子和/或离子的晶型，溶剂合物的溶剂分子可处于规则排列和/或无序排列。本发明的溶剂合物优选是溶剂水合物。The term "solvate" refers to a crystalline form of molecules, atoms and/or ions that also includes solvent molecules that penetrate into the crystal structure, the solvent molecules of a solvate may be in a regular arrangement and/or a disordered arrangement. The solvates of the present invention are preferably solvent hydrates.
术语“代谢物”是指本发明化合物或其衍生物经生理条件代谢后所得活性形式。The term "metabolite" refers to the active form obtained after metabolism of the compound of the present invention or its derivative under physiological conditions.
术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物，或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药，例如1 Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)和J.Rautio’s Prodrugs and Targeted Delivery(2011)31-60(Wiley-VCH,Methods and Principles in Medicinal Chemistry第47卷)和G.Thomas’s Fundamentals of Medicinal Chemistry(2003)195-200(Wiley)中描述的那些方法。The term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are active in their unreacted form. Prodrugs can generally be prepared using known methods, for example 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Edited by Manfred E. Wolff, 5th edition) and J. Rautio's Prodrugs and Targeted Delivery (2011) 31- 60 (Wiley-VCH, Methods and Principles in Medicinal Chemistry Vol. 47) and those methods described in G. Thomas's Fundamentals of Medicinal Chemistry (2003) 195-200 (Wiley).
术语“复合物”是指本发明的化合物进一步与其他小分子或生物大分子以非化学键或者非共价分子间力结合的产物。The term "complex" refers to a product in which the compound of the present invention is further combined with other small molecules or biomacromolecules by non-chemical bonds or non-covalent intermolecular forces.
本发明还提供一种药物组合物，包含所述化合物或其药学上可接受的盐、以及任选地药学上可接受载体。本发明所述药物组合物可以是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。The present invention also provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
本发明所述药学上可接受载体是指本领域技术人员熟知的药学上可接受载体，本发明的药学上可接受载体包括但不限于：填充剂、润湿剂、黏合剂、崩解剂、润滑剂、粘合剂、助流剂、掩味剂、表面活性剂、防腐剂等。填充剂包括但不限于乳糖、微晶纤维素、淀粉、糖粉、糊精、甘露醇、硫酸钙等。润湿剂与黏合剂包括但不限于羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、明胶、蔗糖、聚乙烯吡咯烷酮等。崩解剂包括但不限于羧甲基淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素等。润滑剂包括但不限于硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇、月桂醇硫酸镁等。粘合剂包括但不限于阿拉伯胶、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、葡萄糖结合剂、糊精、右旋糖、乙基纤维素、明胶、液体葡萄糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚乙烯吡咯烷酮、预明胶化淀粉、藻酸钠、山梨醇、淀粉、糖浆和黄 蓍胶。助流剂包括但不限于胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉。掩味剂包括但不限于阿斯巴坦、甜菊苷、果糖、葡萄糖、糖浆、蜂蜜、木糖醇、甘露醇、乳糖、山梨醇、麦芽糖醇、甘草甜素。表面活性剂包括但不限于吐温-80、泊洛沙姆。防腐剂包括但不限于尼泊金酯、苯甲酸钠、山梨酸钾等。The pharmaceutically acceptable carrier in the present invention refers to the pharmaceutically acceptable carrier well known to those skilled in the art. The pharmaceutically acceptable carrier in the present invention includes but not limited to: fillers, wetting agents, binders, disintegrants, Lubricants, adhesives, glidants, taste masking agents, surfactants, preservatives, etc. Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, and the like. Wetting agents and binders include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, and the like. Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, and the like. Lubricants include, but are not limited to, magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and the like. Binders include, but are not limited to, gum arabic, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dextrose, dextrin, dextrose, ethylcellulose, gelatin, liquid dextrose, guar Gum, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Magnesium Aluminum Silicate, Maltodextrin, Methylcellulose, Polymethacrylate, Polyvinylpyrrolidone, Pregelatinized Starch , sodium alginate, sorbitol, starch, syrup and yellow Achillea gum. Glidants include, but are not limited to, colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc. Taste-masking agents include, but are not limited to, aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin. Surfactants include, but are not limited to, Tween-80, poloxamers. Preservatives include, but are not limited to, paraben, sodium benzoate, potassium sorbate, and the like.
制备各种含有各种比例活性成分的药物组合物的方法是已知的，或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述。制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。以已知的方法制造本发明所述药物组合物，包括常规的混合、溶解或冻干方法。Methods for preparing various pharmaceutical compositions containing the active ingredients in various proportions are known, or will be apparent to those skilled in the art in light of this disclosure. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995). The method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents and the like. The pharmaceutical compositions of the present invention are manufactured by known methods, including conventional mixing, dissolving or freeze-drying methods.
在本发明所述药物组合物中，活性成分的比例可以变化，可占给定的单位剂型重量的大约0.01％至大约99％。在这种治疗有用的药物组合物制剂中，活性成分的量使得能够获得有效剂量水平。In the pharmaceutical compositions of the present invention, the proportion of active ingredient may vary from about 0.01% to about 99% by weight of a given unit dosage form. In the preparation of such therapeutically useful pharmaceutical compositions, the amount of active ingredient is such that an effective dosage level will be obtained.
本发明所述的片剂、胶囊剂等可以包含：粘合剂，如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，如磷酸氢二钙；崩解剂，如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂，如硬脂酸镁；和甜味剂，如蔗糖、果糖、乳糖或阿司帕坦；或调味剂，如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时，除了上面类型的材料，它还可以包含液体载体，如植物油或聚乙二醇。各种其他材料可以存在，作为包衣，或以其他方式改变固体单位剂型的物理形式。例如，片剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆可以包含活性成分，蔗糖或果糖作为甜味剂，对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂，染料和调味剂(如樱桃香料或桔子香料)。当然，用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量为无毒。此外，活性成分可以掺入缓释制剂和缓释装置中。Tablets, capsules, etc. of the present invention may contain: binders, such as tragacanth, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as cornstarch, potato Starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, oil of wintergreen, or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form. For example, tablets or capsules may be coated with gelatin, wax, shellac or sugar or the like. A syrup may contain the active ingredient, sucrose or fructose as a sweetening agent, methyl or propyl paraben as a preservative, a dye and flavoring such as cherry flavor or orange flavor. Of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and nontoxic in the amounts employed. Additionally, the active ingredient can be incorporated into sustained release formulations and sustained release devices.
活性成分也可以通过输注或注射到静脉内或腹膜内施用。可以制备活性成分或其盐的水溶液，任选可混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下，这些制剂包含防腐剂以防止微生物生长。The active ingredient can also be administered intravenously or intraperitoneally by infusion or injection. Aqueous solutions of the active ingredient or its salts can be prepared, optionally mixed with nontoxic surfactants. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
适于注射或输注的药物组合物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下，最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质，包括，例如水、乙醇、多元醇(例如，甘油、丙 二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性，例如，通过脂质体的形成，通过在分散剂的情况下维持所需的粒子大小，或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下，优选包括等渗剂，如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如，单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。The dosage form of the pharmaceutical composition suitable for injection or infusion may comprise a sterile aqueous solution containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solution or dispersion. or dispersion or sterile powder. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (e.g., glycerol, acrylic acid, glycols, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, such as sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption (eg, aluminum monostearate and gelatin).
通过将合适的溶剂中的需要量的活性成分与需要的上面列举的各种其他成分结合，然后进行过滤灭菌，制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，这会产生活性成分加上任何另外需要的无菌过滤溶液中存在的成分的粉末。Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional required ingredient present in sterile-filtered solution.
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本发明的药物组合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。Useful solid carriers include comminuted solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like). Useful liquid carriers include water, ethanol or glycol or water-ethanol/glycol mixtures, in which the pharmaceutical compositions of this invention can be dissolved or dispersed in effective amounts, optionally with the aid of nontoxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等，直接用于使用者的皮肤上。Thickening agents (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) can also be used with liquid carriers to form spreadable pastes, gels, and ointments , soap, etc., directly on the user's skin.
活性成分的治疗有效量，不仅取决于选择的特定的盐，而且取决于施药方式、待治疗的疾病的性质和患者的年龄和状态，最终取决于在场医师或临床医生的决定。The therapeutically effective amount of the active ingredient depends not only on the particular salt chosen, but also on the mode of administration, the nature of the disease to be treated and the age and state of the patient, and ultimately at the discretion of the attending physician or clinician.
上述制剂可以以单位剂型存在，该单位剂型是含有单位剂量的物理分散单元，适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂。根据所涉及的具体治疗，活性成分的单位剂量的量可以在大约0.01到大约1000毫克或更多之间进行变化或调整。The formulations described above can be presented in unit dosage form, which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies. The unit dosage form can be a capsule or a tablet. The amount of a unit dose of active ingredient may be varied or adjusted from about 0.01 to about 1000 milligrams or more depending on the particular treatment involved.
本发明使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。The term "treatment" as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.
本发明所述的化合物或其药学上可接受的盐也可以与一种或多种用于治疗癌症的另外的治疗剂组合施用。这种额外的治疗剂包括但不限于蒽环类、环磷酰胺、5-氟尿嘧啶、 顺铂等。A compound described herein, or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional therapeutic agents useful in the treatment of cancer. Such additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, Cisplatin etc.
除非另有说明，本发明中使用的百分比、比例、比例或份数均以重量或体积计。本发明中使用的量是重量或体积量。本领域技术人员可以很容易地确定。All percentages, ratios, proportions or parts used herein are by weight or volume unless otherwise indicated. Amounts used in the present invention are weight or volumetric amounts. Those skilled in the art can easily determine.
在本发明的还有一个方面，本发明还包括由本发明任一可变基团处所定义的任一基团组合的得到化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药。In yet another aspect of the present invention, the present invention also includes compounds obtained by combining any group defined at any variable group of the present invention, or derivatives thereof, pharmaceutically acceptable salts, isomers, solvents compounds, hydrates, adducts, complexes or prodrugs.
本发明还包括以下示例性化合物。

The present invention also includes the following exemplary compounds.

实施例1：化合物WBC208的合成
Embodiment 1: the synthesis of compound WBC208
0.35g(8.8mmol)氢氧化钠溶于5ml水中，室温加入0.5g(4.3mmol)D-环丙氨基酸和2.5mlTHF，搅拌溶解后，滴加1.2g(5.2mmol)二碳酸二叔丁酯，滴加完室温搅拌反应。反应结束，加入10ml乙酸乙酯，用饱各硫酸氢钠溶液调节pH至2-3，分层，有机层用饱和盐水洗涤一次，有机层用无水硫酸钠干燥，过滤，蒸干，油状物用5ml正庚烷结晶，得化合物1(0.86g,收率91.98％)。Dissolve 0.35g (8.8mmol) of sodium hydroxide in 5ml of water, add 0.5g (4.3mmol) of D-cyclopropyl amino acid and 2.5ml of THF at room temperature, stir and dissolve, then add 1.2g (5.2mmol) of di-tert-butyl dicarbonate dropwise, After the dropwise addition, the reaction was stirred at room temperature. After the reaction was completed, add 10ml of ethyl acetate, adjust the pH to 2-3 with saturated sodium bisulfate solution, separate layers, wash the organic layer once with saturated brine, dry the organic layer with anhydrous sodium sulfate, filter, and evaporate to dryness. Crystallize with 5ml of n-heptane to obtain compound 1 (0.86g, yield 91.98%).
0.36g(1.67mmol)化合物1和60mg(0.49mmol)溶于3mlDCM中，0-5度加入280mg(1.46mmol)和300mg(0.83mmol)雷公藤甲素，0-5度搅拌反应。反应结束，依次用5％碳氢钠溶液、5％硫酸氢溶液和盐水洗涤，有机层无水硫酸钠干燥，蒸干，得化合物2(0.44g,收率95.65％)0.36g (1.67mmol) of compound 1 and 60mg (0.49mmol) were dissolved in 3ml DCM, 280mg (1.46mmol) and 300mg (0.83mmol) triptolide were added at 0-5°C, and the reaction was stirred at 0-5°C. After the reaction was completed, it was washed successively with 5% sodium bicarbonate solution, 5% hydrogen sulfate solution and brine, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound 2 (0.44g, yield 95.65%)
0.44g(0.79mmol)化合物2溶于2ml二氯甲烷中，降至0-5度，加入2ml三氟乙酸，0-5度搅拌反应。反应结束，反应液蒸干，加入二氯甲烷溶解，用5％碳酸氢钠调节pH 至7-8，分层，蒸干，得到的粗产品经制备色谱分离纯化得到白色固体化合物WBC208(150mg,收率41.5％)。0.44g (0.79mmol) of compound 2 was dissolved in 2ml of dichloromethane, lowered to 0-5°C, added 2ml of trifluoroacetic acid, and stirred at 0-5°C. After the reaction was completed, the reaction solution was evaporated to dryness, added dichloromethane to dissolve, and adjusted the pH with 5% sodium bicarbonate To 7-8, separate layers, evaporate to dryness, the obtained crude product was separated and purified by preparative chromatography to obtain white solid compound WBC208 (150 mg, yield 41.5%).
LC-MS:m/z 458.15(M+H)。1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J＝2.2Hz,2H),3.84(d,J＝3.1Hz,1H),3.56(d,J＝3.0Hz,1H),3.46(dd,J＝24.6,5.0Hz,2H),2.71(dd,J＝12.2,5.8Hz,1H),2.33(dd,J＝19.3,5.3Hz,1H),2.18(dt,J＝14.8,5.8Hz,1H),1.97–1.85(m,2H),1.59(ddd,J＝12.5,5.7,1.6Hz,1H),1.39–1.12(m,3H),1.14–0.94(m,6H),0.92–0.81(m,3H),0.77–0.56(m,2H),0.50–0.38(m,2H)。LC-MS: m/z 458.15 (M+H). 1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J=2.2Hz,2H),3.84(d,J=3.1Hz,1H),3.56(d,J=3.0Hz ,1H),3.46(dd,J=24.6,5.0Hz,2H),2.71(dd,J=12.2,5.8Hz,1H),2.33(dd,J=19.3,5.3Hz,1H),2.18(dt, J=14.8,5.8Hz,1H),1.97–1.85(m,2H),1.59(ddd,J=12.5,5.7,1.6Hz,1H),1.39–1.12(m,3H),1.14–0.94(m, 6H), 0.92–0.81(m,3H), 0.77–0.56(m,2H), 0.50–0.38(m,2H).
实施例2：化合物WBC209的合成
Embodiment 2: the synthesis of compound WBC209
以D-叔亮氨酸为起始原料，按实施例1操作方法进行制备，得白色固体化合物WBC209(160mg,40.61％)Using D-tert-leucine as the starting material, it was prepared according to the operation method of Example 1 to obtain the white solid compound WBC209 (160mg, 40.61%)
LC-MS:m/z 474.15(M+H)。1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J＝2.2Hz,2H),3.84(d,J＝3.1Hz,1H),3.56(d,J＝3.0Hz,1H),3.46(dd,J＝24.6,5.0Hz,2H),2.71(dd,J＝12.2,5.8Hz,1H)，2.35–2.27(m,1H),2.18(dt,J＝14.7,5.8Hz,1H),1.98–1.87(m,2H),1.58(ddd,J＝12.3,5.5,1.6Hz,1H),1.27–1.16(m,2H),1.07–0.92(m,15H),0.84(d,J＝6.9Hz,3H)。LC-MS: m/z 474.15 (M+H). 1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J=2.2Hz,2H),3.84(d,J=3.1Hz,1H),3.56(d,J=3.0Hz ,1H),3.46(dd,J=24.6,5.0Hz,2H),2.71(dd,J=12.2,5.8Hz,1H),2.35–2.27(m,1H),2.18(dt,J=14.7,5.8 Hz,1H),1.98–1.87(m,2H),1.58(ddd,J＝12.3,5.5,1.6Hz,1H),1.27–1.16(m,2H),1.07–0.92(m,15H),0.84( d, J=6.9Hz, 3H).
实施例3：化合物WBC210的合成
Embodiment 3: the synthesis of compound WBC210
以D-别异亮氨酸为起始原料，按实施例1操作方法进行制备，得白色固体化合物WBC210(180mg,45.69％)Using D-alloisoleucine as the starting material, it was prepared according to the operation method of Example 1 to obtain the white solid compound WBC210 (180mg, 45.69%)
LC-MS:m/z 474.15(M+H)。1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J＝2.2Hz,2H),3.84(d,J＝3.1Hz,1H),3.56(d,J＝3.0Hz,1H),3.46(dd,J＝24.6,5.0Hz,2H),2.71(dd,J＝12.2,5.8Hz,1H)，2.37–2.28(m,1H),2.17(ddt,J＝ 14.5,8.7,4.9Hz,2H),1.99(dtd,J＝8.0,6.5,3.9Hz,1H),1.97–1.84(m,2H),1.62–1.46(m,2H),1.42–1.29(m,1H),1.27–1.17(m,1H),1.04(s,3H),0.97(td,J＝7.1,4.2Hz,9H),0.85(d,J＝6.9Hz,3H).LC-MS: m/z 474.15 (M+H). 1H NMR (500MHz, Chloroform-d) δ5.10(s, 1H), 4.69(p, J=2.2Hz, 2H), 3.84(d, J=3.1Hz, 1H), 3.56(d, J=3.0Hz ,1H), 3.46(dd,J＝24.6,5.0Hz,2H), 2.71(dd,J＝12.2,5.8Hz,1H), 2.37–2.28(m,1H), 2.17(ddt,J＝ 14.5,8.7,4.9Hz,2H),1.99(dtd,J＝8.0,6.5,3.9Hz,1H),1.97–1.84(m,2H),1.62–1.46(m,2H),1.42–1.29(m, 1H), 1.27–1.17(m, 1H), 1.04(s, 3H), 0.97(td, J=7.1, 4.2Hz, 9H), 0.85(d, J=6.9Hz, 3H).
实施例4：化合物WBC211的合成
Embodiment 4: the synthesis of compound WBC211
以N-甲基-D-丙氨酸为起始原料，按实施例1操作方法进行制备，得白色固体化合物WBC211(178mg,47.98％)Using N-methyl-D-alanine as the starting material, it was prepared according to the operation method of Example 1 to obtain the white solid compound WBC211 (178mg, 47.98%)
LC-MS:m/z 446.2(M+H)。1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J＝2.2Hz,2H),3.84(d,J＝3.1Hz,1H),3.56(d,J＝3.0Hz,1H),3.46(dd,J＝24.6,5.0Hz,2H),2.71(dd,J＝12.2,5.8Hz,1H)，2.44(d,J＝11.1Hz,3H),2.37–2.28(m,1H),2.22–2.08(m,2H),1.95–1.84(m,2H),1.62–1.54(m,1H),1.39(d,J＝7.0Hz,2H),1.34(d,J＝6.9Hz,1H),1.22(td,J＝12.3,5.9Hz,1H),1.05(d,J＝2.4Hz,3H),0.98(t,J＝7.1Hz,3H),0.85(dd,J＝10.2,6.9Hz,3H)。LC-MS: m/z 446.2 (M+H). 1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J=2.2Hz,2H),3.84(d,J=3.1Hz,1H),3.56(d,J=3.0Hz ,1H),3.46(dd,J=24.6,5.0Hz,2H),2.71(dd,J=12.2,5.8Hz,1H),2.44(d,J=11.1Hz,3H),2.37–2.28(m, 1H), 2.22–2.08(m, 2H), 1.95–1.84(m, 2H), 1.62–1.54(m, 1H), 1.39(d, J=7.0Hz, 2H), 1.34(d, J=6.9Hz ,1H),1.22(td,J=12.3,5.9Hz,1H),1.05(d,J=2.4Hz,3H),0.98(t,J=7.1Hz,3H),0.85(dd,J=10.2, 6.9Hz, 3H).
实施例5：化合物WBC212的合成
Embodiment 5: the synthesis of compound WBC212
以D-环戊基甘氨酸为起始原料，按实施例1操作方法进行制备，得白色固体化合物WBC212(175mg,43.32％)Using D-cyclopentylglycine as the starting material, it was prepared according to the operation method of Example 1 to obtain the white solid compound WBC212 (175mg, 43.32%)
LC-MS:m/z 486.15(M+H)。1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J＝2.2Hz,2H),3.84(d,J＝3.1Hz,1H),3.56(d,J＝3.0Hz,1H),3.46(dd,J＝24.6,5.0Hz,2H),2.71(dd,J＝12.2,5.8Hz,1H)，2.34(s,1H),2.29–2.09(m,2H),1.96–1.86(m,2H),1.70–1.37(m,4H),1.31–1.22(m,2H),1.22(q,J＝5.7,4.8Hz,1H),1.19(s,4H),1.06–0.91(m,6H),0.84(d,J＝6.9Hz,3H).LC-MS: m/z 486.15 (M+H). 1H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.69(p,J=2.2Hz,2H),3.84(d,J=3.1Hz,1H),3.56(d,J=3.0Hz ,1H),3.46(dd,J=24.6,5.0Hz,2H),2.71(dd,J=12.2,5.8Hz,1H),2.34(s,1H),2.29–2.09(m,2H),1.96– 1.86(m,2H),1.70–1.37(m,4H),1.31–1.22(m,2H),1.22(q,J＝5.7,4.8Hz,1H),1.19(s,4H),1.06–0.91( m,6H),0.84(d,J=6.9Hz,3H).
实施例6：化合物WBC220的合成
Embodiment 6: the synthesis of compound WBC220
向反应瓶中加入WB001-SM2(100mg,0.277mmol)和15ml叔丁醇中，80℃下搅拌溶解。随后往反应液中加入硫氰酸铵(246mg，4.16mmol)。回流反应24小时，TLC检测反应进程。反应结束后，反应液减压蒸去部分叔丁醇，加入20ml的EtOAc。有机层先用水洗涤一次，再用饱和NaCl水溶液洗涤一次，有机层用无水硫酸钠干燥，过滤。减压浓缩，得到白色固体，柱层析纯化，用CH2Cl2/MeOH(100:1)洗脱，收集组分，真空干燥，得产物100mg，收率85.9％。LC-MS:m/z 420.4[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.72(qt,J＝3.4,1.7Hz,2H),4.01(d,J＝5.5Hz,1H),3.76(dd,J＝5.5,1.2Hz,1H),3.45(d,J＝6.0Hz,1H),3.21(s,1H),2.81–2.70(m,1H),2.59–2.45(m,2H),2.45–2.34(m,2H),2.29–2.09(m,2H),2.02(dd,J＝14.9,13.4Hz,1H),1.76(s,1H),1.74–1.65(m,1H),1.16–1.05(m,6H),0.96(d,J＝6.8Hz,3H)。Add WB001-SM2 (100mg, 0.277mmol) and 15ml tert-butanol into the reaction flask, stir and dissolve at 80°C. Ammonium thiocyanate (246 mg, 4.16 mmol) was then added to the reaction solution. The reaction was carried out under reflux for 24 hours, and the progress of the reaction was detected by TLC. After the reaction, part of the tert-butanol was evaporated from the reaction solution under reduced pressure, and 20 ml of EtOAc was added. The organic layer was washed once with water and once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave a white solid, which was purified by column chromatography and eluted with CH 2 Cl 2 /MeOH (100:1). The fractions were collected and dried in vacuo to give 100 mg of the product with a yield of 85.9%. LC-MS: m/z 420.4[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ4.72 (qt, J=3.4, 1.7Hz, 2H), 4.01(d, J=5.5Hz, 1H), 3.76(dd, J＝5.5, 1.2Hz, 1H), 3.45(d, J＝6.0Hz, 1H), 3.21(s, 1H), 2.81–2.70(m, 1H), 2.59–2.45(m ,2H),2.45–2.34(m,2H),2.29–2.09(m,2H),2.02(dd,J＝14.9,13.4Hz,1H),1.76(s,1H),1.74–1.65(m,1H ), 1.16–1.05 (m, 6H), 0.96 (d, J=6.8Hz, 3H).
实施例7：化合物WBC221的合成
Embodiment 7: the synthesis of compound WBC221
向反应瓶中加入WB001-2(100mg,0.179mmol)和15ml叔丁醇，搅拌溶解，升至80℃。加入硫氰酸铵(248mg,4.20mmol)。80℃保温反应24小时，TLC检测反应进程。反应结束后，反应液减压蒸去部分叔丁醇，加入20ml的二氯甲烷。有机层先用水洗涤一次，再用饱和NaCl水溶液水洗一次，有机层用无水硫酸钠干燥，过滤。减压浓缩，得到固体130mg。Add WB001-2 (100mg, 0.179mmol) and 15ml tert-butanol into the reaction flask, stir to dissolve, and raise to 80°C. Ammonium thiocyanate (248 mg, 4.20 mmol) was added. The reaction was incubated at 80° C. for 24 hours, and the progress of the reaction was detected by TLC. After the reaction, part of the tert-butanol was evaporated from the reaction liquid under reduced pressure, and 20 ml of dichloromethane was added. The organic layer was washed once with water and then once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave 130 mg of solid.
上述130mg固体用1ml二氯甲烷熔解，队至0-5℃，加入1ml三氟乙酸，0-5℃保温反应1h，TLC检测反应进程。反应结束，反应液在小于25℃的水浴下减压蒸干，残留物用2ml乙醇和4ml甲基叔丁基醚结晶，得至固体42mg，收率37％。LC-MS:m/z 519.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.80(s,3H),4.91(d,J＝17.7Hz,1H),4.79(d,J＝17.5Hz,1H),4.61(s,1H),4.05(q,J＝5.7Hz,2H),3.86(d,J＝3.9Hz,1H),3.61(d,J＝6.0 Hz,1H),2.70(d,J＝12.1Hz,1H),2.29–2.14(m,3H),2.05–1.95(m,2H),1.85(t,J＝14.2Hz,1H),1.49–1.40(m,1H),1.32–1.22(m,1H),1.08(d,J＝7.0Hz,3H),1.03–0.93(m,6H),0.90–0.81(m,6H)。The above 130 mg of solid was melted with 1 ml of dichloromethane, brought to 0-5 ° C, added 1 ml of trifluoroacetic acid, kept at 0-5 ° C for 1 h, and the progress of the reaction was detected by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure in a water bath less than 25° C., and the residue was crystallized with 2 ml of ethanol and 4 ml of methyl tert-butyl ether to obtain 42 mg of solid, with a yield of 37%. LC-MS: m/z 519.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.80(s,3H),4.91(d,J＝17.7Hz,1H),4.79(d,J =17.5Hz, 1H), 4.61(s, 1H), 4.05(q, J=5.7Hz, 2H), 3.86(d, J=3.9Hz, 1H), 3.61(d, J=6.0 Hz,1H),2.70(d,J=12.1Hz,1H),2.29–2.14(m,3H),2.05–1.95(m,2H),1.85(t,J=14.2Hz,1H),1.49–1.40 (m, 1H), 1.32–1.22 (m, 1H), 1.08 (d, J=7.0Hz, 3H), 1.03–0.93 (m, 6H), 0.90–0.81 (m, 6H).
实施例8：化合物WBC222的合成
Embodiment 8: the synthesis of compound WBC222
向反应瓶中加入WB001B-1(120mg,0.597mmol)、4-二甲氨基吡啶(DMAP,20mg,0.164mmol)和1ml二氯甲烷，搅拌溶解，降至0-5℃。依次加入WB001-SM2(100mg,0.277mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,100mg,0.52mmol)，保温0-5℃升到1小时，TLC检测反应进程。反应结束后，反应液中加入10ml的二氯甲烷。有机层依次用5％碳酸氢钠水溶液洗涤4次，5％硫酸氢钠水溶液洗涤3次，NaCl水溶液水洗2次，有机层用无水硫酸钠干燥，过滤。减压浓缩，得到151mg WB001B-2。Add WB001B-1 (120mg, 0.597mmol), 4-dimethylaminopyridine (DMAP, 20mg, 0.164mmol) and 1ml of dichloromethane into the reaction flask, stir to dissolve, and lower to 0-5°C. Add WB001-SM2 (100mg, 0.277mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 100mg, 0.52mmol) in turn, keep warm at 0-5°C By 1 hour, TLC was used to monitor the progress of the reaction. After the reaction was finished, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed successively with 5% aqueous sodium bicarbonate solution 4 times, 5% aqueous sodium bisulfate solution 3 times, and aqueous NaCl solution 2 times. The organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave 151 mg of WB001B-2.
向反应瓶中加入WB001B-2(151mg,0.277mmol)和15ml叔丁醇，搅拌溶解。加入硫氰酸铵(246mg，4.16mmol)。升到80℃反应24小时，TLC检测反应进程。反应结束后，反应液减压蒸去部分叔丁醇，加入20ml的乙酸乙酯。有机层先用水洗涤一次，再用饱和NaCl水溶液水洗一次，有机层用无水硫酸钠干燥，过滤。减压浓缩，残留物用二氯甲烷溶解，柱层析纯化，用DCM/MeOH＝200:1→100:1冲柱，收集产品，蒸干得到固体130mg。Add WB001B-2 (151mg, 0.277mmol) and 15ml tert-butanol into the reaction flask, stir to dissolve. Ammonium thiocyanate (246 mg, 4.16 mmol) was added. Raised to 80°C for 24 hours, and TLC was used to detect the progress of the reaction. After the reaction, part of the tert-butanol was evaporated from the reaction solution under reduced pressure, and 20 ml of ethyl acetate was added. The organic layer was washed once with water and then once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered. Concentrated under reduced pressure, the residue was dissolved in dichloromethane, purified by column chromatography, washed with DCM/MeOH=200:1→100:1, the product was collected and evaporated to dryness to obtain 130 mg of solid.
上述130mg固体用0.5ml二氯甲烷熔解，队至0-5℃，加入0.5ml三氟乙酸，0-5℃保温反应1h，TLC检测反应进程。反应结束，反应液在小于25℃的水浴下减压蒸干，残留物用0.5ml乙醇和6ml甲基叔丁基醚结晶，得至固体110mg，收率64.19％。LC-MS:m/z505.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),9.00(s,1H),4.90(d,1H),4.79(d,J＝18.2Hz,1H),4.58(s,1H),4.17–4.06(m,3H),3.63(d,J＝6.1Hz,1H),2.70(d,J＝ 13.4Hz,1H),2.59(s,3H),2.29–2.14(m,2H),2.07–1.96(m,1H),1.92–1.78(m,1H),1.58–1.39(m,2H),1.11(s,3H),1.04–0.97(m,3H),0.91–0.79(m,6H)。The above 130 mg of solid was melted with 0.5 ml of dichloromethane, brought to 0-5 °C, added 0.5 ml of trifluoroacetic acid, kept at 0-5 °C for 1 h, and the reaction progress was detected by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure in a water bath less than 25°C, and the residue was crystallized with 0.5 ml of ethanol and 6 ml of methyl tert-butyl ether to obtain 110 mg of solid, with a yield of 64.19%. LC-MS: m/z505.3[M+H]+.1H NMR (400MHz, DMSO-d6) δ9.14(s,1H),9.00(s,1H),4.90(d,1H),4.79( d,J=18.2Hz,1H),4.58(s,1H),4.17–4.06(m,3H),3.63(d,J=6.1Hz,1H),2.70(d,J= 13.4Hz, 1H), 2.59(s, 3H), 2.29–2.14(m, 2H), 2.07–1.96(m, 1H), 1.92–1.78(m, 1H), 1.58–1.39(m, 2H), 1.11 (s, 3H), 1.04–0.97 (m, 3H), 0.91–0.79 (m, 6H).
实施例9：化合物WBC223的合成
Embodiment 9: the synthesis of compound WBC223
向反应瓶中加入WB001G-1(120mg,0.557mmol)、4-二甲氨基吡啶(DMAP,20mg,0.164mmol)和1ml二氯甲烷，搅拌溶解，降至0-5℃。依次加入WB001-SM2(100mg,0.277mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,100mg,0.52mmol)，保温0-5℃升到1小时，TLC检测反应进程。反应结束后，反应液中加入10ml的二氯甲烷。有机层依次用5％碳酸氢钠水溶液洗涤4次，5％硫酸氢钠水溶液洗涤3次，NaCl水溶液水洗2次，有机层用无水硫酸钠干燥，过滤。减压浓缩，得到154mg WB001G-2。Add WB001G-1 (120mg, 0.557mmol), 4-dimethylaminopyridine (DMAP, 20mg, 0.164mmol) and 1ml of dichloromethane into the reaction flask, stir to dissolve, and lower to 0-5°C. Add WB001-SM2 (100mg, 0.277mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 100mg, 0.52mmol) in turn, keep warm at 0-5°C By 1 hour, TLC was used to monitor the progress of the reaction. After the reaction was finished, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed successively with 5% aqueous sodium bicarbonate solution 4 times, 5% aqueous sodium bisulfate solution 3 times, and aqueous NaCl solution 2 times. The organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave 154mg of WB001G-2.
向反应瓶中加入WB001G-2(154mg,0.277mmol)和15ml叔丁醇，搅拌溶解。加入硫氰酸铵(246mg，4.16mmol)。升到80℃反应24小时，TLC检测反应进程。反应结束后，反应液减压蒸去部分叔丁醇，加入20ml的乙酸乙酯。有机层先用水洗涤一次，再用饱和NaCl水溶液水洗一次，有机层用无水硫酸钠干燥，过滤。减压浓缩，残留物用二氯甲烷溶解，柱层析纯化，用DCM/MeOH＝100:1冲柱，收集产品，蒸干得到固体132mg。Add WB001G-2 (154mg, 0.277mmol) and 15ml tert-butanol into the reaction flask, stir to dissolve. Ammonium thiocyanate (246 mg, 4.16 mmol) was added. Raised to 80°C for 24 hours, and TLC was used to detect the progress of the reaction. After the reaction, part of the tert-butanol was evaporated from the reaction solution under reduced pressure, and 20 ml of ethyl acetate was added. The organic layer was washed once with water and then once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure, dissolve the residue with dichloromethane, purify by column chromatography, wash the column with DCM/MeOH=100:1, collect the product, and evaporate to dryness to obtain 132 mg of solid.
上述132mg固体用0.5ml二氯甲烷熔解，队至0-5℃，加入0.5ml三氟乙酸，0-5℃保温反应1h，TLC检测反应进程。反应结束，反应液在小于25℃的水浴下减压蒸干，残留物6ml甲基叔丁基醚结晶，得至固体115mg，收率65.83％。LC-MS:m/z 517.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,3H),4.96–4.86(m,1H),4.80(dd,J＝17.6,3.3Hz,1H),4.59(s,1H),4.05(s,2H),3.59(d,J＝6.1Hz,1H),3.34(d,J＝9.3Hz,1H),2.71(d,J＝13.2Hz,1H),2.29–2.14(m,2H),1.99(m,2H),1.84(dd,J＝15.0,13.4Hz,1H),1.46(dd,J＝12.2,5.3Hz,1H),1.28(m,2H),1.11–0.93(m,4H),0.93–0.82(m,7H),0.74–0.57(m,2H). The above 132 mg of solid was melted with 0.5 ml of dichloromethane, brought to 0-5 °C, added 0.5 ml of trifluoroacetic acid, kept at 0-5 °C for 1 h, and TLC was used to detect the reaction progress. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure in a water bath less than 25°C, and the residue 6ml of methyl tert-butyl ether was crystallized to obtain 115mg of solid, with a yield of 65.83%. LC-MS: m/z 517.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.45(s, 3H), 4.96–4.86(m, 1H), 4.80(dd, J= 17.6,3.3Hz,1H),4.59(s,1H),4.05(s,2H),3.59(d,J=6.1Hz,1H),3.34(d,J=9.3Hz,1H),2.71(d, J＝13.2Hz, 1H), 2.29–2.14(m, 2H), 1.99(m, 2H), 1.84(dd, J＝15.0, 13.4Hz, 1H), 1.46(dd, J＝12.2, 5.3Hz, 1H ),1.28(m,2H),1.11–0.93(m,4H),0.93–0.82(m,7H),0.74–0.57(m,2H).
实施例10：化合物WBC213的合成
Embodiment 10: the synthesis of compound WBC213
重铬酸钾/三氧化铬/硫酸水溶液氧化Potassium dichromate/chromium trioxide/sulfuric acid aqueous oxidation
氧化液的制备：取重铬酸钾(2.95g,10mmol)和三氧化铬(1.35g,1.35mmol)，加热溶于13.5ml蒸馏水中，再加入97％硫酸(4.0g,39.6mmol)混匀。Preparation of oxidizing solution: Take potassium dichromate (2.95g, 10mmol) and chromium trioxide (1.35g, 1.35mmol), heat and dissolve in 13.5ml distilled water, then add 97% sulfuric acid (4.0g, 39.6mmol) and mix well .
取雷公藤内酯醇(0.54g,1.5mmol)加入至25ml丙酮中，升至50-60℃搅拌，固体不完全溶解，边搅拌边滴加上述氧化液2.5ml，保温50-60℃反应20min，滤除固体，减压蒸去溶剂，残渣用20ml二氯甲烷和10ml水搅拌分层，分出二氯甲烷层，先后以饱和碳酸氢钠不溶液及水洗涤，有机层经无水硫酸钠干燥后，减压浓缩，残留物用二氯甲烷和正庚烷结晶，得480mg，收率89.39％。LC-MS:m/z 359.1[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.81–4.64(m,2H),4.07(d,J＝2.9Hz,1H),3.86(d,J＝2.8Hz,1H),3.44(d,J＝5.5Hz,1H),2.89–2.79(m,1H),2.51–2.33(m,2H),2.30–2.10(m,2H),2.01(dd,J＝14.8,13.3Hz,1H),1.68–1.58(m,1H),1.40–1.25(m,1H),1.10(d,J＝0.8Hz,3H),1.00(d,J＝6.8Hz,3H),0.91(d,J＝7.0Hz,3H).Take triptolide (0.54g, 1.5mmol) and add it to 25ml of acetone, heat up to 50-60°C and stir, the solid is not completely dissolved, add 2.5ml of the above oxidation solution dropwise while stirring, keep warm at 50-60°C for 20min, Filter off the solid, evaporate the solvent under reduced pressure, stir the residue with 20ml of dichloromethane and 10ml of water and separate the layers, separate the dichloromethane layer, wash with saturated sodium bicarbonate solution and water successively, and dry the organic layer over anhydrous sodium sulfate Afterwards, it was concentrated under reduced pressure, and the residue was crystallized from dichloromethane and n-heptane to obtain 480 mg with a yield of 89.39%. LC-MS: m/z 359.1[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ4.81–4.64 (m, 2H), 4.07 (d, J=2.9Hz, 1H), 3.86 ( d,J=2.8Hz,1H),3.44(d,J=5.5Hz,1H),2.89–2.79(m,1H),2.51–2.33(m,2H),2.30–2.10(m,2H),2.01 (dd,J=14.8,13.3Hz,1H),1.68–1.58(m,1H),1.40–1.25(m,1H),1.10(d,J=0.8Hz,3H),1.00(d,J=6.8 Hz,3H),0.91(d,J=7.0Hz,3H).
实施例11：化合物WBC204的合成
Embodiment 11: the synthesis of compound WBC204
Step 1：制备化合物IStep 1: Preparation of compound I
将岩藻糖(2.0g，12.18mmol)溶于甲醇(20.0ml)溶液中，室温下滴入乙酰氯(0.1ml)，加热升温到65℃下回流5h，反应结束后，冰水浴条件下加入碳酸氢钠粉末中和，调节PH值为7.过滤减压浓缩，用乙酸乙酯-甲醇＝60:1体系过柱得油状液体化合物a1(1.9g，收率87.5％)Dissolve fucose (2.0g, 12.18mmol) in methanol (20.0ml) solution, add acetyl chloride (0.1ml) dropwise at room temperature, heat up to 65°C and reflux for 5h, after the reaction is complete, add Neutralize with sodium bicarbonate powder, adjust the pH value to 7, filter and concentrate under reduced pressure, pass through the column with ethyl acetate-methanol = 60:1 system to obtain oily liquid compound a1 (1.9 g, yield 87.5%)
将a1(1.0g，5.61mmol)溶于DMF(15.0ml)溶液中，氮气保护下降温到0℃一下，在0℃下加入NaH(807.8mg,33.66mmol),搅拌30min中后，缓慢滴加BnBr(3.35g，19.635mmol)，滴加结束后恢复到室温下搅拌5h。反应结束后用乙酸乙酯萃取，并用水洗5-6次。有机相用无水硫酸钠干燥，过滤，减压浓缩后用乙酸乙酯-石油醚＝1：7体系过柱得化合物a2，直接用于下一步反应Dissolve a1 (1.0g, 5.61mmol) in DMF (15.0ml) solution, lower the temperature to below 0°C under the protection of nitrogen, add NaH (807.8mg, 33.66mmol) at 0°C, stir for 30min, then slowly drop BnBr (3.35 g, 19.635 mmol), returned to room temperature and stirred for 5 h after the dropwise addition. After the reaction, it was extracted with ethyl acetate and washed with water 5-6 times. The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through the column with ethyl acetate-petroleum ether=1:7 system to obtain compound a2, which was directly used in the next reaction
将化合物a2溶于4.0ml，1mol/L的稀盐酸和15.0ml，80％的醋酸水溶液升温回流4h，反应结束后用二氯甲烷萃取并用饱和碳酸氢钠水溶液洗涤2次，用无水硫酸钠干燥后，过滤并减压浓缩。用EA-PE＝1:3体系过柱得白色固体化合物I(800.0mg,收率32.7％)Dissolve compound a2 in 4.0ml, 1mol/L dilute hydrochloric acid and 15.0ml, 80% acetic acid aqueous solution, heat up and reflux for 4h, extract with dichloromethane and wash twice with saturated aqueous sodium bicarbonate solution after the reaction, wash with anhydrous sodium sulfate After drying, it was filtered and concentrated under reduced pressure. The white solid compound I (800.0 mg, yield 32.7%) was obtained by passing through the column with EA-PE=1:3 system
Step2：制备化合物IIStep2: Preparation of compound II
将雷公藤甲素(250.0mg，0.694mmol)溶于二氯甲烷(5.0ml)溶液中。开启搅拌并通入氮气保护，加入丁二酸酐(694.5mg，6.94mmol)和三乙胺(0.5ml)，搅拌5min后加入DMAP(847.8mg，6.94mmol)，加料完毕后25℃下搅拌2h。反应结束后，加入饱和硫酸氢钠猝灭用二氯甲烷萃取，无水硫酸钠干燥后，过滤并减压浓缩。经色谱柱分离提纯后得白色固体化合物II(280.0mg，87.8％)。 Triptolide (250.0 mg, 0.694 mmol) was dissolved in a solution of dichloromethane (5.0 ml). Start stirring with nitrogen protection, add succinic anhydride (694.5mg, 6.94mmol) and triethylamine (0.5ml), stir for 5min, add DMAP (847.8mg, 6.94mmol), and stir at 25°C for 2h after the addition. After the reaction was completed, it was quenched by adding saturated sodium bisulfate and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound II (280.0 mg, 87.8%) was obtained as a white solid after separation and purification by chromatographic column.
Step 3：制备化合物IIIStep 3: Preparation of compound III
将化合物II(255.0mg，0.55mmol)溶于二氯甲烷(5.0ml)中，开始搅拌并通入氮气保护。0℃下加入化合物I(239.25mg，0.55mmol)、DCC(226.79mg，1.1mmol)和DMAP(134.38mg，1.1mmol)。加完后升温到25℃下搅拌3h。反应结束后，加入30.0ml二氯甲烷和20.0ml饱和亚硫酸氢钠，搅拌5min分液，水相用二氯甲烷萃取一次合并有机相用无水硫酸钠干燥，过滤，40℃减压浓缩后经色谱柱分离提纯后得白色固体化合物III(250.0mg，51.4％)。Compound II (255.0 mg, 0.55 mmol) was dissolved in dichloromethane (5.0 ml), stirring was started and nitrogen protection was passed. Compound I (239.25 mg, 0.55 mmol), DCC (226.79 mg, 1.1 mmol) and DMAP (134.38 mg, 1.1 mmol) were added at 0°C. After the addition, the temperature was raised to 25° C. and stirred for 3 h. After the reaction, add 30.0ml of dichloromethane and 20.0ml of saturated sodium bisulfite, stir for 5min to separate the liquids, extract the aqueous phase with dichloromethane once, combine the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C Compound III (250.0 mg, 51.4%) was obtained as a white solid after separation and purification by chromatographic column.
Step 4：制备化合物WBC204Step 4: Preparation of compound WBC204
将化合物III(200.0mg)溶于甲醇：THF＝1:1(5.0ml)溶液中，搅拌溶清后加入30.0mgPd/C(10％),并通入氢气，在室温25℃下搅拌8h。反应结束后，过滤，减压浓缩。经色谱柱分离提纯后得白色固体化合物WBC204(95.0mg，68.7％)。LC-MS:m/z 607.23[M+H]+.1H NMR(400MHz,Chloroform-d)δ6.16(s,1H),5.09(s,1H),4.73–4.63(m,2H),4.12(dd,J＝19.4,4.3Hz,3H),4.10–4.01(m,1H),4.02(s,1H),3.86(d,J＝3.2Hz,1H),3.53(dd,J＝20.9,4.3Hz,2H),2.90–2.59(m,3H),2.43(s,1H),2.34(d,J＝17.9Hz,1H),2.20(dt,J＝14.8,5.9Hz,1H),1.91(ddd,J＝14.0,10.3,6.3Hz,2H),1.59(dd,J＝12.4,5.2Hz,1H),1.37(d,J＝6.5Hz,3H),1.30–1.18(m,1H),1.09(d,J＝16.9Hz,1H),1.07(s,3H),0.97(d,J＝7.0Hz,3H),0.86(d,J＝6.8Hz,3H).Compound III (200.0mg) was dissolved in methanol:THF=1:1 (5.0ml) solution, stirred to dissolve, added 30.0mgPd/C (10%), and hydrogen gas was introduced, and stirred at room temperature 25°C for 8h. After the reaction was completed, it was filtered and concentrated under reduced pressure. White solid compound WBC204 (95.0 mg, 68.7%) was obtained after separation and purification by chromatographic column. LC-MS: m/z 607.23[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ6.16(s,1H),5.09(s,1H),4.73–4.63(m,2H), 4.12(dd, J=19.4, 4.3Hz, 3H), 4.10–4.01(m, 1H), 4.02(s, 1H), 3.86(d, J=3.2Hz, 1H), 3.53(dd, J=20.9, 4.3Hz, 2H), 2.90–2.59(m, 3H), 2.43(s, 1H), 2.34(d, J＝17.9Hz, 1H), 2.20(dt, J＝14.8, 5.9Hz, 1H), 1.91( ddd, J＝14.0, 10.3, 6.3Hz, 2H), 1.59 (dd, J＝12.4, 5.2Hz, 1H), 1.37 (d, J＝6.5Hz, 3H), 1.30–1.18 (m, 1H), 1.09 (d,J=16.9Hz,1H),1.07(s,3H),0.97(d,J=7.0Hz,3H),0.86(d,J=6.8Hz,3H).
实例12：化合物WB005的合成
Example 12: Synthesis of compound WB005
向反应瓶中加入雷公藤甲素(300mg,0.832mmol)、10ml四氢呋喃和10ml氢氧化钠溶液(1mol/L)，混合液室温搅拌反应8h。反应结束后，反应液用硫酸氢钠溶液调节pH至中性，溶液用DCM萃取3次，分去水相，有机层用无水硫酸钠干燥，过滤，浓缩。残留物经柱层析纯化，用CH2Cl2/MeOH(20:1)洗脱，收集组分，蒸干，得产物240mg。固体再用5ml无水乙醇结晶，得到200mg，收率63.49％。LC-MS:m/z 361.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ5.67(s,1H),4.93–4.75(m,2H),4.23(s,1H),3.68(d,J＝6.1Hz,1H),3.40(d,J＝2.0Hz,1H),2.86–2.77(m,1H),2.56(s,1H),2.34–2.18(m,2H),2.19–2.08(m,1H),2.02–1.81(m,2H),1.37–1.27(m,1H),1.27–1.11(m,1H),0.96(d,J＝6.9Hz,3H),0.88(s,3H),0.71(d,J＝6.9Hz,3H). Add triptolide (300mg, 0.832mmol), 10ml tetrahydrofuran and 10ml sodium hydroxide solution (1mol/L) into the reaction flask, and stir the mixture at room temperature for 8h. After the reaction, the pH of the reaction solution was adjusted to neutral with sodium bisulfate solution, the solution was extracted three times with DCM, the water phase was separated, the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with CH 2 Cl 2 /MeOH (20:1), and the fractions were collected and evaporated to dryness to obtain 240 mg of the product. The solid was then crystallized with 5 ml of absolute ethanol to obtain 200 mg with a yield of 63.49%. LC-MS: m/z 361.2[M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δ5.67(s,1H),4.93–4.75(m,2H),4.23(s,1H) ,3.68(d,J=6.1Hz,1H),3.40(d,J=2.0Hz,1H),2.86–2.77(m,1H),2.56(s,1H),2.34–2.18(m,2H), 2.19–2.08(m,1H),2.02–1.81(m,2H),1.37–1.27(m,1H),1.27–1.11(m,1H),0.96(d,J＝6.9Hz,3H),0.88( s,3H),0.71(d,J=6.9Hz,3H).
实例13：化合物WBC225的合成
Example 13: Synthesis of compound WBC225
向反应瓶中加入，雷公藤甲素(40mg，0.111mmol)，叠氮化钠(39mg，0.555mmol)，氯化铵(28mg，0.561mmol)和4ml甲醇，升温至55℃反应48h。反应液蒸干，用EA和水分层，蒸干，过柱。干法上样，依次用DCM/MeOH＝100:1冲柱，收集产品，蒸干，得33mg，收率73.69％。LC-MS:m/z 404.1[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.72(qt,J＝3.4,1.7Hz,2H),3.99(d,J＝5.3Hz,1H),3.80(d,J＝4.9Hz,1H),3.42(d,J＝6.0Hz,1H),3.10(d,J＝10.0Hz,1H),2.80–2.70(m,1H),2.65–2.49(m,2H),2.45–2.34(m,2H),2.29–2.10(m,2H),2.06(d＝14.3Hz,1H),1.73-1.65(m,2H),1.16(s,3H),1.00(d,J＝7.0Hz,3H),0.91(d,J＝7.0Hz,3H)。Add triptolide (40mg, 0.111mmol), sodium azide (39mg, 0.555mmol), ammonium chloride (28mg, 0.561mmol) and 4ml methanol into the reaction flask, heat up to 55°C for 48h. The reaction solution was evaporated to dryness, layered with EA and water, evaporated to dryness, and passed through the column. Load the sample by dry method, wash the column with DCM/MeOH=100:1 successively, collect the product, and evaporate to dryness to obtain 33 mg, with a yield of 73.69%. LC-MS: m/z 404.1[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ4.72(qt, J=3.4, 1.7Hz, 2H), 3.99(d, J=5.3Hz, 1H), 3.80(d, J=4.9Hz, 1H), 3.42(d, J=6.0Hz, 1H), 3.10(d, J=10.0Hz, 1H), 2.80–2.70(m, 1H), 2.65– 2.49(m,2H),2.45–2.34(m,2H),2.29–2.10(m,2H),2.06(d=14.3Hz,1H),1.73-1.65(m,2H),1.16(s,3H) , 1.00 (d, J=7.0Hz, 3H), 0.91 (d, J=7.0Hz, 3H).
实例14：化合物WBC227的合成
Example 14: Synthesis of compound WBC227
在反应瓶中加入，雷公藤甲素(40mg，0.111mmol)，4ml甲醇和0.5ml30％的甲胺甲醇溶液，40℃反应24h。反应液蒸干，用DCM溶解，直接湿法上柱，用DCM/MeOH/TEA＝100:2:0.25冲洗，收集产品，蒸干，得到产物36mg，收率82.44％。LC-MS:m/z 392.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.70(s,2H),3.94(d,J＝3.5Hz,1H),3.82(d,J＝5.3Hz,1H),3.67(s,1H),3.45–3.36(m,1H),3.18–3.07(m,1H),2.88–2.72(m,1H),2.61–2.53(m,5H),2.52–2.32(m,2H),2.28-2.21(m,2H),2.03(d,J＝7.8Hz,1H),1.73-1.65(m,2H),1.19–1.09(m,3H),1.06–0.96(m,6H)。Add triptolide (40mg, 0.111mmol), 4ml of methanol and 0.5ml of 30% methanol solution of methylamine into the reaction flask, and react at 40°C for 24h. The reaction solution was evaporated to dryness, dissolved in DCM, directly applied to the column by wet method, rinsed with DCM/MeOH/TEA=100:2:0.25, the product was collected, evaporated to dryness, and 36 mg of the product was obtained with a yield of 82.44%. LC-MS: m/z 392.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.70(s,2H),3.94(d,J＝3.5Hz,1H),3.82(d,J ＝5.3Hz,1H),3.67(s,1H),3.45–3.36(m,1H),3.18–3.07(m,1H),2.88–2.72(m,1H),2.61–2.53(m,5H), 2.52–2.32(m,2H),2.28-2.21(m,2H),2.03(d,J＝7.8Hz,1H),1.73-1.65(m,2H),1.19–1.09(m,3H),1.06– 0.96(m,6H).
实例15：化合物WBC228的合成
Example 15: Synthesis of compound WBC228
在反应瓶中加入，雷公藤甲素(40mg，0.111mmol)，盐酸羟胺(88mg，1.27mmol)，4ml甲醇和三乙胺(89mg，0.879mmol)，升到60℃反应48h。反应液蒸干，用DCM溶解，直接湿法上柱，用DCM/MeOH/TEA＝100:2:0.25冲洗，收集产品，蒸干，得到产物16mg，收率36.64％。LC-MS:m/z 394.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.71(s,2H),3.97(d,J＝5.0Hz,1H),3.63(d,J＝5.1Hz,1H),3.46(d,J＝6.1Hz,1H),3.31(s,1H),2.80(d,J＝13.5Hz,1H),2.43–2.31(m,2H),2.31–2.00(m,3H),1.78–1.54(m,4H),1.12(s,3H),1.05(d,J＝6.9Hz,3H),0.89(d,J＝6.5Hz,3H)。Add triptolide (40mg, 0.111mmol), hydroxylamine hydrochloride (88mg, 1.27mmol), 4ml methanol and triethylamine (89mg, 0.879mmol) into the reaction flask, rise to 60°C for 48h. The reaction solution was evaporated to dryness, dissolved in DCM, directly applied to the column by wet method, rinsed with DCM/MeOH/TEA=100:2:0.25, the product was collected, evaporated to dryness, and 16 mg of the product was obtained with a yield of 36.64%. LC-MS: m/z 394.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.71(s,2H),3.97(d,J＝5.0Hz,1H),3.63(d,J =5.1Hz,1H),3.46(d,J=6.1Hz,1H),3.31(s,1H),2.80(d,J=13.5Hz,1H),2.43–2.31(m,2H),2.31–2.00 (m, 3H), 1.78–1.54 (m, 4H), 1.12 (s, 3H), 1.05 (d, J=6.9Hz, 3H), 0.89 (d, J=6.5Hz, 3H).
实例16：化合物WBC229的合成
Example 16: Synthesis of compound WBC229
在反应瓶中加入，雷公藤甲素(40mg，0.111mmol)，4ml甲醇和50％水合肼(240mg，2.197mmol)，升温至40℃反应30h。反应液蒸干，过柱，用DCM/MeOH/TEA＝100:2:0.5冲柱，收集产品，蒸干，得26mg，收率59.69％。LC-MS:m/z 393.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.72(t,J＝15.0Hz,2H),3.94–3.83(m,1H),3.72(d,J＝7.0Hz,1H),3.59(d,J＝7.4Hz,1H),3.53–3.38(m,1H),3.36–3.25(m,1H),2.82-2.71(m,1H),2.47–2.03(m,3H),2.01-1.93(m,3H),1.61(dd,J＝12.5,5.6Hz,1H),1.49(t,J＝7.2Hz,1H),1.15–0.98(m,6H),0.93–0.85(m,3H)。Add triptolide (40mg, 0.111mmol), 4ml methanol and 50% hydrazine hydrate (240mg, 2.197mmol) into the reaction flask, heat up to 40°C for 30h. The reaction solution was evaporated to dryness, passed through the column, and washed with DCM/MeOH/TEA=100:2:0.5 to collect the product and evaporated to dryness to obtain 26 mg, with a yield of 59.69%. LC-MS: m/z 393.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.72(t,J＝15.0Hz,2H),3.94–3.83(m,1H),3.72(d ,J=7.0Hz,1H),3.59(d,J=7.4Hz,1H),3.53–3.38(m,1H),3.36–3.25(m,1H),2.82-2.71(m,1H),2.47– 2.03(m,3H),2.01-1.93(m,3H),1.61(dd,J=12.5,5.6Hz,1H),1.49(t,J=7.2Hz,1H),1.15–0.98(m,6H) ,0.93–0.85(m,3H).
实例17：化合物WBC230的合成
Example 17: Synthesis of Compound WBC230
在反应瓶中加入，雷公藤甲素(82.5mg，0.229mmol)，1ml吡啶和4-二甲氨基吡啶(9mg，0.074mmol)，搅拌溶解，室温滴加酸酐(206mg，2.02mmol)室温反应2h。反应结束，反应液蒸干，加入乙酸乙酯溶解，用水洗涤3次，有机层无水硫酸钠干燥，蒸干，得TPL-Ac 90mg，收率97.83％。 Add triptolide (82.5mg, 0.229mmol), 1ml pyridine and 4-dimethylaminopyridine (9mg, 0.074mmol) into the reaction flask, stir to dissolve, add acid anhydride (206mg, 2.02mmol) dropwise at room temperature and react for 2h at room temperature . After the reaction was completed, the reaction liquid was evaporated to dryness, dissolved in ethyl acetate, washed with water three times, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 90 mg of TPL-Ac with a yield of 97.83%.
在反应瓶中加入TPL-Ac(50mg，0.124mmol)，叠氮化钠(44mg，0.6576mmol)氯化铵(37mg，0.691mmol)和4ml甲醇，搅拌升到60℃反应48h。反应结束，反应液蒸干，用DCM和水分层，有机层用无水硫酸钠干燥，蒸干，得固体(55mg，0.123mmol)。固体用1ml乙腈溶解，加入三苯基磷(35mg，0.133mmol)，氮气保护，升温80℃反应4h。反应结束，反应液蒸干，DCM/MeOH/TEA＝100:2:0.5冲柱，收集产品，蒸干，得26mg，收率52.23％。LC-MS:m/z 402.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.76–4.65(m,3H),3.75(d,J＝5.6Hz,1H),3.51(d,J＝6.0Hz,1H),3.23–3.16(m,1H),2.77(d,J＝13.5Hz,1H),2.39-2.30(m,1H),2.28-2.13(m,3H),2.15(s,3H),2.03–1.91(m,1H),1.68-1.57(m,2H),1.07(s,3H),1.00(d,J＝6.8Hz,3H),0.90(d,J＝7.0Hz,3H)。Add TPL-Ac (50mg, 0.124mmol), sodium azide (44mg, 0.6576mmol), ammonium chloride (37mg, 0.691mmol) and 4ml methanol into the reaction flask, stir and raise to 60°C for 48h. After the reaction was completed, the reaction solution was evaporated to dryness, separated with DCM and water, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a solid (55 mg, 0.123 mmol). The solid was dissolved in 1ml of acetonitrile, triphenylphosphine (35mg, 0.133mmol) was added, under nitrogen protection, the temperature was raised to 80°C for 4h. After the reaction was completed, the reaction liquid was evaporated to dryness, DCM/MeOH/TEA=100:2:0.5 was washed into the column, and the product was collected and evaporated to dryness to obtain 26 mg, with a yield of 52.23%. LC-MS: m/z 402.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.76–4.65(m,3H),3.75(d,J＝5.6Hz,1H),3.51(d ,J=6.0Hz,1H),3.23–3.16(m,1H),2.77(d,J=13.5Hz,1H),2.39-2.30(m,1H),2.28-2.13(m,3H),2.15( s,3H),2.03–1.91(m,1H),1.68-1.57(m,2H),1.07(s,3H),1.00(d,J＝6.8Hz,3H),0.90(d,J＝7.0Hz ,3H).
实例18：化合物WBC231的合成
Example 18: Synthesis of Compound WBC231
在反应瓶中加入生物素(145mg，0.593mmol)，4-二甲氨基吡啶(38mg，0.245mmol)和4mlDMF，搅拌，固体不溶解，降至0-5度，依次加入雷公藤甲素(100mg，0.277mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(120mg，0.626mmol)，升至室温反应过夜。反应结束，反应液用EA稀释，5％碳酸氢钠溶液洗涤3次，5％硫酸氢钠溶液洗涤1次，盐水洗涤1次，无水硫酸钠干燥，蒸干，得固体176mg。固体用乙腈22.5ml和水2.5ml溶解，加入三氟乙酸0.4ml，升至80℃反应48h。反应结束，反应液用DCM稀释，用水洗涤2次，盐水洗涤1次，无水硫酸钠干燥，蒸干。残留物DCM/MeOH＝100:1→25:1冲洗，收集产品，得33mg，收率19.7％。LC-MS:m/z 605.3[M+H]+.1H NMR(400MHz,Chloroform-d)δ6.22(s,1H),6.02(d,J＝5.9Hz,1H),4.87(s,1H),4.78(d,J＝23.6Hz,2H),4.68(d,J＝17.5Hz,1H),4.56(dd,J＝7.8,4.8Hz,1H),4.37(d,J＝5.7Hz,1H),4.29(ddd,J＝7.4,4.7,1.8Hz,1H),3.62–3.48(m,2H),3.18–3.06(m,2H),2.94(dd,J＝13.0,4.8Hz,1H),2.81(d,J＝13.7Hz,1H),2.75(d,J＝12.9Hz,1H),2.57(ddd,J＝16.2,10.3,3.0Hz,1H),2.46(ddd,J＝16.2,7.4,3.3Hz,1H),2.37(dd,J＝14.2,7.0Hz,2H),2.22(dt,J＝14.9,5.9Hz,2H),2.07–1.87(m,2H),1.78–1.58(m,4H),1.43(dt,J＝13.5,6.7Hz,2H),1.14(d,J＝7.0Hz,3H),1.09(d,J＝7.1Hz,3H),1.05(s,3H)。 Add biotin (145mg, 0.593mmol), 4-dimethylaminopyridine (38mg, 0.245mmol) and 4mlDMF in the reaction flask, stir, the solid does not dissolve, drop to 0-5 degree, add triptolide (100mg , 0.277mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120mg, 0.626mmol), raised to room temperature and reacted overnight. After the reaction was completed, the reaction solution was diluted with EA, washed three times with 5% sodium bicarbonate solution, once with 5% sodium bisulfate solution, once with brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 176 mg of solid. The solid was dissolved in 22.5ml of acetonitrile and 2.5ml of water, 0.4ml of trifluoroacetic acid was added, and the temperature was raised to 80°C for 48h. After the reaction was completed, the reaction solution was diluted with DCM, washed twice with water and once with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was rinsed with DCM/MeOH=100:1→25:1, and the product was collected to obtain 33 mg with a yield of 19.7%. LC-MS: m/z 605.3[M+H]+.1H NMR(400MHz,Chloroform-d)δ6.22(s,1H),6.02(d,J＝5.9Hz,1H),4.87(s,1H ),4.78(d,J=23.6Hz,2H),4.68(d,J=17.5Hz,1H),4.56(dd,J=7.8,4.8Hz,1H),4.37(d,J=5.7Hz,1H ),4.29(ddd,J＝7.4,4.7,1.8Hz,1H),3.62–3.48(m,2H),3.18–3.06(m,2H),2.94(dd,J＝13.0,4.8Hz,1H), 2.81(d, J=13.7Hz, 1H), 2.75(d, J=12.9Hz, 1H), 2.57(ddd, J=16.2, 10.3, 3.0Hz, 1H), 2.46(ddd, J=16.2, 7.4, 3.3Hz, 1H), 2.37(dd, J＝14.2, 7.0Hz, 2H), 2.22(dt, J＝14.9, 5.9Hz, 2H), 2.07–1.87(m, 2H), 1.78–1.58(m, 4H ), 1.43 (dt, J=13.5, 6.7Hz, 2H), 1.14 (d, J=7.0Hz, 3H), 1.09 (d, J=7.1Hz, 3H), 1.05 (s, 3H).
实例19：化合物WBC264的合成
Example 19: Synthesis of Compound WBC264
在反应瓶中加入IMP-5(30mg，0.083mmol)，2mlDCM溶解，加入TEA(0.1ml，0.692mmol)，降至0-5℃，加入乙基磺酰氯(60mg，0.467mmol)，保温0-5℃搅拌反应1h。反应结束，用水淬灭，DCM萃取，无水硫酸钠干燥，蒸干，硅胶拌样，上柱，PE/EA＝2:1冲柱，收集产品，蒸干，得32mg，收率85％。LC-MS:m/z 453.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ5.42(dd,J＝2.1,0.9Hz,1H),4.81–4.64(m,2H),3.87(d,J＝2.1Hz,1H),3.54(d,J＝5.9Hz,1H),3.28(qd,J＝7.4,1.0Hz,2H),2.86–2.76(m,1H),2.65(d,J＝0.9Hz,1H),2.40–2.08(m,4H),2.05(dd,J＝14.8,13.5Hz,1H),1.56(d,J＝5.1Hz,2H),1.52(t,J＝7.5Hz,3H),1.12–1.06(m,6H),0.80(d,J＝6.9Hz,3H)。Add IMP-5 (30mg, 0.083mmol) to the reaction flask, dissolve in 2ml DCM, add TEA (0.1ml, 0.692mmol), lower to 0-5°C, add ethylsulfonyl chloride (60mg, 0.467mmol), and keep warm for 0- The reaction was stirred at 5°C for 1h. After the reaction was completed, it was quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, evaporated to dryness, mixed with silica gel, applied to the column, PE/EA = 2:1, collected the product, and evaporated to dryness to obtain 32 mg, with a yield of 85%. LC-MS: m/z 453.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ5.42(dd,J＝2.1,0.9Hz,1H),4.81–4.64(m,2H),3.87 (d,J=2.1Hz,1H),3.54(d,J=5.9Hz,1H),3.28(qd,J=7.4,1.0Hz,2H),2.86–2.76(m,1H),2.65(d, J＝0.9Hz, 1H), 2.40–2.08(m, 4H), 2.05(dd, J＝14.8, 13.5Hz, 1H), 1.56(d, J＝5.1Hz, 2H), 1.52(t, J＝7.5 Hz, 3H), 1.12–1.06 (m, 6H), 0.80 (d, J=6.9Hz, 3H).
实例20：化合物WBC266的合成
Example 20: Synthesis of compound WBC266
在反应瓶中加入WBC213(160mg，0.447mmol)，8mL乙腈溶解，加入8mL水和1.6mL TFA，85℃反应24h。停止反应，减压蒸去乙腈，加DCM溶解，水洗分层，有机层再用饱和氯化钠溶液洗涤，无水硫酸钠干燥，蒸干，硅胶拌样，上柱，DCM/MeOH＝500:1冲柱，收集产品，蒸干，得到22mgWBC266，收率：11％。LC-MS:m/z377.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ4.80(dtd,J＝17.3,2.9,1.6Hz,1H),4.70(dddd,J＝9.4,8.0,3.4,1.6Hz,2H),4.09–3.98(m,3H),3.81(q,J＝3.0Hz,1H),3.32–3.23(m,1H),2.53(p,J＝6.9Hz,1H),2.47–2.37(m,1H),2.32–2.17(m,2H),1.74(dt,J＝13.5,3.1Hz,1H),1.64(ddd,J＝12.3,6.2,1.4Hz,1H),1.50–1.37(m,1H),1.18(d,J＝0.8Hz,3H),0.99(t,J＝7.1Hz,6H)。 Add WBC213 (160mg, 0.447mmol) into the reaction flask, dissolve in 8mL acetonitrile, add 8mL water and 1.6mL TFA, and react at 85°C for 24h. Stop the reaction, evaporate acetonitrile under reduced pressure, add DCM to dissolve, wash the layers with water, wash the organic layer with saturated sodium chloride solution, dry over anhydrous sodium sulfate, evaporate to dryness, mix the sample with silica gel, put on the column, DCM/MeOH=500: 1 Punch the column, collect the product, and evaporate to dryness to obtain 22 mg of WBC266, yield: 11%. LC-MS: m/z377.2[M+H]+.1H NMR (400MHz, Chloroform-d) δ4.80 (dtd, J=17.3, 2.9, 1.6Hz, 1H), 4.70 (dddd, J=9.4 ,8.0,3.4,1.6Hz,2H),4.09–3.98(m,3H),3.81(q,J＝3.0Hz,1H),3.32–3.23(m,1H),2.53(p,J＝6.9Hz, 1H),2.47–2.37(m,1H),2.32–2.17(m,2H),1.74(dt,J＝13.5,3.1Hz,1H),1.64(ddd,J＝12.3,6.2,1.4Hz,1H) , 1.50–1.37 (m, 1H), 1.18 (d, J=0.8Hz, 3H), 0.99 (t, J=7.1Hz, 6H).
表1本发明化合物部分数据
Table 1 Partial data of compounds of the present invention
实施例21：本发明的化合物体外抗MYC阳性肿瘤细胞和免疫细胞的活性测定Example 21: Determination of the Anti-MYC Positive Tumor Cells and Immune Cell Activity of Compounds of the Invention in Vitro
(1)实验材料(1) Experimental materials
MYC阳性肿瘤细胞株(购自中科院细胞库)：白血病细胞株：人Molm-13(急性髓系白血病)、THP-1(急性髓系白血病)、Kasumi-1(急性髓系白血病)；H9(急性淋巴细胞白血病，T淋巴细胞)和Jurkat(急性淋巴细胞白血病，T淋巴细胞)；RPMI-8228(骨髓瘤细胞，B淋巴细胞)和U266(骨髓瘤细胞，B淋巴细胞)；Mia-paca2(胰腺癌细胞)。 MYC-positive tumor cell lines (purchased from the Chinese Academy of Sciences Cell Bank): leukemia cell lines: human Molm-13 (acute myeloid leukemia), THP-1 (acute myeloid leukemia), Kasumi-1 (acute myeloid leukemia); H9 ( Acute lymphoblastic leukemia, T lymphocytes) and Jurkat (acute lymphoblastic leukemia, T lymphocytes); RPMI-8228 (myeloma cells, B lymphocytes) and U266 (myeloma cells, B lymphocytes); Mia-paca2 ( pancreatic cancer cells).
MYC低表达正常人细胞：HEK293(人胚肾细胞)和L02(正常肝细胞)Normal human cells with low expression of MYC: HEK293 (human embryonic kidney cells) and L02 (normal liver cells)
主要试剂：本发明化合物。主要仪器：CO2细胞培养箱(Heraeus，德国)，酶标仪(Bio-Rad，美国)Main reagents: compounds of the present invention. Main instruments: CO2 cell incubator (Heraeus, Germany), microplate reader (Bio-Rad, USA)
(2)实验方法(2) Experimental method
取生长良好的细胞，接种到96孔细胞培养板孔内，每孔5000个。培养液为含10％胎牛血清的1640细胞培养液。24小时后加入不同浓度的化合物(0-1000nM)，混匀后，置于二氧化碳(5％CO2)细胞培养箱37℃培养72小时。然后用MTT法测定细胞活力。在本实验中对照组(不加化合物处理)细胞活力设为100％，并计算出化合物作用后细胞活力(％)和72小时细胞半数生长抑制浓度(72小时IC50值)。Well-grown cells were taken and inoculated into the wells of a 96-well cell culture plate, 5000 per well. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. After 24 hours, different concentrations of compounds (0-1000 nM) were added, mixed evenly, and placed in a carbon dioxide (5% CO 2 ) cell incubator at 37° C. for 72 hours. Cell viability was then determined by the MTT assay. In this experiment, the cell viability of the control group (without compound treatment) was set as 100%, and the cell viability (%) and the 72-hour half-inhibitory concentration of the cells (72-hour IC 50 value) were calculated after the compound was acted on.
(3)实验结果(3) Experimental results
实验结果见表2。本发明的化合物WBC100-M11、WBC204、WBC208、WBC209、WBC210、WBC211、WBC212、WBC213、WB005、WBC220、WBC221、WBC222、WBC223、WBC264、WBC266能选择性杀伤MYC阳性各种肿瘤细胞以及MYC阳性B淋巴细胞和T淋巴细胞等免疫细胞，而对MYC低表达正常细胞杀伤作用明显低于MYC阳性肿瘤和T与B免疫细胞。 The experimental results are shown in Table 2. Compounds WBC100-M11, WBC204, WBC208, WBC209, WBC210, WBC211, WBC212, WBC213, WB005, WBC220, WBC221, WBC222, WBC223, WBC264, WBC266 of the present invention can selectively kill various MYC-positive tumor cells and MYC-positive B lymphocytes Cells and T lymphocytes and other immune cells, while the killing effect on normal cells with low expression of MYC was significantly lower than that of MYC-positive tumors and T and B immune cells.
表2化合物与细胞作用72小时50％细胞生长抑制浓度(IC50，nM,72h)


50% cell growth inhibitory concentration (IC50, nM, 72h) of the compound in Table 2 acting on cells for 72 hours


实施例22：本发明化合物WBC213、WBC220、WBC223、WB005和WBC266选择性抑制MYC蛋白实验Example 22: Compounds WBC213, WBC220, WBC223, WB005 and WBC266 of the present invention selectively inhibit MYC protein experiment
本发明应用细胞培养技术和免疫印迹技术检测WBC213、WBC220、WBC223、WB005和WBC266对MYC高表达细胞MYC蛋白影响。The present invention uses cell culture technology and immunoblotting technology to detect the influence of WBC213, WBC220, WBC223, WB005 and WBC266 on the MYC protein of cells with high MYC expression.
(1)实验材料(1) Experimental materials
MYC高表达白血病细胞株：Molm-13(人急性髓系白血病)。MYC highly expressed leukemia cell line: Molm-13 (human acute myeloid leukemia).
试剂：化合物WBC213、WBC220、WBC223、WB005和WBC266Reagents: Compounds WBC213, WBC220, WBC223, WB005 and WBC266
(2)实验方法(2) Experimental method
取生长良好的白血病细胞接种到6孔细胞培养板孔内，密度为1×106/ml。培养液为含10％胎牛血清的1640细胞培养液。加入不同浓度的WBC213、WBC220、WBC223、WB005和WBC266化合物，混匀后，置于二氧化碳(5％CO2)细胞培养箱37℃培养48小时。然后提取细胞蛋白，用免疫印迹检测MYC蛋白及XPB和p53蛋白表达水平。Well-grown leukemia cells were inoculated into wells of a 6-well cell culture plate at a density of 1×10 6 /ml. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Add different concentrations of WBC213, WBC220, WBC223, WB005 and WBC266 compounds, mix well, and place in a carbon dioxide (5% CO 2 ) cell incubator at 37° C. for 48 hours. Then the cell protein was extracted, and the expression levels of MYC protein, XPB and p53 protein were detected by immunoblotting.
(3)实验结果(3) Experimental results
实验结果见下图1。本发明化合物WBC213呈剂量依赖方式下调肿瘤细胞MYC蛋白水平。20nM浓度WBC213即可见明显下调肿瘤细胞Molm-13MYC水平，而对细胞核蛋白XPB没有明显影响。WBC213对细胞核蛋白p53则呈剂量依赖方式上调(图1a)。相类似，WBC220、WB005、WBC223和WBC266也呈剂量依赖方式下调肿瘤细胞MYC蛋白水平(图1b、c、d和e)。这一结果表明，本发明化合物能靶向抑制细胞MYC蛋白，可用于MYC异常高表达相关疾病。 The experimental results are shown in Figure 1 below. The compound WBC213 of the present invention down-regulates the MYC protein level of tumor cells in a dose-dependent manner. WBC213 at a concentration of 20nM can significantly down-regulate the level of Molm-13MYC in tumor cells, but has no significant effect on the nuclear protein XPB. WBC213 up-regulated the nuclear protein p53 in a dose-dependent manner (Fig. 1a). Similarly, WBC220, WB005, WBC223 and WBC266 also down-regulated MYC protein levels in tumor cells in a dose-dependent manner (Fig. 1b, c, d and e). This result shows that the compound of the present invention can target and inhibit cell MYC protein, and can be used for diseases related to abnormal high expression of MYC.

Claims (22)

  1. 由结构式(I)表示的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药∶
    A compound represented by structural formula (I), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
    其中：in:
    R1独立地选自羟基、羰基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。R 1 is independently selected from hydroxyl, carbonyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, -O(C=O)(C 1 -C 6 alkyl) R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 alkyl)(C= O)OR', -O(C=O)R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne radical, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino) , -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 Alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic), -C 0 -C 5 alkyl (3-12 membered heterocyclic), -C 0 -C 5 alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 Heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkyl -O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl(C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, Alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino , carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
  2. 根据权利要求1所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(I)的化合物为结构式(I-1)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 1, or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (I) It is a compound of structural formula (I-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane group, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  3. 根据权利要求1所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(I)的化合物为结构式(I-2)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 1, or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (I) It is a compound of structural formula (I-2), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q, at each occurrence thereof, is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 - C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aryl) , -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 - C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 - C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, Heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  4. 根据权利要求1所述的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(I)的化合物为结构式(I-3)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 1, or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (I) It is a compound of structural formula (I-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、-C1-C6烷基氨基；W at each occurrence thereof is independently selected from hydrogen, hydroxyl, amino, mercapto, aminoC 1 -C 6 alkyl, -C 1 -C 6 alkylamino;
    Q在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q, at each occurrence thereof, is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 - C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aryl) , -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 - C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 - C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, Heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  5. 由结构式(II)表示的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药∶
    A compound represented by structural formula (II), or a derivative thereof, a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug:
    其中：in:
    R1在其每一次出现时独立地选自羟基、羰基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、、-O(C＝O)(C1-C6烷基)R’、-O(C＝O)(C1-C6烷基)(C＝O)R’、-O(C＝O)(C1-C6烷基)(C＝O)OR’、-O(C＝O)R’，其中R’在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。R 1 at each occurrence thereof is independently selected from hydroxyl, carbonyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, -O(C=O )(C 1 -C 6 alkyl) R', -O(C=O)(C 1 -C 6 alkyl)(C=O)R', -O(C=O)(C 1 -C 6 Alkyl)(C=O)OR', -O(C=O)R', wherein R' at each occurrence thereof is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 - C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkane Base (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), Wherein said alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro group, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
    R2在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、氨基C1-C6烷基、C1-C6烷基氨基、-OC(O)OR11、-OC(O)R11、-SO2R11、-OSO2R11、-SO2NR11R12、-S(O)R11,-S(O)NR11R12，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基，R12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基； R2 at each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, R 12 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxy, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl , C 1 -C 6 Haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl;
    R3在其每一次出现时独立地选自羟基、硝基、氰基、氨基、巯基、叠氮基、-NH-OH、-NH-NH2、-SCN、S(O)NH2、S(O)2NH2、氨基C1-C6烷基、C1-C6烷基氨基、-OC(O)OR11、-OC(O)R11、-SO2R11、-OSO2R11、-SO2NR11R12、-S(O)R11,-S(O)NR11R12，其中R11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基，R12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烷酰基、C2-C6烷基酯、C1-C6烷硫基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基C1-C6烷基、氨基C1-C6烷基； R3 in each occurrence thereof is independently selected from hydroxyl, nitro, cyano, amino, mercapto, azido, -NH-OH, -NH- NH2 , -SCN, S(O) NH2 , S (O) 2 NH 2 , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, -OC(O)OR 11 , -OC(O)R 11 , -SO 2 R 11 , -OSO 2 R 11 , -SO 2 NR 11 R 12 , -S(O ) R 11 , -S(O ) NR 11 R 12 , wherein R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxyl , nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, R 12 at each occurrence thereof is independently selected from nonexistent, hydrogen, halogen, hydroxy, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl , C 1 -C 6 Haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl;
    或者，R2和R3连同所连接的碳原子一起连接形成且具有5-14环原子的单环、双环或三环的饱和或不饱和环系统，所述环原子中的0、1、2、3或4个是选自N、O、S的杂原子、其余为碳原子，并且所述环系统任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代；Alternatively, R2 and R3 are connected together with the attached carbon atoms to form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system with 5-14 ring atoms, 0, 1, 2 of the ring atoms , 3 or 4 are heteroatoms selected from N, O, S, the rest are carbon atoms, and the ring system is optionally replaced by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino , carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted;
    或者，R1和R2连同所连接的碳原子一起连接形成3-18元杂环基；Alternatively, R 1 and R 2 are connected together with the attached carbon atoms to form a 3-18 membered heterocyclic group;
    或者，R2和R3连同所连接的碳原子一起连接形成3-18元杂环基。Alternatively, R2 and R3 , together with the carbon atoms to which they are attached, are joined to form a 3-18 membered heterocyclyl.
  6. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-1)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-1), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
  7. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂 化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-2)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    Compound according to claim 5/or derivatives thereof, pharmaceutically acceptable salts, isomers, solvents compounds, hydrates, adducts, complexes or prodrugs, wherein the compound of structural formula (II) is a compound of structural formula (II-2) or its derivatives, pharmaceutically acceptable salts, isomers, Solvates, Hydrates, Adducts, Complexes or Prodrugs:
  8. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-3)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-3), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5 烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 Alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -C 0 -C 5 alkane Base (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl -O-(3-12 membered heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkane Alkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH , amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
  9. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-4)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-4), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂 芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered hetero aryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substituted.
  10. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-5)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-5), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。 Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane group, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  11. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-6)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-6), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl ( C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl , heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl , C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  12. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-7)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-7), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(3-12元杂环基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(5-10元杂芳基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q, at each occurrence thereof, is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -C 0 -C 5 alkyl (5-10 membered heteroaryl) , -C 0 -C 5 alkyl (C 6 -C 12 aryl), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (C 3 - C 12 heterocyclic group), -OC 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl-O-(3-12 membered heterocyclic group), -C 0 - C 5 alkyl-(C=O)O-(3-12 membered heterocyclyl), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkyl, Heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  13. 根据权利要求5所述的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述结构式(II)的化合物为结构式(II-8)的化合物、或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药：
    The compound according to claim 5/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound of structural formula (II) It is a compound of structural formula (II-8), or a derivative thereof, a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, an adduct, a complex or a prodrug:
    其中：in:
    W在其每一次出现时独立地选自氢、羟基、氨基、巯基、氨基C1-C6烷基、C1-C6烷基氨基；W is independently selected from hydrogen, hydroxy, amino, mercapto, amino C 1 -C 6 alkyl, C 1 -C 6 alkylamino at each occurrence thereof;
    Q在其每一次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、羟基C1-C6烷基、氨基C1-C6烷基、C0-C5烷基(单-或二-C1-C6烷基氨基)、-O-C0-C5烷基(单-或二-C1-C6烷基氨基)、-C0-C5烷基(C3-C7环烷基)、-O-C0-C5烷基(C3-C7环烷基)、-C0-C5烷基(C3-C12杂环基)、-C0-C5烷基(3-12元杂环基)、-C0-C5烷基(C6-C12芳基)、-C0-C5烷基(C5-C10杂芳基)、-C0-C5烷基(5-10元杂芳基)、-O-C0-C5烷基(C3-C12杂环基)、-O-C0-C5烷基(3-12元杂环基)、-C0-C5烷基-O-(3-12元杂环基)、-C0-C5烷基-(C＝O)O-(3-12元杂环基)、-O-C0-C5烷基(C6-C12芳基)、-O-C0-C5烷基(C5-C10杂芳基)、-O-C0-C5烷基(5-10元杂芳基)，其中所述烷基、烯基、炔基、卤代烷基、烷基氨基、环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、羰基、巯基、-COOH、氨基C1-C6烷基、C1-C6烷基氨基、或C1-C6烷基取代。Q at each occurrence thereof is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, C 0 -C 5 alkyl (mono- or di-C 1 -C 6 alkylamino), -OC 0 -C 5 alkyl (mono- or di- C 1 -C 6 alkylamino), -C 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 5 alkyl (C 3 -C 7 cycloalkyl), -C 0 -C 5 alkyl (C 3 -C 12 heterocyclic group), -C 0 -C 5 alkyl (3-12 membered heterocyclic group), -C 0 -C 5 alkyl (C 6 -C 12 aromatic base), -C 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -C 0 -C 5 alkyl (5-10 membered heteroaryl), -OC 0 -C 5 alkyl (C 3 -C 12 heterocyclyl), -OC 0 -C 5 alkyl (3-12 member heterocyclyl), -C 0 -C 5 alkyl-O-(3-12 member heterocyclyl), -C 0 -C 5 alkyl-(C=O)O-(3-12 membered heterocyclic group), -OC 0 -C 5 alkyl (C 6 -C 12 aryl), -OC 0 -C 5 alkyl (C 5 -C 10 heteroaryl), -OC 0 -C 5 alkyl (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylamino, cycloalkane radical, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, carbonyl, mercapto, -COOH, amino C 1 -C 6 alkane group, C 1 -C 6 alkylamino, or C 1 -C 6 alkyl substitution.
  14. 化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，其中所述化合物具有以下结构：

    The compound/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug, wherein the compound has the following structure:

  15. 一种药物组合物，其中包含权利要求1-14中任一项的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，和药学上可以接受的赋形剂。A pharmaceutical composition comprising the compound of any one of claims 1-14/or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or pro medicine, and pharmaceutically acceptable excipients.
  16. 权利要求1-14中任一项的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药在制备治疗增殖性疾病或自身免疫性疾病的药物中的用途。The compound of any one of claims 1-14 / or its derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug in the preparation of treatment of proliferative diseases or Use in medicine for autoimmune diseases.
  17. 一种治疗增殖性疾病或自身免疫性疾病的方法，包括给予需要治疗的患者治疗有效量的根据权利要求1-14中任一项的化合物/或其衍生物、药学上可接受的盐、异构体、 溶剂化物、水合物、加成物、复合物或前药。A method for treating a proliferative disease or an autoimmune disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound/or its derivative, pharmaceutically acceptable salt, iso Construct, Solvate, hydrate, adduct, complex or prodrug.
  18. 权利要求1-14中任一项的化合物/或其衍生物、药学上可接受的盐、异构体、溶剂化物、水合物、加成物、复合物或前药，用于治疗增殖性疾病或自身免疫性疾病。The compound of any one of claims 1-14/or derivatives thereof, pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes or prodrugs, for the treatment of proliferative diseases or autoimmune disease.
  19. 根据权利要求16、17或18的用途、方法或化合物，其中，所述增殖性疾病是肿瘤；优选实体瘤或血液肿瘤；更优选MYC阳性实体瘤或血液肿瘤。The use, method or compound according to claim 16, 17 or 18, wherein said proliferative disease is a tumor; preferably a solid tumor or a hematological tumor; more preferably a MYC positive solid tumor or a hematological tumor.
  20. 根据权利要求19的用途、方法或化合物，其中所述肿瘤是乳腺癌、结肠癌、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头颈癌、黑素瘤、结直肠癌、胃癌、鳞癌、肺癌，小细胞肺癌、非小细胞肺癌、睾丸癌、梅克尔细胞癌、胶质母细胞瘤、神经细胞瘤、多发性骨髓瘤、淋巴瘤(霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴T细胞瘤、淋巴B细胞瘤)、白血病(急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML))、肉瘤、宫颈癌，肝癌、甲状腺癌、大肠癌、食管癌、泌尿生殖道癌、胆管细胞癌、肺癌、直肠癌、骨肉瘤、神经胶质瘤、鼻咽癌、喉癌、黑色素瘤、人宫颈癌、脑瘤、中耳肿瘤；优选MYC阳性的。Use, method or compound according to claim 19, wherein said tumor is breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, Squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neurocytoma, multiple myeloma, lymphoma (Hodgkin lymphoma, non-Hodgkin Gold lymphoma, T-cell lymphoma, B-cell lymphoma), leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML)) , sarcoma, cervical cancer, liver cancer, thyroid cancer, colorectal cancer, esophageal cancer, genitourinary tract cancer, cholangiocarcinoma, lung cancer, rectal cancer, osteosarcoma, glioma, nasopharyngeal cancer, laryngeal cancer, melanoma, human Cervical cancer, brain tumor, middle ear tumor; preferably MYC positive.
  21. 根据权利要求16、17或18的用途、方法或化合物，其中，所述自身免疫性疾病是T细胞或B细胞等免疫细胞功能异常相关的自身免疫性疾病；优选MYC阳性的T细胞或B细胞等免疫细胞功能异常相关的自身免疫性疾病。The use, method or compound according to claim 16, 17 or 18, wherein the autoimmune disease is an autoimmune disease related to abnormal function of immune cells such as T cells or B cells; preferably MYC-positive T cells or B cells Autoimmune diseases related to abnormal immune cell function.
  22. 据权利要求21的用途、方法或化合物，其中，所述自身免疫性疾病是类风湿性关节炎、系统性红斑狼疮、银屑病、肾病；优选与MYC阳性T细胞或B细胞相关的类风湿性关节炎、系统性红斑狼疮、银屑病、肾病。 The use, method or compound according to claim 21, wherein said autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, psoriasis, nephropathy; preferably rheumatoid associated with MYC positive T cells or B cells Arthritis, systemic lupus erythematosus, psoriasis, kidney disease.
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