WO2024061357A1 - 三尖杉酯碱类衍生物及其药物组合物、制备方法和用途 - Google Patents

三尖杉酯碱类衍生物及其药物组合物、制备方法和用途 Download PDF

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WO2024061357A1
WO2024061357A1 PCT/CN2023/120776 CN2023120776W WO2024061357A1 WO 2024061357 A1 WO2024061357 A1 WO 2024061357A1 CN 2023120776 W CN2023120776 W CN 2023120776W WO 2024061357 A1 WO2024061357 A1 WO 2024061357A1
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group
alkyl
membered
compound
alkenyl
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PCT/CN2023/120776
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English (en)
French (fr)
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陈莉
郭远强
乔玲
齐明丽
张悦
赵莹
侯剑彤
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南开大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the invention relates to harringtonine derivatives and pharmaceutical compositions, preparation methods and uses thereof, and belongs to the field of pharmaceutical compounds.
  • Harringtonine alkaloids such as Harringtonine (HT), Homoharringtonine (HHT), Deoxyharringtonine (DHT) and Isoharringtonine Isoharringtonine (IHT) is a known anticancer drug.
  • homoharringtonine 2 was included in the Chinese Pharmacopoeia in 1990 for the clinical treatment of acute non-lymphocytic leukemia and has been in clinical use to this day.
  • the inventor's previously authorized Chinese patent ZL201510925650.1 has reported a class of harringtonine alkaloid compounds and their synthesis methods and uses. Some of the compounds in the examples have certain inhibitory activity against HL-60 human leukemia cells.
  • the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound:
  • R S is selected from (R N ) m -G-(CH 2 ) n - or (R Q ) m -G-(CH 2 ) n -:
  • each of R 6 , R 6′ and R 7 is the same or different and is independently selected from H, unsubstituted or optionally substituted with one, two or more R b : C 1-20 alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, C 1-20 alkyloxy, C 2-20 alkenyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy , 5-20 membered heteroaryloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, 3-20 membered heterocyclylthio, C 6-20- membered arylthio, 5-20-membered hetero
  • R Q represents H, halogen, -OH, -CN, the following groups that are unsubstituted or optionally substituted by one, two or more R c : C 1-20 alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, C 1-20 alkyloxy, C 2- 20 alkenyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy, 5-20 membered hetero Aryloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, 3-20 membered heterocyclyl Thio group, C 6-20 arylthio group, 5-20 membered heteroarylthio group,
  • G represents chemical bond, C 1-20 alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5 -20-membered heteroaryl; the condition is that when G is not a chemical bond, the positions of different groups connected to G can be separated by 1-10 atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms; for example, when G is a phenyl group, 1, 2, 3, 4 or 5 carbon atoms can be spaced between the positions of different groups substituted on G,
  • the different groups on G are ortho-substituted, meta-substituted and/or para-substituted, preferably meta- and/or para-substituted;
  • Each m is the same or different, and is independently selected from an integer above 1;
  • n is the same or different, and is independently selected from an integer above 1;
  • Each Y is the same or different and is independently selected from O, S or N, provided that when Y is selected from O or S, R 4 is not present;
  • R 1 and R 2 are the same or different, and are independently selected from H, C 1-6 alkyl or halogen;
  • R 3 is selected from R 8 , R 8 -O-, R 8 -S-;
  • R 5 is selected from H or C 1-6 alkyl
  • R 11' , R 12 and R 13 are the same or different, and are independently selected from the following groups: H, unsubstituted or optionally substituted by one, two or more R f : C 1-20 alkyl , C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl;
  • Each R 14 is the same or different, independently selected from C 1-20 alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl , C 6-20 aryl group, 5-20 membered heteroaryl group;
  • one, two or more carbon atoms of the C 3-20 cycloalkyl or 3-20 membered heterocyclic group may be optionally substituted with oxygen to form a carbonyl group.
  • G represents a chemical bond, C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl, such as chemical bond, C 1-8 alkyl, C 2-8 alkenyl, phenyl, naphthyl.
  • m represents an integer from 1 to 20, preferably an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • n represents an integer from 1 to 20, preferably an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • halogen represents F, Cl, Br or I.
  • Y is selected from O, N or S.
  • R 3 is selected from H, C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl , C 6-15 aryl, 5-15 membered heteroaryl, C 1-8 alkyl-O-, C 2-8 alkenyl-O-, C 3-15 cycloalkyl-O-, C 3- 15- cycloalkenyl-O-, 3-15-membered heterocyclyl-O-, C 6-15- aryl-O-, 5-15-membered heteroaryl-O-, C 1-8 alkyl-S-, C 2-8 alkenyl-S-, C 3-15 cycloalkyl-S-, C 3-15 cycloalkenyl-S-, 3-15 membered heterocyclyl-S-, C 6-15 aryl- S-, 5-15 membered heteroaryl-S-.
  • R 4 is absent or selected from H.
  • R N is selected from nitro, amino, or phenyl substituted by nitro or amino at the ortho, meta and/or para positions, wherein the amino group is unsubstituted or substituted by one or two or more selected from C 1-8 alkylcarbonyl, C 1-8 alkyloxycarbonyl, C 3-8 cycloalkylcarbonyl, C 3-8 cycloalkyloxycarbonyl, C 6-10 aryl Substituted by carbonyl group, C 6-10 aryloxycarbonyl group, C 2-8 alkenyl group.
  • R 10 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-8 membered heterocyclyl, C 6-10 aryl group, 5-10 membered heteroaryl group, NH 2 .
  • each R a and R b are the same or different and are independently selected from halogen, -OH, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R
  • the following groups substituted by d C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aromatic base, 5-15 membered heteroaryl, C 1-8 alkyloxy, C 2-8 alkenyloxy, C 3-15 cycloalkyloxy, C 3-15 cycloalkenyloxy, 3- 15-membered heterocyclyloxy group, C 6-15 aryloxy group, 5-15-membered heteroaryloxy group, C 1-8 alkylthio group, C 2-8 alkenylthio group, C 3-15 ring Alkylthio group, C 3-15 cycloalkenylthio group,
  • R 7 is selected from the following groups such as H, unsubstituted or optionally substituted by one, two or more Re : C 1-8 alkyl, C 3 - 8 ring Alkyl, C 2-8 alkenyl, tris(C 1-8 alkyloxy)silyl C 1-8 alkyl, phenyl, biphenyl, naphthyl.
  • R 7 is selected from H, unsubstituted or the following groups optionally substituted by one, two or more Re : methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, allyl, phenyl,
  • the compound represented by formula (I) can be selected from the compound represented by the following formula (I-1):
  • R 7 , G, n and R 3 are independently selected from the definitions mentioned above, and Y represents O, S or NH.
  • R Q is selected from H, halogen, -OH, -CN, the following groups that are unsubstituted or optionally substituted by one, two or more R c : C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl, C 1-8 alkyloxy, C 2-8 alkenyloxy, C 3-15 cycloalkyloxy, C 3-15 cycloalkenyloxy, 3-15 membered heterocyclyloxy, C 6-15 aryloxy, 5- 15-membered heteroaryloxy group, C 1-8 alkylthio group, C 2-8 alkenylthio group, C 3-15 cycloalkylthio group, C 3-15 cycloalkenylthio group, 3-15 yuan Heterocyclylthio group, C 6-15
  • R Q is selected from H, halogen, -OH, -CN, the following groups that are unsubstituted or optionally substituted by one, two or more R c : C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, such as unsubstituted or The following groups optionally substituted by one, two or more R c : methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, trifluoromethyl-methyl, Pentafluoroethyl, phenyl, naphthyl, thienyl, dihydrobenzofuranyl.
  • RQ is selected from halogen or the above-mentioned groups substituted by halogen.
  • R 3 is selected from H, C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl , C 6-15 aryl, 5-15 membered heteroaryl, C 1-8 alkyl-O-, C 2-8 alkenyl-O-, C 3-15 cycloalkyl-O-, C 3- 15- cycloalkenyl-O-, 3-15-membered heterocyclyl-O-, C 6-15- aryl-O-, 5-15-membered heteroaryl-O-, C 1-8 alkyl-S-, C 2-8 alkenyl-S-, C 3-15 cycloalkyl-S-, C 3-15 cycloalkenyl-S-, 3-15 membered heterocyclyl-S-, C 6-15 aryl- S-, 5-15 membered heteroaryl-S-.
  • R 3 is selected from H, methyl, methoxy, methylthio.
  • the compound represented by formula (I) may be selected from the compounds represented by the following formula (I-2), (I-4) or (I-5):
  • R Q , G, n, R 3 are independently selected from the definitions stated above.
  • R 6 , R 7 , G, n, R 3 are independently selected from the definitions mentioned above;
  • R 6 , R 10 , G, n, R 3 are independently selected from the definitions mentioned above.
  • Y is selected from N.
  • R Q is selected from H, the following groups that are unsubstituted or optionally substituted by one, two or more R c : C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl.
  • R Q is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R c : C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, for example, the following groups which are unsubstituted or optionally substituted with one, two or more R c : methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, thienyl, dihydrobenzofuranyl.
  • R 3 is selected from H, C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl , C 6-15 aryl group, 5-15 membered heteroaryl group.
  • each R 8 and R 9 are the same or different, and are independently selected from H, C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3- 15- cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl, -NR 12 R 13 ;
  • each R 12 and R 13 are the same or different and are independently selected from H, unsubstituted or the following groups optionally substituted by one, two or more R f : C 1-8 alkyl, C 2-8 alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl.
  • R 12 is selected from H
  • R 13 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more R f : C 1-8 alkyl, C 2-8 Alkenyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl, -NR 12 R 13 , for example, choose From cyclopentyl.
  • R 8 is selected from H, -OH, acryloyl, isobutyryl, isopentyl,
  • R 9 is selected from C 1-8 alkyl, C 2-8 alkenyl, NH 2 .
  • each R d is the same or different and is independently selected from halogen, -OH, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R e
  • each R e is the same or different and is independently selected from halogen, -OH, -CN, -NO 2 , unsubstituted or optionally substituted by one, two or more R e
  • each R f is the same or different, and is independently selected from halogen, -OH, -CN, -NO 2 , C 1-8 alkyl, C 2-8 alkenyl, C 3-15 Cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heterocyclyl, C 6-15 aryl, 5-15 membered heteroaryl, C 1-8 alkyloxy, C 2-8 alkenyl Oxygen group, C 3-15 cycloalkyloxy group, C 3-15 cycloalkenyloxy group, 3-15 membered heterocyclyloxy group, C 6-15 aryloxy group, 5-15 membered heteroaryloxy group base, C 1-8 alkylthio group, C 2-8 alkenylthio group, C 3-15 cycloalkylthio group, C 3-15 cycloalkenylthio group, 3-15 membered heterocyclylthio group, C 6-15 arylthio group, 5-15 member
  • the compound represented by formula (I) may be selected from the compounds represented by the following formula (I-3):
  • R Q , G, n, R 3 and R 4 are independently selected from the above definitions.
  • the compound represented by formula (I) described above may be selected from the following compounds:
  • the compound represented by formula (I) described above may be selected from the following compounds:
  • the compound represented by formula (I) described above may be selected from the following compounds:
  • the present invention also provides compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotope markers, N-oxides, hydrates, solvates, polymorphs, and metabolites , a method for preparing pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof, wherein the preparation method may include one selected from the following methods:
  • R 1 , R 2 , R 4 , R 5 and Y have the definitions mentioned above;
  • R 3 is selected from R 8 -O-;
  • the step (1) is carried out in the presence of a base and R 8 -OH to react to prepare the compound of formula (I).
  • the compound of formula (I) is prepared by reduction using the corresponding nitro compound as the substrate.
  • the reduction is carried out in the presence of Zn and AcOH.
  • the compound of formula (I) can be prepared through an acylation reaction using the corresponding amino compound as a substrate.
  • the compound of formula (I) can be prepared by reacting with an isocyanate compound using the corresponding amino compound as a substrate.
  • the substituent RS of the compound of formula (I) contains a guanidine group
  • the corresponding amino compound is used as the substrate and reacts with nitrile amine, acyl nitrile amine or differently substituted carbodiimide compounds to prepare formula ( I) compounds.
  • R 1 , R 2 , R 3 and R 5 have the definitions mentioned above;
  • R 4 is selected from hydroxyl
  • Y is selected from N;
  • the step (1) is carried out in the presence of a base and hydroxylamine hydrochloride to prepare the compound of formula (I).
  • R 1 , R 2 , R 3 and R 5 have the definitions mentioned above;
  • Y is selected from N;
  • the step (1) is carried out in the presence of a base and a C 1-20 alkyl-C(O)-OC(O)-C 1-20 alkyl group to prepare a compound of formula (I).
  • R 1 , R 2 , R 3 and R 5 have the definitions mentioned above;
  • Y is selected from N;
  • R 1 , R 2 , R 3 and R 5 have the definitions mentioned above;
  • R 4 is selected from R 8 -O-;
  • R 8 is selected from C 1-20 alkyl, C 2-20 alkenyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5 -20-membered heteroaryl;
  • Y is selected from N;
  • the step (1) is carried out in the presence of a base and R 8 -L to prepare the compound of formula (I);
  • L is a leaving group, such as halogen, preferably Br or I.
  • R 1 , R 2 , R 3 and R 5 have the definitions mentioned above;
  • Y is selected from N;
  • the preparation method further includes the step of reacting the prepared compound of formula (I) with a pharmaceutically acceptable acid or base to form a salt.
  • the present invention also provides a pharmaceutical composition, which contains the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, N-oxide, hydrate, and solvent At least one of compounds, polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, N-oxide, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound thereof.
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the present invention also provides compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotope markers, N-oxides, hydrates, solvates, polymorphs, and metabolites.
  • the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, N-oxide, hydrate, solvate, poly Crystalline forms, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof, said drugs or said pharmaceutical compositions are used for the prevention and/or treatment of uncontrolled cell growth, Diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses
  • diseases of inflammatory response in particular diseases such as hematological tumors, solid tumors and/or their metastases, such as leukemias and myelodysplastic syndromes, malignant lymphomas, brain tumors including brain tumors and brain metastases head and neck tumors, thoracic tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, including renal tumors, bladder
  • the present invention also provides compounds represented by the formula (I), their racemates, stereoisomers, tautomers, isotope markers, N-oxides, hydrates, solvates, and polymorphs , metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof, the use of the drug or the pharmaceutical composition for inhibiting tumor cells, wherein the tumor cells are selected from the group consisting of hematological tumors and /or tumor cells of solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, doxorubicin-resistant strains of leukemia cells, glioblastoma cells, cervical cancer cells, colon cancer cells, and/or Brain microvascular endothelial cells.
  • the tumor cells are selected from the group consisting of hematological tumors and /or tumor cells of solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, doxorubicin
  • the present invention also provides compounds represented by the formula (I), their racemates, stereoisomers, tautomers, isotope markers, N-oxides, hydrates, solvates, and polymorphs , metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters or prodrug compounds thereof, the use of the drug or the pharmaceutical composition in the preparation of a drug, the drug can be used to treat excessive Proliferative disorders, or used to inhibit, block, reduce, reduce cell proliferation and/or cell division and/or cause apoptosis.
  • Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, benign prostatic hyperplasia (BpH), solid tumors such as breast cancer, respiratory tract cancer, lung cancer, brain cancer, reproductive organ cancer, gastrointestinal cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis.
  • BpH benign prostatic hyperplasia
  • solid tumors such as breast cancer, respiratory tract cancer, lung cancer, brain cancer, reproductive organ cancer, gastrointestinal cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis.
  • the conditions also include lymphoma, sarcoma and leukemia.
  • the drug can also be used to inhibit tumor cells, wherein the tumor cells are selected from tumor cells of hematological tumors and/or solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, leukemia cells, adriamycin drug-resistant strains, glioblastoma cells, cervical cancer cells, colon cancer cells, and/or brain microvascular endothelial cells.
  • tumor cells are selected from tumor cells of hematological tumors and/or solid tumors, such as breast cancer cells, liver cancer cells, lung adenocarcinoma cells, leukemia cells, leukemia cells, adriamycin drug-resistant strains, glioblastoma cells, cervical cancer cells, colon cancer cells, and/or brain microvascular endothelial cells.
  • examples of the tumor cells may be selected from human breast cancer cells MCF-7, liver cancer cells HepG2, lung adenocarcinoma cells A549, human leukemia cells HL-60, and doxorubicin-resistant strains of human leukemia cells HL-60/ADR, human glioblastoma cell U-87MG, human cervical cancer cell HeLa, human colon cancer cell HCT-116, human colon cancer cell Sw620, human colon cancer cell LoVo and human brain microvascular endothelial cell hCMEC/ At least one of D3.
  • the compounds of the present invention can be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition can be prepared in a manner well known in the pharmaceutical field, and they can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal), oral or parenteral.
  • topically e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal
  • oral or parenteral e.g.,
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single large dose form, or it can be administered by, for example, a continuous infusion pump.
  • Topically administered pharmaceutical compositions and preparations can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powder preparations and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be necessary or required.
  • the active ingredient is usually mixed with an excipient, diluted with the excipient or otherwise incorporated into such a vehicle in the form of a capsule, sachet, paper or other container.
  • an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient.
  • compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in liquid vehicles); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of the active compound.
  • excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, poly Vinylpyrrolidone, cellulose, water, syrup and methylcellulose.
  • the preparations may also contain: lubricants such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil; wetting agents; emulsifying and suspending agents; Preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents.
  • the compositions of the present invention may be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to the patient using methods known in the art.
  • compositions may be formulated in unit dosage form, each dosage containing about 5 to 1000 mg, more usually about 100 to 500 mg of active ingredient.
  • unit dosage form refers to physically discrete unit dosage units suitable for use in human patients and other mammals, each unit containing a predetermined quantity of activity calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical excipient. substance.
  • the effective dosage range of the active compound can be very large, and is generally administered in a pharmaceutically effective amount.
  • the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.
  • the principal active ingredients are mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention.
  • these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally evenly distributed throughout the composition such that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the solid preformulation is then divided into unit dosage forms of the type described above containing, for example, about 0.1 to 1000 mg of the active ingredient according to the invention.
  • the tablets or pills of the present invention may be coated or compounded to provide a dosage form that provides a long-acting advantage.
  • the tablet or pill contains an inner dose and an outer dose component, the latter being a film-coated form of the former.
  • the two components may be isolated by an enteric layer that is used to prevent disintegration in the stomach so that the inner component passes intact through the duodenum or is delayed in release.
  • enteric layers or coatings including a variety of polymeric acids and mixtures of polymeric acids and such materials as shellac, cetyl alcohol, and cellulose acetate.
  • Liquid forms for oral or injectable administration into which the compounds and compositions of this invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions; and edible oils such as cottonseed oil, sesame oil, coconut oil, etc. Flavored emulsions of oil or peanut oil; and elixirs and similar medicinal vehicles.
  • compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof.
  • Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above.
  • the compositions are administered by the oral or nasal respiratory route to achieve local or systemic effects.
  • the composition can be atomized by using an inert gas.
  • the nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a mask curtain or intermittent positive pressure ventilator.
  • Solution, suspension or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.
  • the amount of compound or composition administered to a patient is not fixed and depends on the drug administered, the purpose of administration such as prevention or treatment; the condition of the patient, the mode of administration, etc.
  • the composition may be administered to a patient suffering from a disease in an amount sufficient to cure or at least partially inhibit symptoms of the disease and its complications.
  • the effective dose will depend on the disease state treated and the judgment of the attending clinician, which judgment will depend on such factors as the severity of the disease, the age, weight, and general condition of the patient.
  • composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions can be sterilized by conventional sterilization techniques or can be filtered.
  • the aqueous solution can be used as is in packaged form, or it can be lyophilized and the lyophilized preparation mixed with a sterile aqueous vehicle before administration.
  • the pH of the compound formulation is generally from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be appreciated that the use of certain of the foregoing excipients, carriers or stabilizers may result in the formation of pharmaceutical salts.
  • Therapeutic dosages of the compounds of the present invention may be determined based, for example, on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportions or concentrations of the compounds of the present invention in pharmaceutical compositions may not be fixed and depend on a variety of factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration.
  • the compounds of the present invention may be provided for parenteral administration in a physiologically buffered aqueous solution containing about 0.1 to 10% (w/v) of the compound.
  • Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight per day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipients, and their route of administration. Effective doses can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.
  • the present invention provides compounds described in formula (I), their racemates, stereoisomers, tautomers, isotope markers, N-oxides, hydrates, solvates, polymorphs, and metabolites , the use of at least one of a pharmaceutically acceptable salt, a pharmaceutically acceptable ester or a prodrug compound thereof in an analytical test for identifying compounds capable of inhibiting one or more tumor cells.
  • the competitive binding assay comprises contacting a compound according to the invention with tumor cells and detecting any changes in the interaction between the compound according to the invention and the tumor cells.
  • the harringtonine derivatives and pharmaceutical compositions thereof provided by the invention have excellent anti-tumor activity. Moreover, the preparation method of the derivative also has the advantages of cheap and easily available raw materials and simple operation.
  • the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein.
  • the numerical range "1-10” is equivalent to describing each integer value in the numerical range “1-10", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.
  • numbers when certain numerical ranges are defined as “numbers”, it should be understood that the two endpoints of the range, each integer in the range, and the integers in the range are described.
  • "a number from 0 to 10” should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.
  • halogen means fluorine, chlorine, bromine and iodine.
  • C 1-20 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 20 carbon atoms.
  • C 1-10 alkyl means straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • C 1-8 alkyl means straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.
  • C 2-20 alkenyl is understood to preferably mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 20 carbon atoms, preferably “C 2-8 alkenyl” .
  • C 2-8 alkenyl is understood to mean preferably a direct or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, Particularly of 2 or 3 carbon atoms (“ C2-3 alkenyl”), it is understood that in the case where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-en
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane having 3, 4, 5, 6, 7, 8 , 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl, or a bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.
  • a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl
  • a bicyclic Hydrocarbon groups
  • C 5-20 cycloalkenyl is understood to mean a conjugated or non-conjugated monovalent monocyclic or bicyclic hydrocarbon ring with a degree of unsaturation of 1, 2 or 3, which has 5 to 20 carbon atoms, preferably "C 5-10 cycloalkenyl".
  • C 5-10 cycloalkenyl is understood to mean an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 5-10 cycloalkenyl group can be a monocyclic hydrocarbon group, such as 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 2,4-cyclopentadienyl, 2,5 - Cyclohexadienyl or 1,3,5-cycloheptatrienyl or 1,3,6-cycloheptatrienyl, or bicyclic hydrocarbon group such as hexahydronaphthalene ring and octahydronaphthalene ring.
  • the term "C 5-20 cycloalkenyl" includes all possible isomeric forms thereof, such as positional or configurational isomers thereof.
  • 3-20 membered heterocyclyl refers to a saturated or unsaturated non-aromatic ring or ring system, for example, which is a 4-, 5-, 6- or 7-membered monocyclic ring or ring system.
  • Ring, 7-, 8-, 9- or bicyclic ring (such as fused ring, bridged ring, spiro ring) or 10-membered tricyclic ring system and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, where N and S may also optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O ) 2 - state.
  • the heterocyclyl group may be selected from "3-10 membered heterocyclyl group".
  • the heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclyl group may include fused or bridged rings as well as spirocyclic rings.
  • the heterocyclyl group may include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl Or trithialkyl; or 7-membered ring, such as diazacycloheptyl.
  • 4-membered rings such as azetidinyl, oxetanyl
  • 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl
  • the heterocyclyl group may be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • Heterocyclyl may be partially unsaturated, i.e.
  • the carbon atom on the 3-10-membered heterocyclic group can be connected to other groups, or it can be a 3-10-membered heterocyclic group.
  • the heterocyclic atoms on the ring are connected to other groups.
  • the nitrogen atom on the piperazinyl may be connected to other groups.
  • the nitrogen atom on the piperidinyl ring and the carbon atom in the para position may be connected to other groups.
  • C 6-20 aryl is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic or bicyclic (such as fused ring, bridged ring, spirocyclic) hydrocarbon ring having 6 to 20 carbon atoms, It can be a single aromatic ring or polyaromatic rings fused together, in particular a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms.
  • a ring of carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms (“C 10 aryl”), such as naphthyl.
  • C 6-10 aryl group When the C 6-10 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution position, for example, it may be ortho, para or meta substitution.
  • heteroaryl is understood to include monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition In each case, the heteroaryl radical may be benzofused.
  • Heteroaryl also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-,
  • Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • the carbon atoms on the 5-10 membered heteroaryl ring may be connected to other groups, or the heteroatoms on the 5-10 membered heteroaryl ring may be connected to other groups.
  • the 5-10 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted.
  • substitution site for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.
  • spiro ring refers to a ring system in which two rings share one ring-forming atom.
  • fused ring refers to a ring system in which two rings share 2 ring-forming atoms.
  • bridged ring refers to a ring system in which two rings share more than three ring-forming atoms.
  • heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, may be included at the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-position, etc.
  • pyridin-2-yl pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl , pyridin-4-yl and pyridinylene-4-yl
  • thienyl or thienylene group includes thiophene-2-yl, thiophenylene-2-yl, thiophenylene-3-yl and thiophenylene-3-yl
  • each C 1-20 alkyl group may be the same as or different from each other, Independently selected from the definitions stated above.
  • Me represents methyl
  • Et represents ethyl
  • Ph represents phenyl
  • TMS represents trimethylsilyl
  • i-Pr represents isopropyl
  • Ac represents acetyl.
  • the compound represented by formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as amino), which can also form internal salts.
  • the compounds of the invention may exist in the form of solvates (eg hydrates), wherein the compounds of the invention comprise as structural elements of the crystal lattice of said compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • the compounds of the present invention may exist in the form of stereoisomers, which may be enantiomers and cis-trans isomers, or enantiomers and diastereomers.
  • the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form.
  • the compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration.
  • the compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent.
  • suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms.
  • Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • cis-trans isomers means isomers that differ in the orientation of the substituent atoms associated with the carbon-carbon double bond. Substituent atoms (other than H) on either side of the carbon-carbon double bond may be in the E or Z configuration. In the “E” (opposite side) or “chair” configuration, the substituents are on the opposite side to the carbon-carbon double bond; in the “Z” (same side) or “boat” configuration, the substituents is oriented on the same side relative to the carbon-carbon double bond. Compounds with a mixture of "cis” and “trans” species are designated “cis/trans”.
  • Individual isomers of the compounds of the invention can be prepared by either isomer-specific synthesis or resolution from mixtures of isomers.
  • Conventional resolution techniques include the use of optically active salts to form the free base of each isomer of the isomer pair (subsequent fractional crystallization and free base regeneration), the formation of esters or amides of each isomer of the isomer pair (subsequent via Chromatographic separation and removal of chiral auxiliaries) or use of preparative TLC (thin layer chromatography) or chiral HPLC columns to resolve isomer mixtures of either starting materials or final products.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human, and includes one of the following or more of: (1) Prevention of disease: e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibition of disease: e.g., inhibition of a disease, disorder, or condition (i.e., preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing pathology or symptoms of the disease, disorder, or condition.
  • Prevention of disease e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease.
  • Inhibition of disease e.g., inhibition of a disease, disorder
  • disease amelioration e.g., alleviation of a disease, disorder, or condition (i.e., reversal of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.
  • the therapeutically effective dose can be estimated initially from cell culture assays, or the initial dose can be estimated from in vivo data. Using these preliminary guidelines, one of ordinary skill in the art can determine effective doses in humans.
  • the toxicity and therapeutic efficacy of the compounds described herein can also be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example by determination of LD50 and ED50 .
  • Carriers or “diluents” of the present invention are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (edited by A.R. Gennaro 1985).
  • the choice of pharmaceutical carrier, excipient, or diluent can be based on the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical composition may contain or additionally contain any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickening agent, Preservatives (including antioxidants) and the like, as well as substances included to render the preparation isotonic with the blood of the recipient.
  • compositions suitable for oral administration wherein the carrier is a solid are most preferably in unit dosage form, such as pills, capsules or tablets, each containing a predetermined quantity of the active compound.
  • Tablets may be made by compression or moulding, optionally with more than one accessory ingredient.
  • the compacts may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating substance, surfactant or dispersing agent tablet. Molded tablets may be prepared by molding the active compound and an inert liquid diluent. Tablets may be optionally coated or, if not coated, optionally printed with symbols.
  • Capsules can be prepared by filling capsule shells with the active compound alone or in admixture with one or more accessory ingredients and sealing in the conventional manner. Cachelets are similar to capsules in which the active compound is sealed in a rice paper membrane along with any accessory ingredients.
  • the active compounds may also be formulated as dispersible granules, which may, for example, be suspended in water or sprinkled on food prior to administration. The granules can be packaged, for example, in sachets.
  • Formulations suitable for oral administration wherein the carrier may be liquid may be presented as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water liquid emulsions.
  • pharmaceutically acceptable salts includes suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts see J Pharm Sci, 66, 199, 1977, Berge et al.
  • esters refers to the use of organic acids or alcohols/hydroxides to form esters with functional groups in the structure of the compounds of the present invention that can be esterified.
  • isotope label means that at least one atom in the compound of the invention is replaced by an isotope.
  • isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as the corresponding 2H , 3H , 13C , 14C , 15N , 17O , 18O , 31P , 32P , 35S , 18F and 36Cl .
  • isotopes such as deuterium (i.e. 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances.
  • the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom.
  • prodrug compound refers to a covalently bonded compound that releases the active parent drug according to formula (I) in vivo.
  • Such prodrugs are generally compounds of the invention in which one or more appropriate groups have been modified so that the modification may be reversed after administration to a human or mammalian subject. Reversal is usually performed by enzymes naturally present in such subjects, although a second agent may be administered with the prodrug for reversal in vivo. Examples of such modifications include pharmaceutically acceptable esters as described above, where such reversal may be performed by esterases and the like.
  • polymorph refers to the various crystalline, polymorphic and hydrated forms of the compounds of the invention. It is well established in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by means of purification and/or isolation of the solvents used in the synthetic preparation of such compounds.
  • administration means that the pharmaceutical composition of the present invention is suitable for rectal, intranasal, intrabronchial, topical (including oral and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermally), intraperitoneally, or intrathecally.
  • the formulation is for oral administration.
  • the preparations may conveniently be presented in unit dosage form, ie, as discrete portions containing a unit dose or a plurality of units or subunits of a unit dose.
  • the formulations may be in the form of tablets and sustained-release capsules, and may be prepared by any method well known in the pharmaceutical art.
  • Formulations for oral administration according to the invention may be presented: as discrete units such as capsules, gels, drops, cachets, pills or tablets each containing a predetermined amount of active agent; as powder or granules; as Solutions, emulsions or suspensions of active agents in aqueous or non-aqueous liquids; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions; or as bolus injection preparations, etc.
  • these compositions contain from 1 to 250 mg and more preferably from 10 to 100 mg of active ingredient per dose.
  • compositions for oral administration e.g., tablets and capsules
  • solvents and/or commonly used excipients such as binders, such as syrups, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, are also included (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers such as cornstarch, gelatin, lactose, sucrose, micron Crystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metal stearates, glycerol stearic acid, stearic acid , silicone fluids, talc, oils and colloidal silica.
  • Flavorings such as peppermint, oil of wintergreen, cherry spice, etc. can also be used.
  • compositions suitable for oral administration include tablets containing a flavored base, usually sucrose and an active agent in gum arabic or gum tragacanth; soft lozenges containing an inert base such as gelatin and glycerol, or sucrose and an active agent in gum arabic. agents; and mouthwashes containing the active agent in a suitable liquid carrier.
  • injectable forms usually contain between 10 and 1000 mg, preferably between 10 and 250 mg of active ingredient per dose.
  • the form of administration can also be combined administration, that is, more than one compound of the present invention is administered in combination with more than one other active agent.
  • the compound of the invention may be administered continuously, simultaneously or sequentially with one or more other active agents.
  • step 1.1 Same as step 1.1, except m-nitrophenylpropionaldehyde and 3-nitrophenylpropionaldehyde were used instead of p-nitrophenylpropionaldehyde to obtain the following compounds 6 and 7 respectively:
  • step 1.2 Same as step 1.2, except that raw material 5 is replaced by 6 and 7, and compounds 9 and 10 can be prepared respectively:
  • step 1.3 Same as step 1.3, except that raw material 8 is replaced by 9 and 10, and compounds 12 and 13 can be prepared respectively:
  • step 1.4 Same as step 1.4, except that raw material 11 is replaced by 12 and 13, and compounds 15 and 16 can be prepared respectively:
  • step 1.5 same as step 1.5, except that raw material 14 is replaced by 15 and 16, and compounds 18 and 19 can be prepared respectively:
  • step 1.6 Same as step 1.6, except that raw material 17 is replaced by 18 and 19, and compounds 21 and 22 can be prepared respectively:
  • step 1.7 Same as step 1.7, except that raw material 20 is replaced by 21 and 22 to prepare compounds I-2-2 ⁇ I-2-4 respectively:
  • Example 2 Refer to Example 2, except that the raw material I-2-2 is replaced by I-2-1, I-2-3 and I-2-4 to prepare compounds I-2-6 to I-2-8 respectively.
  • Compound I-2-7 is a light yellow amorphous solid product with a yield of 88%.
  • HRMS(ESI)m/z calcd for C 25 H 33 N 2 O 8 ,[M+H] + 489.2231,found 489.2230.
  • Compound I-2-8 is a light yellow amorphous solid product with a yield of 92%.
  • Embodiment 4 Preparation of Harringtonine Analog I-2-9
  • Example 4 Refer to Example 4, except that different acid chlorides are used instead of acetyl chloride to react with compound I-2-5 to prepare compounds I-2-23 to I-2-28 and I-1-100, respectively.
  • cyclopentyl isocyanate cyclopropyl isocyanate, cyclohexyl isocyanate, tert-butyl isocyanate, benzyl isocyanate, 4-methoxyphenyl isocyanate, 3-chloro-4-tolyl isocyanate are used respectively.
  • Compounds I-1-2, I-1-7, I-1-9, and I can be prepared respectively by using isocyanate, 3,5-ditrifluoromethylphenyl isocyanate, and 4-fluorophenyl isocyanate instead of p-toluene isocyanate. -1-12, I-1-22, I-1-26, I-1-97, I-1-98, I-1-99
  • Example 10 Preparation of harringtonine analogues I-1-3 to I-1-36 (compounds other than Example 9)
  • Example 8 except that differently substituted isocyanates are used to react with compound I-2-7 to prepare compounds I-1-34 to I-1-63, respectively.
  • Compound I-1-82 was prepared with reference to Example 8, except that benzenesulfonyl isocyanate was used instead of p-tolyl isocyanate.
  • Example 8 The difference is that differently substituted nitrile amines, acyl nitrile amines or differently substituted carbodiimides are used to react with compounds I-2-5, I-2-7 or I-2-8 respectively. Compounds I-1-83 to I-1-96 were prepared.
  • step 1.7 of Example 1 the difference is that compound 23-40 is used to perform a ring-opening methyl esterification reaction, and compounds I-2-29 to I-2-46 can be prepared respectively:
  • Example 26 In vitro biological activity testing
  • Human breast cancer cells MCF-7, liver cancer cells HepG2, and lung adenocarcinoma cells A549 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.
  • Human leukemia cells HL-60, human leukemia cell doxorubicin-resistant strain HL-60/ADR, and human glioblastoma cells U-87MG were purchased from Shanghai Chuanqiu Biotechnology Co., Ltd.
  • Human cervical cancer HeLa was purchased from Shanghai Jikai Gene Chemical Technology Co., Ltd.
  • Human colon cancer cell HCT-116 and human brain microvascular endothelial cells hCMEC/D3 were preserved by Tianjin Suntech Yaoyuan Technology Co., Ltd.
  • Human colon cancer cell Sw620 and human colon cancer cell LoVo were provided by the affiliated Hospital of Tianjin Medical University.
  • Human breast cancer cell MCF-7, liver cancer cell HepG2, lung adenocarcinoma cell A549, human leukemia cell HL-60, human leukemia cell doxorubicin-resistant strain HL-60/ADR, human glioblastoma cell U-87MG , human cervical cancer cell HeLa, human colon cancer cell HCT-116, human colon cancer cell Sw620, human colon cancer cell LoVo, and human brain microvascular endothelial cells HCMEC/D3 were cultured in DMEM medium.
  • the culture medium is added with 10% fetal bovine serum and 1% double antibodies (penicillin + streptomycin).
  • the culture environment is an incubator filled with 5% CO 2 and a temperature of 37°C; when the cells are basically full The bottom of the dish (approximately 80%-90%) for subculture.
  • MTT solution Weigh 50 mg of MTT, dissolve in 10 mL of phosphate buffered saline (PBS), aliquot, and store in the dark at 4°C. It will be valid within two weeks.
  • PBS phosphate buffered saline
  • test drugs Dilute a series of compounds with culture medium to prepare a 1 mg/ml stock solution. Before use, accurately draw an appropriate amount of the sample stock solution and dilute it with culture medium into working solutions with different concentration gradients, such as 100 ⁇ g/ml, 10 ⁇ g/ml, 1 ⁇ g/ml, 0.1 ⁇ g/ml, 0.01 ⁇ g/ml, 0.001 ⁇ g/ml, etc.
  • Cell inhibition rate (%) [1-OD value of test group/OD value of blank control group] ⁇ 100%, and calculate half of the cell growth inhibited by the sample. Inhibition concentration IC 50 value.

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Abstract

本发明涉及三尖杉酯类衍生物及其药物组合物、制备方法和用途，属于药物化合物领域。本发明提供的三尖杉酯类衍生物及其药物组合物具有优异的抗肿瘤活性。并且，所述衍生物的制备方法还具有原材料便宜易得，操作简便等优点。

Description

三尖杉酯碱类衍生物及其药物组合物、制备方法和用途
本申请要求享有申请人2022年9月22日向中国国家知识产权局提交的申请号为202211161020.8，名称为“三尖杉酯碱类衍生物及其药物组合物、制备方法和用途”的在先发明专利申请的优先权。该在先申请的全文以引用的方式并入本文。
技术领域
本发明涉及三尖杉酯碱类衍生物及其药物组合物、制备方法和用途，属于药物化合物领域。
背景技术
三尖杉酯类生物碱如三尖杉酯碱1(Harringtonine，HT)、高三尖杉酯碱2(Homoharringtonine，HHT)、脱氧三尖杉酯碱3(Deoxyharringtonine，DHT)和异三尖杉酯碱4(Isoharringtonine，IHT)是已知的抗癌药物。
其中，高三尖杉酯碱2于1990年载入我国药典，用于临床治疗急性非淋巴性白血病，并一直临床应用至今。
目前药用三尖杉酯类生物碱是从粗榧属植物中分离得到，但是天然三尖杉酯类生物碱在总生物碱中只占一小部分，而且主要存在于植物的不可再生部分。三尖杉酯类生物碱除了以低浓度存在于天然植物原料中以外，还与许多结构非常相似的同类物相混合，因此从天然产物中分离得到高纯度的三尖杉酯类生物碱十分困难。同时，由于粗榧属植物数量剧减，已成为稀有保护植物，导致从植物中分离三尖杉酯类生物碱已经远远不能满足临床应用的需要。
发明人此前获得授权的中国专利ZL201510925650.1曾报道了一类三尖杉酯生物碱类化合物及其合成方法和用途，其中部分实施例化合物对于HL-60人白血病细胞具有一定的抑制活性。
目前，仍需要对此类化合物的衍生物进行进一步研究，从而开发活性得到具有改善抗癌活性的药物化合物。
发明内容
为改善上述技术问题，本发明提供式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物：
其中，RS选自(RN)m-G-(CH2)n-或(RQ)m-G-(CH2)n-：
RN代表包含氮原子的取代基，例如硝基、无取代或任选被一个、两个或更多个Ra取代的下列基团：-NR6R7、-NR6’-C(＝Y-R4)-NR6R7；
每一个R6、R6’和R7相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R10C(＝O)-、R10C(＝O)O-、R10C(＝O)NH-、R10OC(＝O)-、R10NHC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
RQ代表H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20 烷基)硅基；
G代表化学键、C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；条件是当G不为化学键时，G连接的不同基团在G上取代的位置之间可以间隔1-10个原子，例如间隔1、2、3、4、5、6、7、8、9或10个原子；例如，当G为苯基时，其连接的不同基团在G上取代的位置之间可以间隔1、2、3、4或5个碳原子，例如所述不同基团在G上为邻位取代、间位取代和/或对位取代，优选为间位和/或对位取代；
每一个m相同或不同，彼此独立地选自1以上的整数；
每一个n相同或不同，彼此独立地选自1以上的整数；
每一个Y相同或不同，彼此独立地选自O、S或N，条件是当Y选自O或S时，R4不存在；
R1和R2相同或不同，彼此独立地选自H、C1-6烷基或卤素；
R3选自R8、R8-O-、R8-S-；
R4不存在，或选自H、无取代或任选被一个、两个或更多个Rd取代的下列基团：R8-O-、R8-S-、R9C(＝O)O-、R10OC(＝O)O-、R10NHC(＝O)-、R10NHC(＝O)O-、R10C(＝O)NH-；
R5选自H或C1-6烷基；
每一个Ra、Rb、Rc和Rd相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、氧代(＝O)，无取代或任选被一个、两个或更多个Re取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R11C(＝O)-、R11C(＝O)O-、R11C(＝O)NH-、R11OC(＝O)-、R11NHC(＝O)-、R11S(O)2-、R11S(O)2O-、R11OS(O)2-、R11S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
每一个R8、R9、R10和R11相同或不同，彼此独立地选自H、C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R11’C(＝O)-、R11’C(＝O)O-、R11’C(＝O)NH-、R11’OC(＝O)-、R11’NHC(＝O)-、R11’S(O)2-、R11’S(O)2O-、R11’OS(O)2-、R11’S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
每一个R11’、R12和R13相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
每一个Re和Rf相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、-NH2、氧代(＝O)，无取代或任选被一个、两个或更多个Rg取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R14C(＝O)-、R14C(＝O)O-、R14OC(＝O)-、R14S(O)2-、R14S(O)2O-、R14OS(O)2-、R14S(O)-；
每一个R14相同或不同，彼此独立地选自C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
每一个Rg相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、-NH2、氧代(＝O)，C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基；
任选地，所述C3-20环烷基或3-20元杂环基的一个、两个或更多碳原子可以任选地被氧取代以形成羰基。
根据本发明的实施方案，G代表化学键、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基，例如化学键、C1-8烷基、C2-8烯基、苯基、萘基。
根据本发明的实施方案，m代表1～20的整数，优选1～10的整数，如1、2、3、4、5、6、7、8、9或10。
根据本发明的实施方案，n代表1～20的整数，优选1～10的整数，如1、2、3、4、5、6、7、8、9或10。
根据本发明的实施方案，卤素代表F、Cl、Br或I。
根据本发明的实施方案，Y选自O、N或S。
根据本发明的实施方案，R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基-O-、C2-8烯基-O-、C3-15环烷基-O-、C3-15环烯基-O-、3-15元杂环基-O-、C6-15芳基-O-、5-15元杂芳基-O-、C1-8烷基-S-、C2-8烯基-S-、C3-15环烷基-S-、C3-15环烯基-S-、3-15元杂环基-S-、C6-15芳基-S-、5-15元杂芳基-S-。
根据本发明的实施方案，R4不存在或选自H。
根据本发明的实施方案，RN代表包含氮原子的取代基，例如硝基、无取代或任选被一个、两个或更多个Ra取代的下列基团：-NR6R7、-NH-C(＝Y-R4)-NR6R7。
根据本发明的实施方案，RN代表硝基、无取代或任选被一个、两个或更多个Ra取代的下列基团：-NR6R7、-NH-C(＝Y-R4)-NR6R7，其中Y选自O、N或S，R4不存在或选自H。
根据本发明的实施方案，RN选自-NR6R7、-NH-C(＝O)-NR6R7、-NH-C(＝S)-NR6R7或-NH-C(＝NH)-NR6R7。
或者根据本发明的实施方案，RN选自硝基、氨基，或邻位、间位和/或对位被硝基或氨基取代的苯基，其中所述氨基无取代或被一个、两个或更多个选自C1-8烷基羰基、C1-8烷基氧基羰基、C3-8环烷基羰基、C3-8环烷基氧基羰基、C6-10芳基羰基、C6-10芳基氧基羰基、C2-8烯基的取代基取代。
根据本发明的实施方案，R6选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；。
根据本发明的实施方案，R7选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基。
根据本发明的实施方案，R7选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-8烷基氧基)硅基C1-8烷基、三(C1-8烷基)硅基。
根据本发明的实施方案，R10选自C1-8烷基、C2-8烯基、C3-10环烷基、C3-10环烯基、3-8元杂环基、C6-10芳基、5-10元杂芳基、NH2。
根据本发明的实施方案，每一个Ra和Rb相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、无取代或任选被一个、两个或更多个Rd取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基氧基、C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基、R11C(＝O)-、R11C(＝O)O-、R11OC(＝O)-、R11S(O)2-、R11S(O)2O-、R11OS(O)2-、R11S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13；三(C1-20烷基氧基)硅基C1-20烷基；
根据本发明示例性的实施方案，R7选自例如H、无取代或任选被一个、两个或更多个Re取代的下列基团：C1-8烷基、C3-8环烷基、C2-8烯基、三(C1-8烷基氧基)硅基C1-8烷基、苯基、联苯基、萘基。
例如，R7选自H、无取代或任选被一个、两个或更多个Re取代的下列基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基、正庚基、环丙基、环丁基、环戊基、环己基、环庚基、烯丙基、苯基、
根据本发明的实施方案，式(I)所示的化合物可以选自如下式(I-1)所示的化合物：
其中，R7、G、n、R3彼此独立地选自上文所述的定义，Y代表O、S或NH。
根据本发明的实施方案，RQ选自H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基氧基、 C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基。
根据本发明的实施方案，RQ选自H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-6烷基、C2-6烯基、C3-10环烷基、C3-10环烯基、3-10元杂环基、C6-10芳基、5-10元杂芳基，例如无取代或任选被一个、两个或更多个Rc取代的下列基团：甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、三氟甲基-甲基、五氟乙基、苯基、萘基、噻吩基、二氢苯并呋喃基。
根据本发明示例性的实施方案，RQ选自卤素或被卤素取代的上述基团。
根据本发明的实施方案，R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基-O-、C2-8烯基-O-、C3-15环烷基-O-、C3-15环烯基-O-、3-15元杂环基-O-、C6-15芳基-O-、5-15元杂芳基-O-、C1-8烷基-S-、C2-8烯基-S-、C3-15环烷基-S-、C3-15环烯基-S-、3-15元杂环基-S-、C6-15芳基-S-、5-15元杂芳基-S-。
根据本发明示例性的实施方案，R3选自H、甲基、甲氧基、甲硫基。
根据本发明的实施方案，式(I)所示的化合物可以选自如下式(I-2)、(I-4)或(I-5)所示的化合物：
其中，RQ、G、n、R3彼此独立地选自上文所述的定义。
其中，R6、R7、G、n、R3彼此独立地选自上文所述的定义；
其中，R6、R10、G、n、R3彼此独立地选自上文所述的定义。
根据本发明的实施方案，Y选自N。
根据本发明的实施方案，RQ选自H、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基。
根据本发明示例性的实施方案，RQ选自无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-6烷基、C2-6烯基、C3-10环烷基、C3-10环烯基、3-10元杂环基、C6-10芳基、5-10元杂芳基，例如无取代或任选被一个、两个或更多个Rc取代的下列基团：甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、噻吩基、二氢苯并呋喃基。
根据本发明的实施方案，R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基。
根据本发明的实施方案，R4选自无取代或任选被一个、两个或更多个Rd取代的下列基团：R8-O-、R8-S-、R9C(＝O)O-。
根据本发明的实施方案，每一个R8和R9相同或不同，彼此独立地选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、-NR12R13；
根据本发明的实施方案，每一个R12和R13相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基。
根据本发明的实施方案，R12选自H，R13选自无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、-NR12R13，例如选自环戊基。
根据本发明的实施方案，R8选自H、-OH、丙烯酰基、异丁酰基、异戊基、
根据本发明的实施方案，R9选自C1-8烷基、C2-8烯基、NH2。
根据本发明的实施方案，每一个Rd相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、无取代或任选被一个、两个或更多个Re取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基，例如选自无取代或任选被一个、两个或更多个Re取代的下列基团：苯基、萘基、。
根据本发明的实施方案，每一个Re相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、无取代或任选被一个、两个或更多个Re取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基氧基、C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基。
根据本发明的实施方案，每一个Rf相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基氧基、C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基。
根据本发明的实施方案，式(I)所示化合物可以选自如下式(I-3)所示的化合物：
其中，RQ、G、n、R3、R4彼此独立地选自上文所述的定义。
根据本发明示例性的实施方案，上文所述的式(I)所示化合物可选自下列化合物：
其中，基团R、G、R4和n具有下表所述的定义：
根据本发明示例性的实施方案，上文所述的式(I)所示化合物可选自下列化合物：
其中，基团R、R3和n具有下表所述的定义：
根据本发明示例性的实施方案，上文所述的式(I)所示化合物可选自下列化合物：
其中，基团R、R3和R8具有下表所述的定义：
除非另有说明，尽管上述各基团的定义被用于描述通式化合物所涵盖的具体化合物结构，但本领域技术人员应当理解本说明书同样记载了上述每一个基团的独立定义，该独立定义可以单独或与其他基团一起，用于进一步限定通式化合物中的一个、两个或更多个相应的取代基团，从而进一步限定所述通式化合物。
本发明还提供式(I)所示化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物的制备方法，其中所述制备方法可以包括选自下列方法中的一种：
方法(1)
其中，R1、R2、R4、R5、Y具有上文所述的定义；
R3选自R8-O-；
所述步骤(1)在碱和R8-OH的存在下进行反应，制备式(I)化合物。
方法(2)
当式(I)化合物的取代基RS中包含氨基时，以相应的硝基化合物为底物，还原制备式(I)化合物。
优选地，所述还原为在Zn和AcOH的存在下进行。
方法(3)
当式(I)化合物的取代基RS中包含酰基氨基时，以相应的氨基化合物为底物，通过酰化反应，制备式(I)化合物。
方法(4)
当式(I)化合物的取代基RS中包含脲基团时，以相应的氨基化合物为底物，通过与异氰酸酯类化合物反应，制备式(I)化合物。
方法(5)
当式(I)化合物的取代基RS中包含胍基团时，以相应的氨基化合物为底物，通过与腈胺、酰基腈胺或者不同取代的碳二亚胺类化合物反应，制备式(I)化合物。
方法(6)
其中，R1、R2、R3、R5具有上文所述的定义；
R4选自羟基；
Y选自N；
所述步骤(1)在碱和盐酸羟胺的存在下进行反应，制备式(I)化合物。
方法(7)
其中，R1、R2、R3、R5具有上文所述的定义；
R4选自R9C(＝O)O-；
Y选自N；
所述步骤(1)在碱和C1-20烷基-C(O)-O-C(O)-C1-20烷基的存在下进行反应，制备式(I)化合物。
方法(8)
其中，R1、R2、R3、R5具有上文所述的定义；
R4选自R9C(＝O)O-；
Y选自N；
所述步骤(1)在碱和R9C(＝O)Cl或R9C(＝O)OH的存在下进行反应，制备式(I)化合物。
方法(9)
其中，R1、R2、R3、R5具有上文所述的定义；
R4选自R8-O-；
R8选自C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
Y选自N；
所述步骤(1)在碱和R8-L的存在下进行反应，制备式(I)化合物；
L为离去基团，例如卤素，优选Br或I。
方法(10)
其中，R1、R2、R3、R5具有上文所述的定义；
R4选自R10NHC(＝O)O-；
Y选自N；
所述步骤(1)在R10-N＝C＝O的存在下进行反应，制备式(I)化合物。
任选地，所述制备方法还包括将制备得到的式(I)化合物与药学上可接受的酸或碱反应成盐的步骤。
本发明还提供一种药物组合物，其包含式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
本发明还提供一种药物组合物，其包含治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
根据本发明的实施方案，所述药物组合物还包括一种或多种药学上可接受的辅料。
根据本发明的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。
本发明还提供式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种在制备药物中的用途。
根据本发明的实施方案，所述式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物、所述药物或所述药物组合物用于预防和/或治疗由不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答引起的疾病，或者伴有不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答的疾病的用途，特别地，所述疾病为例如血液肿瘤、实体瘤和/或它们的转移，如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头部和颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤、包括肾肿瘤、膀胱瘤和前列腺瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移。
本发明还提供所述式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物、所述药物或所述药物组合物用于抑制肿瘤细胞的用途，其中所述肿瘤细胞选自血液肿瘤和/或实体瘤的肿瘤细胞，例如乳腺癌细胞、肝癌细胞、肺腺癌细胞、白血病细胞、白血病细胞阿霉素耐药株、胶质母细胞瘤细胞、宫颈癌细胞、结肠癌细胞和/或脑微血管内皮细胞。
本发明还提供所述式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物、所述药物或所述药物组合物在制备药物中的用途，所述药物可以用于治疗哺乳动物的过度增殖性病症，或用于抑制、阻断、降低、减少等细胞增殖和/或细胞分裂和/或引起凋亡。过度增殖性病症包括但不限于银屑病、瘢痕疙瘩和其它影响皮肤的增生、良性前列腺增生(BpH)、实体瘤例如乳腺癌、呼吸道癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌以及它们的远端转移。所述病症还包括淋巴瘤、肉瘤和白血病。
所述药物还可以用于抑制肿瘤细胞，其中所述肿瘤细胞选自血液肿瘤和/或实体瘤的肿瘤细胞，例如乳腺癌细胞、肝癌细胞、肺腺癌细胞、白血病细胞、白血病细胞阿霉素耐药株、胶质母细胞瘤细胞、宫颈癌细胞、结肠癌细胞和/或脑微血管内皮细胞。
根据本发明的实施方案，所述肿瘤细胞的实例可以选自人乳腺癌细胞MCF-7、肝癌细胞HepG2、肺腺癌细胞A549、人白血病细胞HL-60、人白血病细胞阿霉素耐药株HL-60/ADR、人胶质母细胞瘤细胞U-87MG、人宫颈癌细胞HeLa、人结肠癌细胞HCT-116、人结肠癌细胞Sw620、人结肠癌细胞LoVo和人脑微血管内皮细胞hCMEC/D3中的至少一种。
作为药物时，可按药物组合物的形式给予本发明化合物。可按药剂领域中熟知的方式制备这些组合物，可通过多种途径给予它们，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本发明的组合物时，通常将活性成分与赋形剂混合，通过赋形剂稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时，它可以是固体、半固体或液体物质，用作溶媒、载体或活性成分的介质。因此，组合物可以是以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)；含例如高达10％重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂还可含有：润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油；湿润剂；乳化剂和悬浮剂； 防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯；甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物，每一剂量含约5～1000mg，更通常约100～500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位，各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大，通常按药用有效量给药。但是，可以理解实际给予的化合物的量通常由医师根据相关情况决定，它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物；患者个体的年龄、重量和反应；患者症状的严重程度等。
对于制备固体组合物例如片剂，将主要的活性成分与药物赋形剂混合，形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时，是指活性成分通常均匀地分布在整个组合物中，致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1～1000mg本发明活性成分的单位剂型。
可将本发明片剂或丸剂包衣或复合，得到提供长效作用优点的剂型。例如，片剂或丸剂含内剂量和外剂量组分，后者是前者的被膜形式。可通过肠溶层将两种组分隔离，肠溶层用于在胃中阻止崩解，以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂，此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和组合物，用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液；和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂；以及酏剂和类似的药用溶媒。
用于吸入或吹入的组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中，通过口服或鼻呼吸途径给予组合物，实现局部或全身作用。可通过使用呈惰性的气体，使组合物成雾化。可直接由雾化装置吸入雾化溶液，或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末组合物。
给予患者的化合物或组合物的量不固定，取决于给予的药物、给药的目的例如预防或治疗；患者的状态、给药的方式等。在治疗应用时，可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断，该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌，将这些组合物灭菌。可将水溶液包装原样使用，或冻干，给药前，将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3～11，更优选5～9，最优选7～8。可以理解，使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％(w/v)该化合物的生理缓冲水溶液提供本发明化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本发明提供式(I)所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种在分析测试中的用途，所述分析试验用于鉴定能够抑制一种或多种肿瘤细胞的化合物。
更优选地，竞争性结合试验包括将本发明化合物与肿瘤细胞接触，并检测根据本发明的化合物与肿瘤细胞之间的相互作用的任何变化。
有益效果
本发明提供的三尖杉酯类衍生物及其药物组合物具有优异的抗肿瘤活性。并且，所述衍生物的制备方法还具有原材料便宜易得，操作简便等优点。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-10”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10。此外，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内 的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
应当理解，本文在描述一个、两个或更多个中，“更多个”应当是指大于2，例如大于等于3的整数，例如3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-20烷基”应理解为表示具有1～20个碳原子的直链或支链饱和一价烃基。例如，“C1-10烷基”表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基，“C1-8烷基”表示具有1、2、3、4、5、6、7或8个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C2-20烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2～20个碳原子，优选“C2-8烯基”。“C2-8烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7或8个碳原子，特别是2或3个碳原子(“C2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C3-20环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。
术语“C5-20环烯基”应理解为表示不饱和度为1、2或3的共轭或非共轭的一价单环或双环烃环，其具有5～20个碳原子，优选“C5-10环烯基”。术语“C5-10环烯基”应理解为表示不饱和的一价单环或双环烃环，其具有5、6、7、8、9或10个碳原子。所述C5-10环烯基可以是单环烃基，如3-环戊烯基、1-环己烯基、2-环己烯基、2,4-环戊二烯基、2,5-环己二烯基或1,3,5-环庚三烯基或1,3,6-环庚三烯基，或者是双环烃基如六氢化萘环、八氢化萘环。除非另有说明，术语“C5-20环烯基”包括其所有可能的异构形式，例如其位置异构体或构型异构体。
除非另有定义，术语“3-20元杂环基”是指饱和的或不饱和的非芳族的环或环系，例如，其是4-、5-、6-或7-元的单环、7-、8-、9-或元的二环(如稠环、桥环、螺环)或者10-元的三环环系，并且含有至少一个，例如1、2、3、4、5个或更多个选自O、S和N的杂原子，其中N和S还可以任选被氧化成各种氧化状态，以形成氮氧化物、-S(O)-或-S(O)2-的状态。优选地，所述杂环基可以选自“3-10元杂环基”。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。所述3-10元杂环基与其它基团相连构成本发明的化合物时，可以为3-10元杂环基上的碳原子与其它基团相连，也可以为3-10元杂环基环上杂环原子与其它基团相连。例如当3-10元杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与其它基团相连。或当3-10元杂环基选自哌啶基时，可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环或二环(如稠环、桥环、螺环)烃环，其可以是单芳族环或稠合在一起的多芳族环，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如萘基。当所述C6-10芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、二环(如稠环、桥环、螺环)或三环芳族环系：其具有5～10个环原子且包含1-5个独立选自N、O和S的杂原子，优选1-3各独立选自N、O和S的杂原子并且，另 外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团，其中所述连接的根基或点在杂芳族环上。非限制性实例包括1-、2-、3-、5-、6-、7-或8-吲嗪基、1-、3-、4-、5-、6-或7-异吲哚基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-吲唑基、2-、4-、5-、6-、7-或8-嘌呤基、1-、2-、3-、4-、6-、7-、8-或9-喹嗪基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、1-、4-、5-、6-、7-或8-酞嗪基(phthalazinyl)、2-、3-、4-、5-或6-萘啶基、2-、3-、5-、6-、7-或8-喹唑啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、6-或7-蝶啶基、1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基、1-、2-、3-、4-、5-、6-、7-或8-咔唑基咔唑基、1-、3-、4-、5-、6-、7-、8-或9-咔啉基、1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基、1-、2-、3-、4-、5-、6-、7-、8-或9-吖啶基、1-、2-、4-、5-、6-、7-、8-或9-啶基、2-、3-、4-、5-、6-、8-、9-或10-菲咯啉基、1-、2-、3-、4-、6-、7-、8-或9-吩嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩噻嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩嗪基、2-、3-、4-、5-、6-或1-、3-、4-、5-、6-、7-、8-、9-或10-苯并异喹啉基、2-、3-、4-或噻吩并[2,3-b]呋喃基、2-、3-、5-、6-、7-、8-、9-、10-或11-7H-吡嗪并[2,3-c]咔唑基、2-、3-、5-、6-或7-2H-呋喃并[3,2-b]-吡喃基、2-、3-、4-、5-、7-或8-5H-吡啶并[2,3-d]-邻-嗪基、1-、3-或5-1H-吡唑并[4,3-d]-唑基、2-、4-或54H-咪唑并[4,5-d]噻唑基、3-、5-或8-吡嗪并[2,3-d]哒嗪基、2-、3-、5-或6-咪唑并[2,1-b]噻唑基、1-、3-、6-、7-、8-或9-呋喃并[3,4-c]噌啉基、1-、2-、3-、4-、5-、6-、8-、9-、10或11-4H-吡啶并[2,3-c]咔唑基、2-、3-、6-或7-咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基、2-、4-、4-、5-、6-或7-苯并噻唑基、1-、2-、4-、5-、6-、7-、8-或9-苯并氧杂基(benzoxapinyl)、2-、4-、5-、6-、7-或8-苯并嗪基、1-、2-、3-、5-、6-、7-、8-、9-、10-或11-1H-吡咯并[1,2-b][2]苯并氮杂基(benzazapinyl)。典型的稠合杂芳基包括但不限于2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基和2-、4-、5-、6-或7-苯并噻唑基。。当所述5-10元杂芳基与其它基团相连构成本发明的化合物时，可以为5-10元杂芳基环上的碳原子与其它基团相连，也可以为5-10元杂芳基环上的杂原子与其它基团相连。当所述5-10元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
术语“螺环”是指两个环共用1个成环原子的环系。
术语“稠环”是指两个环共用2个成环原子的环系。
术语“桥环”是指两个环共用3个以上成环原子的环系。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
术语“氧代”是指取代基中的碳原子、氮原子或硫原子被氧化后形成的氧基取代(＝O)。
除非另有说明，本文中术语的定义同样适用于包含该术语的基团，例如C1-20烷基的定义也适用于C1-20烷基氧基等术语。
在术语“三(C1-20烷基氧基)硅基”与术语“三(C1-20烷基)硅基”中，每一个C1-20烷基之间可以彼此相同或不同，独立地选自上文所述的定义。
本文中使用的基团缩写具有本领域熟知的含义，例如Me代表甲基，Et代表乙基，Ph代表苯基，TMS代表三甲基硅基，i-Pr代表异丙基，Ac代表乙酰基。
本领域技术人员可以理解，式(I)所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。
本发明的化合物可以溶剂合物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本发明的化合物可以以立体异构体的形式存在，所述立体异构体可以为对映异构体与顺反异构体，或对映体构体与非对映异构体。
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物涵盖了各手性碳为R或S构型的异构体或其混合物、消旋体。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
术语“顺反异构体”意指与碳-碳双键相关的取代基原子方位不同的异构体。在碳-碳双键两边的取代基原子(不是H)可为E或Z构型。在“E”(对侧)或“椅式”构型中，取代基在相对于碳-碳双键的对侧；在“Z”(同侧)或“船式”构型中，取代基的方向在相对于碳-碳双键的同侧。具有“顺式”和“反式”种类混合物的化合物被指定为“顺/反”。
如本文描述的符号“R”、“S”、“E”、“Z”、“顺式(cis)”、“反式(trans)”等是为了表示相对于核心分子的原子构型并且如IUPAC Recommendations for Fundamental Stereochemistry(Section E)),Pure Appl.Chem.,1976,45:13-30定义的方式使用。
可通过或者异构体-特异性合成或者由异构体混合物进行拆分，制备本发明化合物的单个异构体。常规的拆分技术包括采用光学活性盐形成异构体对的各异构体的游离碱(随后分级结晶和游离碱再生)、形成异构体对的各异构体的酯或酰胺(随后经色谱法分离和去除手性辅剂)或采用制备型TLC(薄层色谱)或手性HPLC柱使或者起始原料或者最终产物的异构体混合物拆分。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。治疗有效量最初可以由细胞培养测定来进行估计,也可以从体内数据估计初始剂量。使用这些初步指导，本领域普通技术人员可以确定人类的有效剂量。此外，也可以通过细胞培养物或实验动物中的标准药物程序来确定本文所述化合物的毒性和治疗功效，例如通过测定LD50和ED50。
本发明所述“辅料”的实例见“Handbook of Pharmaceutical Excipients，第2版，1994，由A Wade和PJ Weller编辑”。
本发明所述“载体”或“稀释剂”在制药领域是熟知的，并且在例如Remington's Pharmaceutical Sciences，Mack Publishing Co.(A.R.Gennaro编辑1985)中进行了描述。
药物载体、辅料或稀释剂的选择可以根据预期给药途径和标准药学实践来进行选择。药物组合物可以包含或额外包含作为载体、辅料或稀释剂的任何合适的粘合剂、润滑剂、悬浮剂、包衣剂、增溶剂、缓冲剂、调味剂、表面活性剂、增稠剂、防腐剂(包括抗氧化剂)等，以及为了使得制剂与接受者的血液等渗所包含的物质。
其中载体是固体的适用于口服给药的药物制剂最优选地是单位剂量制剂形式，如各自含有预定量的活性化合物的丸剂、胶囊或片剂。可以通过压制或模制，任选地与一种以上的辅助成分一起制备片剂。可以通过在合适的机器中压制处于自由流动形式(诸如粉末或颗粒)的活性化合物，任选地与粘合剂、润滑剂、惰性稀释剂、润滑物质、表面活性剂或分散剂混合来制备压制片剂。可以通过模制活性化合物和惰性液体稀释剂来制备模制的片剂。可以任选地将片剂包衣，如果不进行包衣的话，可以任选地打印符号。可以通过将活性化合物单独地或与一种以上的辅助成分混合填充到胶囊壳中，然后以常规方式进行密封来制备胶囊。扁囊剂类似于胶囊，其中将活性化合物与任何辅助成分一起密封在米纸膜中。也可以将活性化合物配制成可分散的颗粒，例如可以在给药前将其悬浮于水中，或洒在食物上。可以将颗粒包装在例如小袋中。其中载体可以是液体的适合于口服给药的制剂，可以作为以水性或非水性液体方式的溶液或悬浮液，或作为水包油液体乳剂呈现。
术语“药学上可接受的盐”包括其合适的酸加成盐或碱盐。关于合适的药物盐见J Pharm Sci，66，199，1977，Berge等。
术语“药学上可接受的酯”是指使用有机酸或醇/氢氧化物，与本发明化合物结构中可被酯化的官能团形成酯。
术语“同位素标记物”，表示本发明化合物中至少一个原子被同位素代替。所述同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如相应的2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。用同位素如氘(即2H)取代可以提供由更大的代谢稳定性，例如增加的体内半衰期或降低的剂量需求产生的某些治疗优势，因此在某些情况下可能是优选的。例如，本发明包括其中任一氢原子被氘原子代替的通式(I)的化合物。
术语“前药化合物”，表示在体内释放根据通式(I)的活性母体药物的共价键合的化合物。这样的前药通常是其中一个以上的适当基团已被修饰，使得在给药至人或哺乳动物受试者后该修饰可能被逆转的本发明化合物。通常通过这类受试者中天然存在的酶来进行逆转，尽管可能将第二药剂与这种前药一起给药以便在体内进行逆转。这类修饰的实例包括上文所述的药学上可接受的酯，其中可以由酯酶等进行这种逆转。
术语“多晶型物”，表示各种结晶形式、多晶形式和水合形式的本发明化合物。在制药工业中已明确，可以通过在这类化合物的合成制备中使用的溶剂的纯化和/或分离的方法而以任何这些形式分离化学化合物。
术语“给药”，表示本发明的药物组合物可适用于直肠、鼻内、支气管内、局部(包括口腔和舌下)、阴道或肠胃外(包括皮下、肌内、静脉内、动脉内和皮内)、腹膜内或鞘内给药。优选地，所述制剂是口服给药的制剂。制剂可以方便地以单位剂型，即以包含单位剂量或者单位剂量的多个单位或子单位的离散部分的形式呈现。作为实例，制剂可以是以片剂和缓释胶囊的形式，并且可以通过药学领域熟知的任何方法进行制备。
本发明的用于口服给药的制剂可以呈现为：离散单位，如各自含有预定量的活性剂的胶囊、凝胶剂、滴剂、扁囊剂、丸剂或片剂；作为粉末或颗粒；作为水性液体或非水性液体中的活性剂的溶液、乳液或悬浮液；或作为水包油液体乳剂或油包水液体乳剂；或作为团注制剂等。优选地，每剂量的这些组合物含有1至250mg且更优选10-100mg的活性成分。
对于用于口服给药的组合物(例如，片剂和胶囊)，还包括溶剂和/或常用辅料，例如粘合剂，例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄芪胶、聚乙烯吡咯烷酮(聚维酮)、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、蔗糖和淀粉；填料和载体，例如玉米淀粉、明胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露醇、磷酸二钙、氯化钠和海藻酸；和润滑剂，如硬脂酸镁、硬脂酸钠和其它金属硬脂酸酯、甘油硬脂酸、硬脂酸、硅酮流体、滑石蜡、油和胶体二氧化硅。调味剂如薄荷、冬青油、樱桃香料等也可以使用。可能需要添加着色剂以使剂型容易被识别。片剂也可以通过本领域熟知的方法进行包衣。
适用于口服给药的其它制剂包括包含调味基质，通常为蔗糖和阿拉伯胶或黄芪胶中的活性剂的锭剂；包含惰性基质如明胶和甘油、或蔗糖和阿拉伯胶中的活性剂的软锭剂；和包含合适液体载体中的活性剂的漱口剂。
其它给药形式包括进行静脉内、动脉内、鞘内、皮下、皮内、腹膜内或肌肉内注射并由无菌或可灭菌溶液制备的溶液或乳剂。可注射形式通常每剂含有10-1000mg，优选10-250mg之间的活性成分。
所述给药的形式还可以为联合给药，即将一种以上的本发明化合物与一种以上的其它活性剂联合给药。在这种情况下，可以将本发化合物与一种以上的其它活性剂连续、同时或序贯给药。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
分析方法
在室温下在所述溶剂中，使用Bruker AV 400光谱仪进行1H核磁共振(NMR)光谱，除非另有说明。在所有情况下，NMR数据与所提出的结构一致。使用用于指定主峰的常规缩写，以份每百万计给出特有的化学位移(δ)：例如，s，单峰；d，二重峰；t，三重峰；q，四重峰；dd，双二重峰；br，宽。使用Agilent 1290 Infinity/6460 triple Quad LCMS记录质谱。当使用薄层色谱(TLC)时，它是指硅胶TLC。
实施例1：含有硝基取代苯环的三尖杉酯碱类似物的合成
步骤1.1
化合物5的制备
氩气保护下，将对硝基苯丙醛(0.18g,1mmol)、NC·TMS(0.12g,1.2mmol)、IMESCL(0.03g,0.1mmol)溶于THF(5mL)中，在室温搅拌下加入t-BuOK(0.01g,0.1mmol)室温下反应5min。TLC板监测反应完全后，浓缩，加入EtOAc(10mL)、2M HCl(5mL)淬灭，分液，EtOAc(2×10mL)萃取，合并有机相，氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，浓缩。柱分离PE:EA＝4:1。
化合物5:淡黄色液体,1.90g,收率94％。1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.3Hz,2H),7.38(d,J＝8.3Hz,2H),4.49(t,J＝6.5Hz,1H),3.26(s,1H),2.97(t,J＝7.8Hz,2H),2.20(ddd,J＝11.4,8.9,5.6Hz,2H)ppm.
同步骤1.1，不同之处用间硝基苯丙醛和3-硝基丙醛代替对硝基苯丙醛，分别得到下列化合物6和7：
化合物6:淡黄色液体,8.10g,收率94％。1H NMR(400MHz,CDCl3)δ8.11(dd,J＝7.6,1.4Hz,2H),7.56(dt,J＝7.7,1.5Hz,1H),7.50(td,J＝7.5,1.1Hz,1H),4.51(t,J＝6.5Hz,1H),2.98(t,J＝7.8Hz,2H),2.30–2.15(m,2H)ppm.
化合物7：无色液体，7.2g，收率79％。1H NMR(400MHz,CDCl3)δ4.75–4.61(m,2H),4.61–4.51(m,1H),2.64–2.54(m,1H),2.53–2.42(m,1H)ppm.
步骤1.2
化合物8的制备
通用操作：氩气保护下，将化合物5(1.90g,9.21mmol)溶于CH3OH(30mL)溶液中，加入浓HCl(6.5mL),将混合物升温至80℃加热回流大约过夜。TLC板监测反应完全后，冷却到室温，浓缩，加入EtOAc(20mL)、H2O淬灭，分液，EtOAc(2×20mL)萃取，合并有机相，氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，浓缩。
化合物8[35]:淡黄色液体,2.15g,收率98％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.37(d,J＝8.8Hz,2H),4.19(dd,J＝8.1,3.8Hz,1H),3.77(s,3H),2.97–2.76(m,2H),2.24–2.08(m,2H)ppm.
同步骤1.2，不同之处是将原料5替换为6和7，可以分别制备化合物9和10：
化合物9:淡黄色液体,9.38g,收率98％。1H NMR(400MHz,CDCl3)δ8.11–8.02(m,2H),7.55(d,J＝7.5Hz,1H),7.45(t,J＝7.8Hz,1H),4.19(dd,J＝8.0,3.9Hz,1H),3.77(s,3H),2.97–2.79(m,2H),2.16(dddd,J＝13.7,9.7,7.2,3.9Hz,1H),2.06–1.92(m,1H)ppm.
化合物10：无黄色液体，6.7g，收率60％。1H NMR(400MHz,CDCl3)δ4.63–4.47(m,2H),4.31(dd,J＝8.7,4.1Hz,1H),3.82(s,3H),2.58(ddd,J＝14.6,11.5,7.2Hz,1H),2.27(dt,J＝14.8,7.6Hz,1H)ppm.
步骤1.3
化合物11的制备
将化合物8(2.15g,9.00mmol)溶于CH2Cl2(80mL)溶液中，加入Dess-Martin(11.45g,27.0mmol)，室温反应过夜。TLC板监测反应完全后，加入饱和碳酸氢钠溶液和饱和硫代硫酸钠溶液(1:1)淬灭，分液，CH2Cl2(2×40mL)萃取，合并有机相，碳酸氢钠溶液洗涤，氯化钠洗涤，无水硫酸钠干燥，抽滤，浓缩。柱分离PE:EA＝4:1。
化合物11:淡黄色液体,1.37g,收率64％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.38(d,J＝8.7Hz,2H),3.87(s,3H),3.24(t,J＝7.1Hz,2H),3.07(t,J＝7.3Hz,2H)ppm.
同步骤1.3，不同之处是将原料8替换为9和10,可以分别制备化合物12和13：
化合物12:淡黄色液体,6.82g,收率73％。1H NMR(400MHz,CDCl3)δ8.08(dd,J＝7.5,1.4Hz,2H),7.56(d,J＝7.6Hz,1H),7.47(t,J＝8.1Hz,1H),3.87(s,3H),3.26(t,J＝7.3Hz,2H),3.08(t,J＝7.3Hz,2H)ppm.
化合物13：无色液体,4.5g,收率68％。1H NMR(400MHz,CDCl3)δ4.73(t,J＝5.9Hz,2H),3.93(s,3H),3.53(t,J＝5.9Hz,2H)ppm.
步骤1.4
化合物14的制备
通用操作：室温下将对硝基苯环侧链酮酯11(2.00g,8.40mmol)的CH3OH(2mL)溶液滴加到2M NaOH(0.67g,16.80mmol)水溶液中，室温下反应(大约2h)。TLC板监测反应完全后，浓缩(除去甲醇)，加入Et2O(10mL)，分液，水相用2M HCl(10mL)淬灭，调至pH<1，Et2O(3×10mL)萃取，合并有机相，氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，浓缩。
化合物14[36]:淡黄色液体,1.00g,收率99％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.39(d,J＝8.8Hz,2H),3.31(t,J＝7.3Hz,2H),3.09(t,J＝7.2Hz,2H)ppm.
同步骤1.4，不同之处是将原料11替换为12和13,可以分别制备化合物15和16：
化合物15:淡黄色液体,1.00g,收率99％。1H NMR(400MHz,CDCl3)δ8.13–8.07(m,2H),7.56(d,J＝7.6Hz,1H),7.51–7.46(m,1H),3.36(t,J＝7.3Hz,2H),3.11(t,J＝7.3Hz,2H)ppm.
化合物16:无色液体4.3g,收率96％。1H NMR(400MHz,CDCl3)δ4.66(t,J＝5.9Hz,2H),3.48(t,J＝5.9Hz,2H)ppm.
步骤1.5
化合物17的制备
通用操作：氩气保护下，在0℃下向对硝基苯基侧链α-酮酸14(0.23g,1mmol)的CH2Cl2(10mL)溶液中滴加DMF(0.01g,0.02mmol)、草酰氯(0.25g,2.0mmol)。移至室温反应过夜。TLC板监测反应完全后，浓缩。得到粗产品，其无需进一步纯化直接用于下一步骤。
氩气保护下，将CET(0.16g,0.5mmol)溶于吡啶(1mL)和CH2Cl2(5mL)溶液中，0℃下滴加上述生成的对硝基苯基侧链酮酰氯(0.48g,2.00mmol)的CH2Cl2(5mL)溶液，0℃下反应过夜。升温至室温，用大量水洗涤，分液，CH2Cl2(2×10mL)萃取，合并有机相，有机相分别用碳酸氢钠溶液、氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩，梯度柱分离(CH2Cl2:Et2O＝200:1～100:1)。
化合物17:淡黄色无定形固体,552mg,收率26％。1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.5Hz,2H),7.24(d,J＝8.7Hz,2H),6.56(s,1H),6.45(s,1H),5.88(d,J＝9.3Hz,1H),5.80(s,1H),5.75(s,1H),5.11(s,1H),3.82(d,J＝9.4Hz,1H),3.70(s,3H),3.21–3.09(m,1H),3.10–3.02(m,2H),2.94–2.85(m,1H),2.81(t,J＝7.3Hz,2H),2.65(dt,J＝7.2,3.1Hz,1H),2.61–2.54(m,2H),2.30(dd,J＝14.6,7.0Hz,1H),2.00(dd,J＝8.4,3.5Hz,1H),1.94–1.86(m,1H),1.78–1.71(m,2H)ppm.HRMS(ESI)m/z calcd for C28H29N2O8,[M+H]+521.1918,found 521.1945.
同步骤1.5，不同之处是将原料14替换为15和16,可以分别制备化合物18和19：
化合物18:淡黄色无定形固体,3.916g,收率52％。1H NMR(400MHz,CDCl3)δ7.89(dt,J＝6.6,2.5Hz,1H),7.80(s,1H),7.27(d,J＝6.5Hz,2H),6.38(s,1H),6.24(s,1H),5.71(d,J＝9.2Hz,1H),5.60(d,J＝1.4Hz,1H),5.55(d,J＝1.4Hz,1H),4.93(s,1H),3.65(d,J＝9.4Hz,1H),3.53(s,3H),3.03–2.94(m,1H),2.92–2.87(m,1H),2.75–2.70(m,1H),2.64(t,J＝7.3Hz,2H),2.48–2.38(m,4H),2.14(dd,J＝14.5,7.0Hz,1H),1.88–1.81(m,1H),1.72(ddd,J＝12.2,7.6,4.6Hz,1H),1.57(dd,J＝11.1,5.7Hz,2H)ppm.HRMS(ESI)m/z calcd for C28H29N2O8,[M+H]+521.1918,found 521.1919.
化合物19：淡黄色无定形固体，2.84g，收率67％。HRMS(ESI)m/z calcd for C22H25N2O8,[M+H]+445.1605,found 445.1610.
步骤1.6
化合物20的制备
通用操作：氩气保护下，在0℃下向对硝基苯三尖杉α-酮酯碱17(0.52g,1mmol)的CH2Cl2(10mL)溶液中滴加三氟化硼乙醚(0.57g,4mmol)。20min后，再滴加TMS-ketene(0.25g,.5mmol)的CH2Cl2(10mL)溶液，0℃下过夜反应。TLC板监测反应完全后，加入碳酸氢钠溶液淬灭，调至pH＝9，CH2Cl2(3×10mL)萃取。合并有机相，氯化钠溶液洗涤，浓缩除去溶剂，得到中间产物。室温下，将中间产物溶于CH3CN(10mL)溶液中，加入KF·2H2O(0.47g,5mmol)，反应大约4h。TLC板监测反应完全后，过滤，滤液用无水硫酸钠干燥。抽滤，浓缩。柱分离PE:EA＝4:1,0.5％TEA。
化合物20:淡黄色无定形固体,40mg,收率22％。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),6.61(s,1H),6.58(s,1H),5.92(dd,J＝9.5,0.9Hz,1H),5.77(d,J＝1.5Hz,1H),5.60(d,J＝1.5Hz,1H),5.13(s,1H),3.84(d,J＝9.5Hz,1H),3.73(s,3H),3.15–3.00(m,3H),2.98–2.84(m,2H),2.65–2.51(m,4H),2.43–2.20(m,3H),2.08–1.97(m,1H),1.96–1.88(m,1H),1.82–1.71(m,2H)ppm.HRMS(ESI)m/z calcd for C30H31N2O9,[M+H]+563.2024,found 563.2026.
同步骤1.6，不同之处是将原料17替换为18和19,可以分别制备化合物21和22：
化合物21:淡黄色无定形固体,708mg,收率16％。1H NMR(400MHz,CDCl3)δ8.09(dt,J＝5.9,2.3Hz,1H),8.01(s,1H),7.47(d,J＝5.2Hz,2H),6.63(s,1H),6.57(s,1H),5.94(dd,J＝9.4,0.9Hz,1H),5.79(d,J＝1.5Hz,1H),5.65(d,J＝1.5Hz,1H),5.15(s,1H),3.86(d,J＝9.5Hz,1H),3.76(s,3H),3.16–3.05(m,2H),3.01(d,J＝16.5Hz,1H),2.93(td,J＝11.5,6.9Hz,1H),2.80(d,J＝16.5Hz,1H),2.72(td,J＝12.9,4.5Hz,1H),2.64–2.56(m,3H),2.46(dd,J＝14.2,6.8Hz,1H),2.36–2.25(m,1H),2.15–2.06(m,1H),1.97–1.88(m,2H),1.79–1.73(m,2H)ppm.HRMS(ESI)m/z calcd for C30H31N2O9,[M+H]+563.2024,found 563.2024.
化合物22:淡黄色无定形固体,1.20g,收率76％。HRMS(ESI)m/z calcd for C24H27N2O9,[M+H]+487.1711,found 487.1712.
步骤1.7
化合物I-2-1的制备
通用操作：氩气保护下，在室温条件下向对硝基苯三尖杉内酯20(0.56g,1mmol)的CH3OH(10mL)溶液中缓慢滴加现制的CH3ONa的CH3OH溶液(0.05g,1mmol)，室温反应(大约20min)。TLC板监测反应完全后，加入饱和的氯化铵溶液(10mL)淬灭。浓缩(除去甲醇)，加入10mL水和10mL CH2Cl2，搅拌后分液，水相用CH2Cl2(3×10mL)萃取，合并有机相，浓缩除去部分溶剂。加入pH＝6.8的缓冲溶液(2×10mL)洗涤至三尖杉碱完全除去，碳酸氢钠溶液、氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩。柱分离PE:EA＝4:1,0.5％TEA。
化合物I-2-1:淡黄色无定形固体,25mg,收率52％。1H NMR(400MHz,CDCl3)δ8.13(d,J＝8.6Hz,2H),7.25(d,J＝8.4Hz,2H),6.58(s,1H),6.56(s,1H),6.04(d,J＝9.7Hz,1H),5.83(d,J＝1.6Hz,1H),5.74(d,J＝1.6Hz,1H),5.11(s,1H),3.81(d,J＝9.8Hz,1H),3.69(s,3H),3.65(s,1H),3.59(s,3H),3.19–3.05(m,2H),2.94(td,J＝11.6,6.9Hz,1H),2.75(td,J＝12.7,5.3Hz,1H),2.66–2.54(m,2H),2.49–2.32(m,2H),2.29(d,J＝16.4Hz,1H),2.11–1.96(m,2H),1.92(ddd,J＝12.2,7.6,4.6Hz,1H),1.82–1.69(m,4H)ppm.HRMS(ESI)m/z calcd for C31H35N2O10,[M+H]+595.2286,found 595.2288.
同步骤1.7，不同之处是将原料20替换为21和22，分别制备化合物I-2-2～I-2-4：
化合物I-2-2:淡黄色无定形固体,516mg,收率69％。1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.0Hz,1H),7.96(s,1H),7.47–7.41(m,2H),6.57(s,1H),6.56(s,1H),6.06(d,J＝9.7Hz,1H),5.83(s,1H),5.76(s,1H),5.14(s,1H),3.83(d,J＝9.8Hz,1H),3.73(s,3H),3.68(s,1H),3.59(s,3H),3.21–3.07(m,2H),2.98(td,J＝11.8,10.8,6.3Hz,1H),2.78(td,J＝13.0,5.1Hz,1H),2.70–2.59(m,2H),2.46(td,J＝13.1,4.4Hz,1H),2.38(dd,J＝14.0,6.8Hz,1H),2.28(d,J＝16.6Hz,1H),2.12–2.04(m,1H),2.00–1.90(m,3H),1.82–1.72(m,3H)ppm.HRMS(ESI)m/z calcd for C31H35N2O10,[M+H]+595.2286,found 595.2284.
化合物I-2-3:淡黄色无定形固体,720mg,收率75％。HRMS(ESI)m/z calcdfor C25H31N2O10,[M+H]+519.1973,found 519.1970.
化合物I-2-4:淡黄色无定形固体,680mg,收率70％。HRMS(ESI)m/z calcdfor C26H33N2O10,[M+H]+533.2130,found 533.2135.
实施例2三尖杉酯物碱类似物I-2-5制备
将I-2-2(1mmol)溶于1mL AcOH中，加入Zn粉(20mmol)，室温反应，TLC板监测反应完全后，混合液经硅藻土过滤，CH2Cl2洗涤硅藻土，得滤液，向滤液中加入CH2Cl2和碳酸氢钠溶液，搅拌30min，分液，水相用CH2Cl2萃取，合并有机相，干燥，过滤，浓缩。柱层析，得到本标题化合物I-2-5的淡黄色固体产物(收率93％).1H NMR(400MHz,CDCl3)δ7.05(t,J＝7.7Hz,1H),6.59(s,1H),6.55(s,1H),6.53–6.48(m,2H),6.44(t,J＝2.0Hz,1H),6.05(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.75(d,J＝1.6Hz,1H),5.08(s,1H),3.80(d,J＝9.8Hz,1H),3.70(s,3H),3.58(s,4H),3.20–3.09(m,2H),3.02–2.93(m,1H),2.64–2.50(m,3H),2.38(dd,J＝14.2,6.8Hz,1H),2.33–2.23(m,2H),2.07–1.92(m,3H),1.82–1.74(m,2H),1.70(dt,J＝11.9,5.7Hz,2H)ppm.HRMS(ESI)m/z calcd for C31H37N2O8,[M+H]+565.2544,found 565.2541.
实施例3化合物I-2-6～I-2-8的制备
参照实施例2，不同之处是将原料I-2-2替换为I-2-1、I-2-3和I-2-4，分别制备化合物I-2-6～I-2-8。
化合物I-2-6：淡黄色无定形产物，收率90％。HRMS(ESI)m/z calcd for C31H37N2O8,[M+H]+565.2544,found 565.2540.
化合物I-2-7的淡黄色无定形固体产物，收率88％。HRMS(ESI)m/z calcd for C25H33N2O8,[M+H]+489.2231,found 489.2230.
化合物I-2-8的淡黄色无定形固体产物，收率92％。HRMS(ESI)m/z calcdfor C26H35N2O8,[M+H]+503.2388,found 503.2392.
实施例4三尖杉酯物碱类似物I-2-9制备
氩气保护下，在0℃下向I-2-5(1mmol)的CH2Cl2(5mL)中，一次滴加入TEA(3mmol)、乙酰氯(1.1mmol)，滴加完毕后，移至室温过夜反应。TLC板监测反应完全后，加入碳酸氢钠溶液淬灭，调pH＝8，CH2Cl2萃取，合并有机相，干燥，过滤，浓缩。柱层析，得到本标题化合物(I-2-9)的淡黄色固体产物(收率93％).1H NMR(400MHz,CDCl3)δ7.32(d,J＝7.9Hz,1H),7.25(s,2H),7.20(t,J＝7.8Hz,1H),6.84(d,J＝7.5Hz,1H),6.59(s,1H),6.55(s,1H),6.04(d,J＝9.7Hz,1H),5.83(d,J＝1.4Hz,1H),5.72(d,J＝1.5Hz,1H),5.09(s,1H),3.80(d,J＝9.8Hz,1H),3.70(s,3H),3.58(s,4H),3.20–3.06(m,2H),3.01–2.89(m,1H),2.66–2.56(m,3H),2.38(dd,J＝14.2,6.9Hz,1H),2.33–2.27(m,2H),2.16(s,3H),2.06–1.97(m,3H),1.96–1.87(m,2H),1.72(dt,J＝11.9,5.7Hz,2H)ppm.HRMS(ESI)m/z calcd for C33H39N2O9,[M+H]+607.2650,found 607.2651.
实施例5化合物I-2-10和I-2-12的制备
参照实施例4，不同之处是将原料I-2-5替换为I-2-6～I-2-8，分别制备化合物I-2-10～I-2-12。
化合物I-2-10：淡黄色固体产物，收率90％。HRMS(ESI)m/z calcd for C33H39N2O9,[M+H]+607.2650,found 607.2651.
化合物I-2-11：淡黄色固体产物，收率88％。HRMS(ESI)m/z calcd for C27H35N2O9,[M+H]+531.2337,found 531.2339.
化合物I-2-12：淡黄色固体产物，收率88％。HRMS(ESI)m/z calcd for C28H37N2O9,[M+H]+545.2494,found 545.2490.
实施例6化合物I-2-13～I-2-22的制备
参照实施例5化合物I-2-9的制备方法，不同之处是将不同酰氯代替乙酰氯与化合物I-2-7或者I-2-8反应，分别制备化合物I-2-13～I-2-22。

实施例7化合物I-2-23～I-2-28和I-1-100的制备
参照实施例4，不同之处是将不同酰氯代替乙酰氯与化合物I-2-5反应，分别制备化合物I-2-23～I-2-28和I-1-100。
实施例8：三尖杉酯物碱类似物I-1-1制备
氩气保护下，向I-2-5(1mmol)的CH2Cl2(5mL)中，滴加对甲苯异氰酸酯(1mmol)，滴加完毕后，室温过夜反应。TLC板监测反应完全后，浓缩。柱层析，得到本标题化合物I-1-1的淡黄色固体产物(收率96％).1H NMR(400MHz,CDCl3)δ7.23(d,J＝8.4Hz,3H),7.19(d,J＝7.9Hz,1H),7.13(d,J＝8.2Hz,2H),7.04(s,1H),6.83(d,J＝6.8Hz,1H),6.70(d,J＝7.5Hz,1H),6.56(s,1H),6.54(s,1H),6.02(d,J＝9.7Hz,1H),5.82(d,J＝1.4Hz,1H),5.71(d,J＝1.4Hz,1H),5.07(s,1H),3.79(d,J＝9.8Hz,1H),3.68(s,3H),3.58(s,3H),3.20–3.03(m,2H),3.00–2.85(m,1H),2.68–2.52(m,3H),2.36(dd,J＝14.2,6.8Hz,2H),2.32(s,3H),2.28(d,J＝6.1Hz,1H),2.08–1.97(m,3H),1.97–1.85(m,2H),1.72–1.65(m,2H)ppm.HRMS(ESI)m/z calcd for C39H44N3O9,[M+H]+698.3072,found 698.3072.
实施例9：三尖杉酯物碱类似物I-1-2、I-1-7、I-1-9、I-1-12、I-1-22、I-1-97、I-1-98和I-1-99制备
参照实施例8，不同之处是分别用环戊基异氰酸酯、环丙基异氰酸酯、环己基异氰酸酯、叔丁基异氰酸酯、苄基异氰酸酯、4-甲氧苯基异氰酸酯、3-氯-4-甲苯基异氰酸酯、3,5-二三氟甲基苯基异氰酸酯、4-氟苯基异氰酸酯代替对甲苯基异氰酸酯，可以分别制备化合物I-1-2、I-1-7、I-1-9、I-1-12、I-1-22、I-1-26、I-1-97、I-1-98、I-1-99
本标题化合物I-1-2为淡黄色固体产物(收率69％)。1H NMR(400MHz,CDCl3)δ7.17(d,J＝4.9Hz,2H),7.00(s,1H),6.78(d,1H),6.58(s,1H),6.54(s,1H),6.03(d,J＝9.7Hz,1H),5.82(d,J＝1.4Hz,1H),5.72(d,J＝1.3Hz,1H),5.08(s,1H),3.79(d,J＝9.8Hz,1H),3.68(s,3H),3.58(s,3H),3.20–3.03(m,3H),3.00–2.87(m,1H),2.65–2.54(m,3H),2.37(dd,J＝14.0,6.8Hz,2H),2.29(d,J＝16.5Hz,2H),2.03(d,J＝8.7Hz,2H),2.01–1.90(m,4H),1.77–1.66(m,4H),1.66–1.58(m,4H)ppm.HRMS(ESI)m/z calcd for C37H46N3O9,[M+H]+676.3229,found 676.3226.
本标题化合物I-1-7为淡黄色固体产物(收率92％)。1H NMR(400MHz,Chloroform-d)δ7.24-7.20(m,1H),7.11(t,J＝7.8Hz,1H),7.04(s,2H),6.71(d,J＝7.5Hz,1H),6.52(s,1H),6.48(s,1H),5.97(d,J＝9.7Hz,1H),5.76(d,J＝1.6Hz,1H),5.65(d,J＝1.6Hz,1H),5.20(s,1H),5.02(s,1H),3.73(d,J＝9.8Hz,1H),3.63(s,3H),3.58(s,1H),3.51(s,3H),3.15–2.99(m,2H),2.88(td,J＝11.5,6.8Hz,1H),2.64–2.48(m,4H),2.36–2.29(m,1H),2.24(dd,J＝17.4,6.2Hz,2H),2.05–1.93(m,2H),1.93–1.84(m,1H),1.73(d,J＝8.0Hz,2H),1.69–1.60(m,2H),0.73(q,J＝4.7Hz,2H),0.54(q,J＝5.1,4.7Hz,2H)ppm.HRMS(ESI)m/z calcd for C35H42N3O9,[M+H]+648.2916,found 648.2915.
本标题化合物I-1-9为淡黄色固体产物(收率89％)。1H NMR(400MHz,Chloroform-d)δ7.20–7.13(m,2H),7.01(s,1H),6.84(s,1H),6.76(d,J＝6.7Hz,1H),6.58(s,1H),6.54(s,1H),6.02(d,J＝9.7Hz,1H),5.82(d,J＝1.6Hz,1H),5.72(d,J＝1.6Hz,1H),5.08(s,1H),3.79(d,J＝9.8Hz,1H),3.67(s,3H),3.64(s,1H),3.59-3.63(s,1H),3.58(s,3H),3.19–3.05(m,2H),2.92(td,J＝11.5,6.9Hz,1H),2.59(ddt,J＝17.6,12.4,6.6Hz,3H),2.41–2.34(m,1H),2.35–2.25(m,2H),2.08–1.96(m,3H),1.95–1.89(m,3H),1.79–1.64(m,6H),1.57(dd,J＝10.5,6.4Hz,1H),1.37–1.28(m,2H),1.17–1.06(m,3H)ppm.HRMS(ESI)m/z calcd for C38H48N3O9,[M+H]+690.3385,found 690.3382.
本标题化合物I-1-12为淡黄色固体产物(收率90％)。1H NMR(400MHz,Chloroform-d)δ7.12-7.04(m,2H),6.95(s,1H),6.76(d,J＝12.6Hz,1H),6.66(d,J＝6.8Hz,1H),6.51(s,1H),6.47(s,1H),5.96(d,J＝9.7Hz,1H),5.76(d,J＝1.5Hz,1H),5.66(d,J＝1.6Hz,1H),5.07-4.98(m,2H),3.72(d,J＝9.8Hz,1H),3.62-3.57(m,4H),3.50(s,3H),3.12–2.98(m,2H),2.86(td,J＝11.6,7.0Hz,1H),2.60–2.47(m,3H),2.31(dd,J＝14.4,6.7Hz,1H),2.23(dd,J＝14.7,6.9Hz,2H),2.02–1.92(m,2H),1.90–1.82(m,1H),1.70(dd,J＝12.1,5.4Hz,2H),1.67–1.61(m,2H),1.28(s,9H)ppm.HRMS(ESI)m/z calcd for C36H46N3O9,[M+H]+664.3229,found 664.3226.
本标题化合物I-1-17为淡黄色固体产物(收率93％)。1H NMR(400MHz,Chloroform-d)δ7.24–7.17(m,5H),7.09(d,J＝6.4Hz,2H),6.95(s,1H),6.82(s,1H),6.71(d,J＝6.7Hz,1H),6.47(s,1H),6.43(s,1H),5.93(d,J＝9.6Hz,1H),5.71(d,J＝1.6Hz,1H),5.59(d,J＝1.6Hz,1H),5.48(s,1H),5.00(s,1H),4.40–4.28(m,2H),3.69(d,J＝9.7Hz,1H),3.60(s,3H),3.54(s,1H),3.50(s,3H),3.12–2.99(m,2H),2.86(td,J＝11.5,6.7Hz,1H),2.63–2.43(m,3H),2.30 (dd,J＝14.2,6.6Hz,1H),2.25–2.17(m,2H),2.01–1.91(m,2H),1.89–1.82(m,1H),1.74–1.66(m,J＝7.7Hz,2H),1.64–1.57(m,2H)ppm.HRMS(ESI)m/z calcd for C39H44N3O9,[M+H]+698.3072,found 698.3070.
本标题化合物I-1-22为淡黄色固体产物(收率90％)。1H NMR(400MHz,Chloroform-d)δ7.42-7.38(m,2H),7.23-7.15(m,3H),7.10(t,J＝7.7Hz,1H),7.03(s,1H),6.80–6.75(m,2H),6.72(d,J＝7.5Hz,1H),6.50(d,J＝12.4Hz,2H),5.99(d,J＝9.7Hz,1H),5.80(s,1H),5.69(s,1H),5.04(s,1H),3.76(s,1H),3.72(s,3H),3.69(s,1H),3.64(s,3H),3.54(s,3H),3.16–3.04(m,2H),2.88(td,J＝11.6,6.9Hz,1H),2.66–2.49(m,3H),2.33(td,J＝6.7Hz,J＝12.0,1H),2.30–2.23(m,2H),2.03–1.87(m,3H),1.74(m,2H),1.69–1.61(m,2H)ppm.HRMS(ESI)m/z calcd for C39H44N3O10,[M+H]+714.3021,found 714.3023.
本标题化合物I-1-97为淡黄色固体产物(收率88％)。1H NMR(400MHz,Chloroform-d)δ7.70(d,J＝13.8Hz,2H),7.37(d,J＝2.2Hz,1H),7.23–7.16(m,1H),7.15–7.08(m,2H),7.07–6.98(m,2H),6.73(d,J＝7.5Hz,1H),6.57(s,1H),6.52(s,1H),6.02(d,J＝9.7Hz,1H),5.82(d,J＝1.5Hz,1H),5.73(d,J＝1.6Hz,1H),5.07(s,1H),3.80(s,1H),3.77(d,J＝9.7Hz,1H),3.65(s,3H),3.55(s,3H),3.18–3.03(m,2H),2.95–2.85(m,1H),2.65–2.50(m,3H),2.39–2.29(m,2H),2.25(s,3H),2.18-2.12(m,1H),2.07–1.87(m,3H),1.80–1.73(m,2H),1.73–1.66(m,2H).HRMS(ESI)m/z calcd for C39H43ClN3O9,[M+H]+732.2682,found 732.2678.
本标题化合物I-1-98为淡黄色固体产物(收率84％)。1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),8.00(s,2H),7.95(s,1H),7.46(s,1H),7.42(d,J＝7.3Hz 1H),7.16(t,J＝7.8Hz,1H),7.03(s,1H),6.73(d,J＝7.6Hz,1H),6.60(s,1H),6.51(s,1H),6.04(d,J＝9.7Hz,1H),5.83(d,J＝1.5Hz,1H),5.75(d,J＝1.5Hz,1H),5.11(s,1H),4.04(s,1H),3.78(d,J＝9.7Hz,1H),3.64(s,3H),3.54(s,3H),3.18–3.05(m,2H),2.93(td,J＝11.4,6.9Hz,1H),2.63(ddd,J＝16.4,13.4,7.8Hz,3H),2.42(ddt,J＝13.9,10.5,7.1Hz,2H),2.30(d,J＝16.9Hz,1H),2.10–1.97(m,2H),1.97–1.88(m,1H),1.82-1.70(m,4H).HRMS(ESI)m/z calcd for C40H40F6N3O9,[M+H]+820.2663,found 820.2652.
本标题化合物I-1-99为淡黄色固体产物(收率84％)。1H NMR(400MHz,Chloroform-d)δ7.85–7.62(m,2H),7.32–7.22(m,2H),7.19(d,J＝8.1Hz,1H),7.12(t,J＝7.6Hz,1H),7.05(s,1H),6.90(t,J＝8.0Hz,2H),6.74(d,J＝7.6Hz,1H),6.55(s,1H),6.50(s,1H),6.01(d,J＝9.7Hz,1H),5.82(d,J＝1.6Hz,1H),5.72(d,J＝1.6Hz,1H),5.06(s,1H),3.77(d,J＝9.8Hz,1H),3.66(s,3H),3.59(s,1H),3.55(s,3H),3.19–3.05(m,2H),2.90(td,J＝11.5,6.8Hz,1H),2.69–2.48(m,3H),2.40–2.28(m,2H),2.27(d,J＝16.7Hz,1H),2.07–1.99(m,1H),1.97(d,J＝16.9Hz,1H),1.95–1.85(m,1H),1.83–1.70(m,2H),1.73–1.64(m,2H).HRMS(ESI)m/z calcd for C38H41FN3O9,[M+H]+702.2821,found 702.2829.
实施例10：三尖杉酯物碱类似物I-1-3～I-1-36(除实施例9外的化合物)的制备
参照实施例8，不同之处是用不同取代的异氰酸酯，分别制备化合物I-1-3～I-1-33。
实施例11：三尖杉酯物碱类似物I-1-34～I-1-63的制备
参照实施例8，不同之处是用不同取代的异氰酸酯与化合物I-2-7反应，分别制备化合物I-1-34～I-1-63。
实施例12：三尖杉酯物碱类似物I-1-64～I-1-72的制备
参照实施例8，不同之处是用不同取代的异氰酸酯与化合物I-2-8反应，分别制备化合物I-1-64～I-1-72。
实施例13：三尖杉酯物碱类似物I-1-73的制备
参照实施例8，不同之处是用苯甲酰基异氰酸酯代替对甲苯基异氰酸酯与化合物I-2-5反应，制备化合物I-1-73。
本标题化合物I-1-73的淡黄色固体产物(收率92％)。1H NMR(400MHz,CDCl3)δ10.80(s,1H),8.75(s,1H),7.94(s,1H),7.82(d,J＝8.6Hz,1H),7.65(d,J＝7.4Hz,1H),7.54(t,J＝7.6Hz,2H),7.51–7.43(m,2H),6.91(s,1H),6.60(s,1H),6.56(s,1H),6.06(d,J＝9.9Hz,1H),5.84(d,J＝1.4Hz,1H),5.75(d,J＝1.4Hz,1H),5.13(s,1H),3.81(d,J＝9.8Hz,1H),3.73(s,3H),3.64(s,1H),3.59(s,3H),3.27–3.00(m,2H),3.00–2.88(m,1H),2.85–2.47(m,3H),2.46–2.34(m,1H),2.31(d,J＝16.6Hz,1H),2.08–1.97(m,2H),1.94(d,J＝10.2Hz,1H),1.88–1.65(m,3H),1.58(s,2H)ppm.HRMS(ESI)m/z calcd for C39H42N3O10,[M+H]+712.2865,found 712.2865.
实施例14：三尖杉酯物碱类似物I-1-74～I-1-81的制备
参照实施例8，不同之处是用不同的酰基异氰酸酯代替对甲苯基异氰酸酯分别与化合物I-2-5、I-2-7或者I-2-8反应，分别制备化合物I-1-74～I-1-81。
实施例15：三尖杉酯物碱类似物I-1-82的制备
参照实施例8，不同之处是用苯磺酰基异氰酸酯代替对甲苯基异氰酸酯，制备化合物I-1-82。
本标题化合物I-1-82的淡黄色固体产物(收率83％)。1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.1Hz,2H),7.25–7.11(m,3H),7.10–7.00(m,1H),6.70(d,J＝5.8Hz,1H),6.55(s,1H),6.47(s,1H),6.00(d,J＝9.4Hz,1H),5.80(d,J＝1.4Hz,1H),5.68(d,J＝1.4Hz,1H),5.08(s,1H),3.82(d,J＝9.1Hz,1H),3.60(s,3H),3.54(s,3H),3.41–3.27(m,1H),3.27–3.12(m,2H),3.12–3.00(m,1H),2.61–2.39(m,2H),2.36(s,3H),2.31–2.13(m,3H),2.09–1.89(m,3H),1.89–1.72(m,2H),1.72–1.54(m,2H)ppm.HRMS(ESI)m/z calcd for C39H44N3O11S,[M+H]+762.2691,found 762.2691.
实施例16：三尖杉酯物碱类似物I-1-83～I-1-96的制备
参照实施例8，不同之处是用不同取代的腈胺、酰基腈胺或者不同取代的碳二亚胺分别与化合物I-2-5、I-2-7或者I-2-8反应，分别制备化合物I-1-83～I-1-96。
实施例17：β-环内酯三尖杉酯类生物碱23-40的制备
参照实施例1步骤1.6，不同之处是用侧链不同取代的三尖杉α-酮酯碱分别与三甲基硅基烯酮反应，制备化合物23-40。
化合物23：浅黄色固体，收率23％。(c 0.45,CHCl3).1H NMR(400MHz,CDCl3)δ6.60(d,J＝2.6Hz,2H),5.92(d,J＝9.6Hz,1H),5.86(dd,J＝7.3,1.5Hz,2H),5.09(s,1H),3.82(d,J＝9.5Hz,1H),3.69(s,3H),3.13–3.03(m,2H),3.00(d,J＝16.5Hz,1H),2.95–2.89(m,1H),2.74(d,J＝16.5Hz,1H),2.62–2.57(m,2H),2.35(dd,J＝14.2,6.8Hz,1H),2.09–2.00(m,3H),1.91(ddd,J＝12.1,7.6,4.2Hz,2H),1.80–1.71(m,3H),1.56–1.47(m,2H).HRMS(ESI)m/z calcd for C26H29F3NO7,[M+H]+524.1891,found 524.1889.
化合物24：淡黄色固体产物(收率30％)。(c 0.7,CHCl3).1H NMR(400MHz,CDCl3)δ6.60(d,J＝4.2Hz,2H),5.90(d,J＝9.5Hz,1H),5.87(dd,J＝10.3,1.5Hz,2H),5.11(s,1H),3.82(d,J＝9.4Hz,1H),3.68(s,2H),3.11–3.03(m,2H),3.04(d,J＝16.4Hz,1H),2.93(td,J＝11.9,11.4,6.8Hz,1H),2.80(d,J＝16.4Hz,1H),2.62–2.56(m,2H),2.36(dd,J＝14.0,6.5Hz,1H),2.28–2.20(m,1H),2.04(ddd,J＝12.6,10.8,7.0Hz,3H),1.97–1.88(m,3H),1.75–1.72(m,2H).HRMS(ESI)m/z calcd for C26H27F5NO7,[M+H]+560.1702,found 560.1700.
化合物25：淡黄色无定形固体，收率50％。1H NMR(400MHz,CDCl3)δ7.09(dd,J＝7.9,5.7Hz,2H),6.98(t,J＝8.6Hz,2H),6.63(s,1H),6.59(s,1H),5.95(d,J＝9.5Hz,1H),5.81(s,1H),5.61(s,1H),5.14(s,1H),3.86(d,J＝9.5Hz,1H),3.74(s,3H),3.17–3.06(m,2H),3.01(d,J＝16.5Hz,1H),2.94(td,J＝11.7,7.1Hz,1H),2.83(d,J＝16.5Hz,1H),2.64–2.56(m,2H),2.48(td,J＝12.6,4.7Hz,1H),2.37(dd,J＝14.3,6.9Hz,1H),2.32–2.26(m,1H),2.25–2.17(m,1H),2.10–2.03(m,1H),1.97–1.88(m,2H),1.81–1.74(m,2H)ppm.HRMS(ESI)m/z calcd for C30H31FNO7,[M+H]+536.2082,found 536.2085.
化合物26：淡黄色无定形固体，收率80％。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),6.62(s,1H),6.58(s,1H),5.94(dd,J＝9.5,0.9Hz,1H),5.78(d,J＝1.5Hz,1H),5.57(d,J＝1.5Hz,1H),5.13(d,J＝0.9Hz,1H),3.85(d,J＝9.5Hz,1H),3.73(s,3H),3.10(ddt,J＝13.3,8.9,6.7Hz,2H),3.02(d,J＝16.5Hz,1H),2.93(td,J＝11.6,6.9Hz,1H),2.86(d,J＝16.5Hz,1H),2.67–2.47(m,3H),2.42–2.28(m,2H),2.22(ddd,J＝14.1,12.1,4.7Hz,1H),2.05(dt,J＝12.3,9.6Hz,1H),1.98–1.86(m,2H),1.83–1.70(m,2H)ppm.HRMS(ESI)m/z calcd for C31H31F3NO7,[M+H]+586.2047,found 586.2053.
化合物27：淡黄色无定形固体，收率97％。1H NMR(400MHz,CDCl3)δ7.07(q,J＝8.1Hz,1H),6.84–6.72(m,2H),6.61(s,1H),6.56(s,1H),5.93(d,J＝9.5Hz,1H),5.80(s,1H),5.64(s,1H),5.11(s,1H),3.83(d,J＝9.6Hz,1H),3.71(s,3H),3.16–3.04(m,2H),3.01(d,J＝16.5Hz,1H),2.92(td,J＝11.5,7.0Hz,1H),2.81(d,J＝16.6Hz,1H),2.63–2.55(m,2H),2.49(dd,J＝12.5,4.7Hz,1H),2.40–2.30(m,2H),2.17(td,J＝13.1,12.4,4.9Hz,1H),2.08–2.01(m,1H),1.95–1.85(m,2H),1.79–1.72(m,2H)ppm.HRMS(ESI)m/z calcd for C30H30F2NO7,[M+H]+554.1987,found 554.1990.
化合物28：淡黄色无定形固体，收率50％。1H NMR(400MHz,CDCl3)δ6.71–6.56(m,5H),5.93(d,J＝9.5Hz,1H),5.81(d,J＝1.6Hz,1H),5.69(d,J＝1.5Hz,1H),5.13(s,1H),3.85(d,J＝9.5Hz,1H),3.74(s,3H),3.12–3.05(m,2H),2.99(d,J＝16.5Hz,1H),2.92(td,J＝11.9,7.2Hz,1H),2.78(d,J＝16.5Hz,1H),2.63–2.55(m,2H),2.49(td,J＝12.8,12.3,5.0Hz,1H),2.38–2.14(m,3H),2.06–2.01(m,1H),1.96–1.88(m,2H),1.80–1.73(m,2H)ppm.HRMS(ESI)m/z calcd for C30H30F2NO7,[M+H]+554.1979,found 554.1990.
化合物29：淡黄色无定形固体，收率95％。1H NMR(400MHz,CDCl3)δ6.98–6.92(m,1H),6.91–6.82(m,2H),6.62(s,1H),6.56(s,1H),5.95(d,J＝9.5Hz,1H),5.81(d,J＝1.5Hz,1H),5.68(d,J＝1.5Hz,1H),5.12(s,1H),3.88–3.81(m,1H),3.73(s,3H),3.15–3.05(m,2H),3.04–2.92(m,2H),2.79(d,J＝16.5Hz,1H),2.63–2.55(m,3H),2.40–2.30(m,2H),2.23–2.12(m,1H),2.10–2.00(m,1H),1.98–1.86(m,2H),1.81–1.72(m,2H)ppm.HRMS(ESI)m/z calcd for C30H30F2NO7,[M+H]+554.1983,found 554.1990.
化合物30：淡黄色无定形固体，收率97％。1H NMR(400MHz,CDCl3)δ7.05–6.96(m,2H),6.87(t,J＝7.1Hz,1H),6.61(s,1H),6.56(s,1H),5.93(d,J＝9.5Hz,1H),5.80(s,1H),5.66(s,1H),5.11(s,1H),3.84(d,J＝9.5Hz,1H),3.72(s,3H),3.15–3.06(m,2H),3.01(d,J＝16.5Hz,1H),2.92(td,J＝11.8,7.0Hz,1H),2.79(d,J＝16.5Hz,1H),2.66–2.52(m,3H),2.46(dt,J＝18.0,9.1Hz,1H),2.35(dd,J＝14.2,6.8Hz,1H),2.26–2.19(m,1H),2.07–1.99(m,1H),1.95–1.86(m,2H),1.81–1.69(m,2H)ppm.HRMS(ESI)m/z calcd for C30H30F2NO7,[M+H]+554.1983,found 554.1990.
化合物31：淡黄色无定形固体，收率89％。1H NMR(400MHz,CDCl3)δ7.61(dd,J＝7.9,1.4Hz,1H),7.48(dd,J＝8.3,6.9Hz,1H),7.32(t,J＝7.7Hz,1H),7.26(d,J＝7.6Hz,1H),6.61(s,1H),6.54(s,1H),5.97(dd,J＝9.5,1.0Hz,1H),5.78(d,J＝1.5Hz,1H),5.57(d,J＝1.5Hz,1H),5.11(d,J＝1.0Hz,1H),3.84(d,J＝9.6Hz,1H),3.72(s,3H),3.16–3.06(m,2H),3.02(d,J＝16.5Hz,1H),2.92(td,J＝11.7,7.0Hz,1H),2.80(d,J＝16.5Hz,1H),2.70(td,J＝13.0,4.6Hz,1H),2.63–2.54(m,3H),2.34(dd,J＝14.3,6.9Hz,1H),2.23–2.15(m,1H),2.07–2.02(m,1H),1.94–1.88(m,2H),1.79–1.73(m,2H)ppm.HRMS(ESI)m/z calcd for C31H31F3NO7,[M+H]+586.2045,found 586.2053.
化合物32：淡黄色无定形固体，收率80％。1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.7Hz,1H),7.45–7.36(m,2H),7.31(d,J＝7.6Hz,1H),6.62(s,1H),6.57(s,1H),5.96(d,J＝9.5Hz,1H),5.79(d,J＝1.5Hz,1H),5.61(d,J＝1.5Hz,1H),5.13(s,1H),3.85(d,J＝9.5Hz,1H),3.73(s,3H),3.18–3.04(m,2H),2.98(d,J＝16.5Hz,1H),2.93(td,J＝11.5,6.9Hz,1H),2.81(d,J＝16.5Hz,1H),2.69–2.49(m,3H),2.42–2.30(m,1H),2.23(td,J＝12.9,12.2,4.7Hz,1H),2.11–1.99(m,1H),1.96–1.87(m,1H),1.79–1.72(m,2H),1.71–1.62(m,2H)ppm.HRMS(ESI)m/z calcd for C31H31F3NO7,[M+H]+586.2044,found 586.2053.
化合物33：淡黄色无定形固体，收率56％。1H NMR(400MHz,CDCl3)δ7.32(dd,J＝9.1,2.7Hz,1H),7.26–7.22(m,1H),7.18(td,J＝8.1,2.6Hz,1H),6.61(s,1H),6.55(s,1H),5.95(d,J＝9.5Hz,1H),5.79(d,J＝1.5Hz,1H),5.59(d,J＝1.6Hz,1H),5.11(s,1H),3.84(d,J＝9.5Hz,1H),3.72(s,3H),3.17–3.03(m,2H),3.01(d,J＝16.6Hz,1H),2.92(td,J＝11.6,7.0Hz,1H),2.80(d,J＝16.5Hz,1H),2.72–2.44(m,4H),2.34(dd,J＝14.3,6.9Hz,1H),2.18(ddd,J＝14.3,12.1,4.8Hz,1H),2.08–1.98(m,1H),1.97–1.79(m,2H),1.82–1.70(m,2H)ppm.HRMS(ESI)m/z calcd for C31H30F4NO7,[M+H]+604.1952,found 604.1958.
化合物34：淡黄色无定形固体，收率63％。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),6.62(s,1H),6.58(s,1H),5.94(dd,J＝9.5,0.9Hz,1H),5.78(d,J＝1.5Hz,1H),5.57(d,J＝1.5Hz,1H),5.13(d,J＝0.9Hz,1H),3.85(d,J＝9.5Hz,1H),3.73(s,3H),3.10(ddt,J＝13.3,8.9,6.7Hz,2H),3.02(d,J＝16.5Hz,1H),2.93(td,J＝11.6,6.9Hz,1H),2.86(d,J＝16.5Hz,1H),2.67–2.47(m,3H),2.42–2.28(m,2H),2.22(ddd,J＝14.1,12.1,4.7Hz,1H),2.05(dt,J＝12.3,9.6Hz,1H),1.98–1.86(m,2H),1.83–1.70(m,2H)ppm.HRMS(ESI)m/z calcd for C31H34NO7,[M+H]+532.2331,found 532.2335.
化合物35：淡黄色无定形固体，收率89％。1H NMR(400MHz,CDCl3)δ7.98–7.91(m,1H),7.86(dd,J＝7.1,2.2Hz,1H),7.74(d,J＝8.2Hz,1H),7.56–7.44(m,2H),7.39(dd,J＝8.2,7.0Hz,1H),7.7.29–7.25(m,1H),6.64(s,1H),6.50(s,1H),6.04(dd,J＝9.5,0.9Hz,1H),5.72(d,J＝1.5Hz,1H),5.42(d,J＝1.5Hz,1H),5.16(s,1H),3.88(d,J＝9.6Hz,1H),3.73(s,3H),3.27–3.13(m,1H),3.15–3.05(m,1H),3.01–2.82(m,4H),2.80(d,J＝16.5Hz,1H),2.69–2.56(m,2H),2.46–2.29(m,2H),2.10–2.00(m,1H),2.00–1.90(m,1H),1.83–1.73(m,2H),1.72–1.67(m,1H)ppm.HRMS(ESI)m/z calcd for C34H34NO7,[M+H]+568.2326,found 568.2335.
化合物36：淡黄色无定形固体，收率85％。1H NMR(400MHz,CDCl3)δ7.84–7.73(m,3H),7.56(s,1H),7.48–7.41(m,2H),7.25(d,J＝8.5Hz,1H),6.63(s,1H),6.58(s,1H),5.98(d,J＝9.5Hz,1H),5.74(s,1H),5.51(s,1H),5.13(s,1H),3.86(d,J＝9.5Hz,1H),3.75(s,3H),3.21–3.04(m,2H),3.01(d,J＝16.5Hz,1H),2.98–2.89(m,1H),2.86(d,J＝16.5Hz,1H),2.68–2.54(m,3H),2.45(dt,J＝13.0,6.4Hz,1H),2.41–2.26(m,2H),2.09–1.97(m,2H),1.98–1.87(m,1H),1.83–1.71(m,2H)ppm.HRMS(ESI)m/z calcd for C34H34NO7,[M+H]+568.2321,found 568.2335.
化合物37：淡黄色无定形固体，收率89％。1H NMR(400MHz,CDCl3)δ7.03(d,J＝8.2Hz,2H),6.82(d,J＝8.1Hz,2H),6.61(s,1H),6.58(s,1H),5.94(d,J＝9.5Hz,1H),5.80(d,J＝1.6Hz,1H),5.61(d,J＝1.6Hz,1H),5.12(s,1H),3.84(d,J＝9.5Hz,1H),3.78(s,3H),3.73(s,3H),3.18–3.03(m,2H),2.96(d,J＝16.7Hz,1H),2.97–2.87(m,1H),2.78(d,J＝16.5Hz,1H),2.66–2.54(m,2H),2.45(td,J＝12.8,4.8Hz,1H),2.35(dd,J＝14.2,6.9Hz,1H),2.26(td,J＝13.1,12.6,4.6Hz,1H),2.16(ddd,J＝16.5,11.7,4.7Hz,1H),2.05(dt,J＝12.8,9.6Hz,1H),1.95–1.86(m,2H),1.86–1.70(m,2H)ppm.HRMS(ESI)m/z calcd for C31H34NO8,[M+H]+548.2276,found 548.2284.
化合物38：淡黄色无定形固体，收率69％。1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ7.11(s,4H),6.63(s,1H),6.59(s,1H),5.89(dd,J＝37.7,9.1Hz,1H),5.74(d,J＝10.2Hz,1H),5.50(d,1H),5.13(d,J＝14.4Hz,1H),3.88(d,J＝9.4Hz,1H),3.76(s,3H),3.18(ddt,J＝13.5,8.9,6,5Hz,2H),3.08(d,J＝16.5Hz,1H),2.97(td,J＝11.4,6.7Hz,1H),2.72(d,J＝16.5Hz,1H),2.50–2.27(m,3H),2.24–2.16(m,2H),2.00(ddd,J＝14.2,12.2,4.8Hz,1H),1.98(dtJ＝12.4,9.7Hz,1H),1.98–1.87(m,2H),1.82–1.67(m,2H)ppm.HRMS(ESI)m/z calcd for C31H31F3NO8,[M+H]+602.2002,found 602.1993.
化合物39：淡黄色无定形固体，收率89％。1H NMR(400MHz,CDCl3)δ7.18(d,J＝8.2Hz,2H),7.04(d,J＝8.3Hz,2H),6.61(s,1H),6.58(s,1H),5.94(dd,J＝9.5,0.9Hz,1H),5.80(d,J＝1.6Hz,1H),5.59(d,J＝1.5Hz,1H),5.11(d,J＝0.9Hz,1H),3.84(d,J＝9.5Hz,1H),3.72(s,3H),3.17–3.05(m,2H),2.98(d,J＝16.5Hz,1H),2.92(dt,J＝12.0,5.8Hz,1H),2.83(d,J＝16.5Hz,1H),2.63–2.55(m,2H),2.49–2.40(m,4H),2.35(dd,J＝14.2,6.9Hz,1H),2.30–2.13(m,2H),2.09–2.01(m,1H),1.95–1.85(m,2H),1.80–1.70(m,2H)ppm.HRMS(ESI)m/z calcd for C31H34NO7S,[M+H]+564.2056,found 564.2038.
化合物40：淡黄色无定形固体，收率87％。1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.2Hz,2H),7.52(d,J＝8.0Hz,2H),7.44(t,J＝7.5Hz,2H),7.39–7.30(m,1H),7.20(d,J＝8.0Hz,2H),6.63(s,1H),6.59(s,1H),5.97(d,J＝9.5Hz,1H),5.80(s,1H),5.60(s,1H),5.12(s,1H),3.86(d,J＝9.5Hz,1H),3.74(s,3H),3.18–3.06(m,2H),3.02(d,J＝16.6Hz,1H),2.94(td,J＝11.7,7.9Hz,1H),2.84(d,J＝16.5Hz,1H),2.66–2.48(m,3H),2.40–2.31(m,1H),2.30–2.18(m,1H),2.12–1.97(m,2H),1.99–1.88(m,2H),1.83–1.71(m,2H)ppm.HRMS(ESI)m/z calcd for C36H36NO7,[M+H]+594.2478,found 594.2492.
实施例18：三尖杉酯类生物碱I-2-29～I-2-46的制备
参照实施例1步骤1.7，不同之处是用化合物23-40进行开环甲酯化反应，可以分别制备化合物I-2-29～I-2-46：
化合物I-2-29：淡黄色固体产物(收率67％).(c 1,CHCl3).1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.53(s,1H),6.01(dd,J＝9.8,1.0Hz,1H),5.86(dd,J＝5.9,1.5Hz,2H),5.05(s,1H),3.77(d,J＝9.8Hz,1H),3.72(s,1H),3.66(s,3H),3.57(s,3H),3.14–3.04(m,2H),2.94(td,J＝11.4,6.8Hz,1H),2.62–2.56(m,3H),2.37(dd,J＝14.0,6.7Hz,1H),2.24(d,J＝16.5Hz,1H),2.05–2.02(m,2H),1.95–1.86(m,2H),1.87(d,J＝16.5Hz,1H),1.81–1.70(m,3H),1.53–1.49(m,2H).HRMS(ESI)m/z calcd for C27H33F3NO8,[M+H]+556.2153,found 556.2145.
化合物I-2-30：淡黄色固体产物(收率85％)。(c 1.1,CHCl3).1H NMR(400MHz,CDCl3)δ6.64(s,1H),6.53(s,1H),6.03(d,J＝9.8Hz,1H),5.87(d,J＝5.5Hz,2H),5.07(s,1H),3.78(d,J＝9.9Hz,1H),3.70(s,1H),3.63(s,3H),3.58(s,3H),3.13–3.03(m,2H),2.95(td,J＝11.4,6.6Hz,1H),2.63–2.56(m,2H),2.39(dd,J＝13.9,6.5 Hz,1H),2.29(d,J＝16.6Hz,1H),2.08–2.00(m,2H),1.97–1.87(m,3H),1.78–1.67(m,4H).HRMS(ESI)m/z calcd for C27H31F5NO8,[M+H]+592.1965,found 592.1962.
化合物I-2-31：淡黄色无定形固体，收率55％。1H NMR(400MHz,CDCl3)δ7.05(dd,J＝8.5,5.6Hz,2H),6.95(t,J＝8.7Hz,2H),6.58(s,1H),6.55(s,1H),6.05(dd,J＝9.8,0.9Hz,1H),5.84(d,J＝1.6Hz,1H),5.73(d,J＝1.6Hz,1H),5.09(s,1H),3.81(d,J＝9.8Hz,1H),3.69(s,3H),3.61(s,1H),3.59(s,3H),3.21–3.06(m,2H),2.97(td,J＝11.3,6.7Hz,1H),2.68–2.55(m,3H),2.42–2.25(m,2H),2.30(d,J＝16.4Hz,1H),2.12–1.88(m,3H),1.98(d,J＝16.4Hz,1H),1.83–1.65(m,4H)ppm.HRMS(ESI)m/z calcd for C31H35FNO8,[M+H]+568.2341,found 568.2347.
化合物I-2-32：淡黄色无定形固体，收率50％。1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.9Hz,2H),7.21(d,J＝7.9Hz,2H),6.58(s,1H),6.56(s,1H),6.06(d,J＝9.8Hz,1H),5.83(d,J＝1.5Hz,1H),5.71(d,J＝1.5Hz,1H),5.10(s,1H),3.81(d,J＝9.8Hz,1H),3.69(s,3H),3.64(s,1H),3.59(s,3H),3.21–3.05(m,2H),2.95(td,J＝11.6,6.9Hz,1H),2.71(td,J＝12.8,5.2Hz,1H),2.61(dd,J＝10.7,7.7Hz,2H),2.47–2.34(m,2H),2.30(d,J＝16.5Hz,1H),2.10–2.02(m,1H),1.99(d,J＝16.4Hz,1H),1.92(ddd,J＝12.2,7.7,4.5Hz,1H),1.82–1.68(m,4H)ppm.HRMS(ESI)m/z calcd for C29H29F3NO6,[M+H]+618.2305,found 618.2315.
化合物I-2-33：淡黄色无定形固体，收率82％。1H NMR(400MHz,CDCl3)δ7.07(q,J＝8.1Hz,1H),6.82–6.70(m,2H),6.59(s,1H),6.54(s,1H),6.04(d,J＝9.8Hz,1H),5.85(d,J＝1.6Hz,1H),5.75(d,J＝1.6Hz,1H),5.08(s,1H),3.80(d,J＝9.8Hz,1H),3.67(s,3H),3.64(s,1H),3.58(s,3H),3.23–3.05(m,2H),2.95(td,J＝11.5,7.0Hz,1H),2.66–2.54(m,3H),2.46(dd,J＝12.0,5.7Hz,1H),2.36(dd,J＝14.2,6.9Hz,1H),2.28(d,J＝16.5Hz,1H),2.09–1.99(m,1H),1.96–1.87(m,2H),1.80–1.72(m,2H),1.73–1.65(m,2H)ppm.HRMS(ESI)m/z calcd for C31H34F2NO8,[M+H]+586.2248,found 586.2252.
化合物I-2-34：淡黄色无定形固体，收率70％。1H NMR(400MHz,CDCl3)δ6.66–6.58(m,3H),6.58(s,1H),6.56(s,1H),6.04(d,J＝9.5Hz,1H),5.84(m,1H),5.78(s,1H),5.11(s,1H),3.81(d,J＝9.6Hz,1H),3.70(s,3H),3.63(s,1H),3.59(s,3H),3.20–3.00(m,2H),2.94(td,J＝11.6,7.2Hz,1H),2.66–2.49(m,3H),2.41–2.24(m,3H),2.09–1.86(m,3H),1.82–1.68(m,4H)ppm.HRMS(ESI)m/z calcd for C31H34F2NO8,[M+H]+586.2246,found 586.2252.
化合物I-2-35：淡黄色无定形固体，收率41％。1H NMR(400MHz,CDCl3)δ6.93(td,J＝8.7,4.4Hz,1H),6.89–6.77(m,2H),6.59(s,1H),6.54(d,J＝5.7Hz,1H),6.04(d,J＝9.8Hz,1H),5.85(d,J＝1.6Hz,1H),5.77(d,J＝1.6Hz,1H),5.09(s,1H),3.80(d,J＝9.8Hz,1H),3.68(s,3H),3.65(s,1H),3.58(s,3H),3.22–3.07(m,2H),2.94(td,J＝11.6,7.0Hz,1H),2.66–2.54(m,3H),2.48–2.32(m,2H),2.28(d,J＝16.5Hz,1H),2.09–2.00(m,1H),1.96–1.88(m,2H),1.82–1.72(m,2H),1.70(dd,J＝9.8,7.4Hz,2H)ppm.HRMS(ESI)m/z calcd for C31H34F2NO8,[M+H]+586.2243,found 586.2252.
化合物I-2-36：淡黄色无定形固体，收率47％。1H NMR(400MHz,CDCl3)δ7.03–6.93(m,2H),6.87(dd,J＝8.3,5.3Hz,1H),6.59(s,1H),6.54(s,1H),6.05(d,J＝9.7Hz,1H),5.85(d,J＝1.5Hz,1H),5.76(d,J＝1.6Hz,1H),5.09(s,1H),3.80(d,J＝9.8Hz,1H),3.69(s,3H),3.66(s,1H),3.59(s,3H),3.23–3.06(m,2H),2.95(td,J＝11.6,7.0Hz,1H),2.71–2.48(m,4H),2.37(dd,J＝14.2,6.9Hz,1H),2.28(d,J＝16.6Hz,1H),2.05(td,J＝12.4,9.5Hz,1H),1.96–1.86(m,2H),1.80–1.64(m,4H)ppm.HRMS(ESI)m/z calcd for C31H34F2NO8,[M+H]+586.2254,found 586.2252.
化合物I-2-37：淡黄色无定形固体，118mg，收率47％。1H NMR(400MHz,CDCl3)δ7.45(d,J＝7.9Hz,1H),7.38(t,J＝7.7Hz,1H),7.34(s,1H),7.30(d,J＝7.5Hz,1H),6.58(s,1H),6.56(s,1H),6.07(d,J＝9.8Hz,1H),5.84(d,J＝1.7Hz,1H),5.75(d,J＝1.7Hz,1H),5.12(s,1H),3.82(d,J＝9.9Hz,1H),3.69(s,3H),3.66(s,1H),3.59(s,3H),3.21–3.07(m,2H),3.00–2.90(m,1H),2.73(td,J＝13.0,5.0Hz,1H),2.62(t,J＝9.2Hz,2H),2.47–2.33(m,2H),2.28(d,J＝16.5Hz,1H),2.06(q,J＝10.1Hz,1H),1.98–1.91(m,2H),1.76(dd,J＝12.2,7.5Hz,4H)ppm.HRMS(ESI)m/z calcd for C29H29F3NO6,[M+H]+618.2307,found 618.2315.
化合物I-2-38：淡黄色无定形固体，收率60％。1H NMR(400MHz,CDCl3)δ7.59(d,J＝7.8Hz,1H),7.45(t,J＝7.5Hz,1H),7.27(q,J＝8.0Hz,2H),6.56(s,1H),6.53(s,1H),6.03(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.71(d,J＝1.6Hz,1H),5.08(s,1H),3.79(d,J＝9.8Hz,1H),3.69(s,3H),3.68(s,1H),3.60(s,3H),3.17(td,J＝12.0,11.3,6.7Hz,1H),3.15–3.05(m,1H),2.94(td,J＝11.6,7.0Hz,1H),2.82(td,J＝13.0,4.3Hz,1H),2.66–2.52(m,3H),2.35(dd,J＝14.2,6.9Hz,1H),2.28(d,J＝16.5Hz,1H),2.08–1.98(m,1H),1.92(dt,J＝9.0,4.7Hz,1H),1.86(d,J＝16.5Hz,1H),1.75(dt,J＝13.8,5.1Hz,2H),1.68–1.59(m,2H)ppm.HRMS(ESI)m/z calcd for C32H35F3NO8,[M+H]+618.2312,found 618.2315.
化合物I-2-39：淡黄色无定形固体，收率84％。1H NMR(400MHz,CDCl3)δ7.30(dd,J＝9.4,2.7Hz,1H),7.26–7.18(m,1H),7.20–7.11(m,1H),6.57(s,1H),6.53(s,1H),6.02(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.73(d,J＝1.6Hz,1H),5.09(s,1H),3.79(d,J＝9.8Hz,1H),3.69(s,3H),3.68(s,1H),3.60(s,3H),3.22–3.05(m,2H),2.94(td,J＝11.6,7.0Hz,1H),2.78(td,J＝13.3,4.7Hz,1H),2.64–2.45(m,3H),2.35(dd,J＝14.2,6.9Hz,1H),2.27(d,J＝16.5Hz,1H),2.08–1.96(m,1H),1.95–1.89(m,1H),1.86(d,J＝16.6Hz,1H),1.81–1.63(m,4H)ppm.HRMS(ESI)m/z calcd for C32H34F4NO8,[M+H]+636.2212,found 636.2221.
化合物I-2-40：淡黄色无定形固体，收率60％。1H NMR(400MHz,CDCl3)δ7.11(s,4H),6.58(s,1H),6.56(s,1H),6.05(d,J＝10.0Hz,1H),5.83(d,J＝1.5Hz,1H),5.71(d,J＝1.6Hz,1H),5.10(s,1H),3.81(d,J＝9.8Hz,1H),3.69(s,3H),3.59(s,3H),3.56(s,1H),3.20–3.03(m,2H),2.96(td,J＝11.4,6.9Hz,1H),2.68–2.54(m,3H),2.43–2.26(m,3H),2.09–1.96(m,2H),1.98–1.87(m,1H),1.82–1.67(m,4H)ppm.HRMS(ESI)m/z calcd for C32H35F3NO9,[M+H]+634.2263,found 634.2264.
化合物I-2-41：淡黄色无定形固体，收率56％。1H NMR(400MHz,CDCl3)δ7.18(d,J＝8.2Hz,2H),7.03(d,J＝8.2Hz,2H),6.59(s,1H),6.55(s,1H),6.06(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.73(d,J＝1.6Hz,1H),5.09(s,1H),3.80(d,J＝9.8Hz,1H),3.69(s,3H),3.61(s,1H),3.58(s,3H),3.20–3.06(m,2H),2.95(td,J＝11.6,7.0Hz,1H),2.66–2.56(m,3H),2.46(s,3H),2.41–2.26(m,3H),2.10–2.01(m,1H),2.00–1.88(m,2H),1.81–1.64(m,4H)ppm.HRMS(ESI)m/z calcd for C32H38NO8S,[M+H]+596.2313,found 596.2318.
化合物I-2-42：淡黄色无定形固体，收率71％。1H NMR(400MHz,CDCl3)δ7.10(d,J＝7.6Hz,2H),7.02(d,J＝7.7Hz,2H),6.60(s,1H),6.57(s,1H),6.08(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.74(d,J＝1.6Hz,1H),5.11(s,1H),3.82(d,J＝9.8Hz,1H),3.71(s,4H),3.59(s,3H),3.26–3.06(m,2H),2.99(dt,J＝12.6,6.2Hz,1H),2.76–2.54(m,3H),2.44–2.27(m,6H),2.15–2.02(m,1H),2.01–1.89(m,2H),1.84–1.68(m,4H)ppm.HRMS(ESI)m/z calcd for C32H38NO8,[M+H]+564.2591,found 564.2597.
化合物I-2-43：淡黄色无定形固体，收率60％。1H NMR(400MHz,CDCl3)δ8.09–7.85(m,2H),7.75(d,J＝8.2Hz,1H),7.51(dd,J＝6.3,3.3Hz,2H),7.42(t,J＝7.6Hz,1H),7.36–7.26(m,1H),6.59(s,1H),6.55(s,1H),6.20(d,J＝9.9Hz,1H),5.91–5.82(m,1H),5.71(d,J＝1.6Hz,1H),5.21(s,1H),3.88(d,J＝9.9Hz,1H),3.82(s,1H),3.71(s,3H),3.64(s,3H),3.33(td,J＝13.1,7.7Hz,1H),3.22–3.07(m,2H),3.09–2.90(m,2H),2.80–2.63(m,2H),2.39(dd,J＝14.3,6.9Hz,1H),2.32(d,J＝16.6Hz,1H),2.17–2.06(m,1H),2.05–1.92(m,2H),1.90(d,J＝16.5Hz,1H),1.87–1.76(m,3H)ppm.HRMS(ESI)m/z calcd for C35H38NO8,[M+H]+600.2592,found600.2597.
化合物I-2-44：淡黄色无定形固体，153mg，收率61％。1H NMR(400MHz,CDCl3)δ7.83–7.70(m,3H),7.54(s,1H),7.50–7.37(m,2H),7.25(d,J＝9.0Hz,1H),6.59(s,1H),6.57(s,1H),6.09(d,J＝9.7Hz,1H),5.81(s,1H),5.69(s,1H),5.11(s,1H),3.83(d,J＝9.6Hz,1H),3.71(s,3H),3.67(s,1H),3.60(s,3H),3.20(td,J＝13.1,7.9Hz,1H),3.11(q,J＝8.0,7.3Hz,1H),2.96(td,J＝11.5,7.0Hz,1H),2.82(td,J＝12.8,5.3Hz,1H),2.68–2.47(m,3H),2.44–2.30(m,2H),2.05(dt,J＝25.3,13.3Hz,2H),1.97–1.73(m,5H)ppm.HRMS(ESI)m/z calcd for C35H38NO8,[M+H]+600.2600,found 600.2597.
化合物I-2-45：淡黄色无定形固体，收率56％。1H NMR(400MHz,CDCl3)δ7.02(d,J＝8.3Hz,2H),6.82(d,J＝8.5Hz,2H),6.59(s,1H),6.55(s,1H),6.06(d,J＝9.8Hz,1H),5.83(d,J＝1.6Hz,1H),5.73(d,J＝1.6Hz,1H),5.09(s,1H),3.81(d,J＝9.9Hz,1H),3.78(s,4H),3.70(s,3H),3.58(s,3H),3.21–3.07(m,2H),2.97(td,J＝11.3,6.5Hz,1H),2.65–2.57(m,3H),2.41–2.26(m,3H),2.30(d,J＝16.4Hz,1H),2.06(dt,J＝12.0,9.6Hz,1H),1.99–1.89(m,2H),1.96(d,J＝16.4Hz,1H),1.81–1.67(m,4H)ppm.HRMS(ESI)m/z calcd for C32H38NO9,[M+H]+580.2544,found 580.2547.
化合物I-2-46：淡黄色无定形固体，收率50％。1H NMR(400MHz,CDCl3)δ7.57(d,J＝7.0Hz,2H),7.51(d,J＝7.9Hz,2H),7.43(t,J＝7.5Hz,2H),7.33(t,J＝6.8Hz,1H),7.18(d,J＝7.8Hz,2H),6.60(s,1H),6.56(s,1H),6.08(d,J＝9.8Hz,1H),5.84(d,J＝1.6Hz,1H),5.73(d,J＝1.7Hz,1H),5.10(s,1H),3.82(d,J＝9.8Hz,1H),3.72(s,3H),3.64(s,1H),3.59(s,3H),3.24–3.06(m,2H),2.96(td,J＝11.6,6.9Hz,1H),2.76–2.55(m,3H),2.47–2.28(m,3H),2.10–2.02(m,1H),1.99(d,J＝16.5Hz,1H),1.93(dd,J＝9.6,5.5Hz,1H),1.83–1.72(m,4H)ppm.HRMS(ESI)m/z calcd for C37H40NO8,[M+H]+626.2746,found 626.2754.
实施例19：酮肟类化合物的制备
通用操作：氩气保护下，室温向α-酮酯(4mmol)的丙酮(5mL)溶液中加入辛可宁催化剂(0.16mmol)、间硝基苯甲酸(0.8mmol)，反应8h后，除去大部分溶剂后柱层析分离,得到酮类似物。
室温下，将酮化合物(2mmol)溶于CH3CN/H2O(v/v＝9:1，5mL)中，搅拌下加入盐酸羟胺(2mmol)、乙酸钠(2.5mmol)，TLC监测反应完全后加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到E/Z酮肟类似物。
参考上述方法，得到下列化合物：
化合物I-2-47：柱层析PE:EA＝7:1,0.5％TEA，得到黄色无定形固体(收率87％)。1H NMR(400MHz,CDCl3):δ6.60(s,1H),6.55(s,1H),5.98(d,J＝9.8Hz,1H),5.85(dd,J＝13.6,1.5Hz,2H),5.79–5.64(m,1H),5.03(s,1H),5.00–4.87(m,2H),3.76(d,J＝9.8Hz,1H),3.67(s,3H),3.57(s,1H),3.10(ddd,J＝23.8,13.2,7.6Hz,2H),2.92(td,J＝11.6,7.0Hz,1H),2.63–2.52(m,2H),2.46(d,J＝17.5Hz,1H),2.36(dd,J＝14.1,6.9Hz,1H),2.22(d,J＝17.5Hz,1H),2.11–1.95(m,2H),1.89(s,3H),1.87–1.67(m,4H),1.55–1.38(m,2H)ppm；HRMS-ESI(m/z):Calcd for C27H34NO7[M+H]+484.2336.Found 484.2257.
化合物I-2-48：柱层析PE:EA＝7:1,0.5％TEA，得到黄色无定形固体(收率96％)。1H NMR(400MHz,CDCl3):δ6.60(s,1H),6.54(s,1H),5.96(d,J＝9.8Hz,1H),5.87–5.80(m,2H),5.02(s,1H),5.03–4.94(m,1H),3.75(d,J＝9.8Hz,1H),3.66(s,3H),3.56(s,1H),3.20–3.02(m,2H),2.92(td,J＝11.5,6.9Hz,1H),2.62–2.51(m,2H),2.42(d,J＝17.3Hz,1H),2.36(dd,J＝14.2,7.0Hz,1H),2.13(d,J＝17.4Hz,1H),2.07–1.93(m,3H),1.91–1.85(m,1H),1.88(s,3H),1.75(dt,J＝13.8,7.5Hz,4H),1.65(s,3H),1.56(s,3H)ppm.HRMS-ESI(m/z):Calcd for C29H38NO7[M+H]+512.2649.Found 512.2570.
化合物I-2-49：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率88％)。1H NMR(400MHz,CDCl3):δ7.10(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.2,3.4Hz,1H),6.73(d,J＝2.3Hz,1H),6.60(s,1H),6.56(s,1H),6.04(d,J＝9.8Hz,1H),5.80(dd,J＝11.2,1.5Hz,2H),5.05(s,1H),3.78(d,J＝9.9Hz,1H),3.70(s,1H),3.67(s,3H),3.22–3.04(m,2H),3.00–2.82(m,2H),2.65–2.53(m,3H),2.49(d,J＝17.6Hz,1H),2.38(dd,J＝14.2,6.9Hz,1H),2.20(d,J＝17.6Hz,1H),2.10–1.97(m,1H),1.94–1.88(m,1H),1.89(s,3H),1.84–1.69(m,4H)ppm.HRMS-ESI(m/z):Calcd for C29H34NO7S[M+H]+540.2057.Found 540.1987.
化合物I-2-50：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率98％)。1H NMR(400MHz,CDCl3):δ6.94(s,1H),6.82(d,J＝8.1Hz,1H),6.68(d,J＝8.0Hz,1H),6.57(d,J＝3.2Hz,2H),6.03(d,J＝9.8Hz,1H),5.77(dd,J＝26.9,1.5Hz,2H),5.07(s,1H),4.53(t,J＝8.6Hz,2H),3.79(d,J＝9.8Hz,1H),3.69(s,3H),3.66(s,1H),3.16(t,J＝8.6Hz,2H),3.14–3.04(m,2H),2.93(td,J＝11.5,7.0Hz,1H),2.65–2.48(m,3H),2.46(d,J＝17.5Hz,1H),2.36(dd,J＝14.1,6.9Hz,1H),2.33–2.21(m,1H),2.19(d,J＝17.5Hz,1H),2.10–1.99(m,1H),1.94–1.88(m,1H),1.90(s,3H),1.75(p,J＝9.2,8.1Hz,2H),1.72–1.59(m,2H)ppm.HRMS-ESI(m/z):Calcd for C33H38NO8[M+H]+576.2598.Found 576.2519.
化合物I-2-51：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率95％)。HRMS-ESI(m/z):Calcd for C28H38NO8[M+H]+500.2643.Found 500.2648.
化合物I-3-1：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率37％)。1H NMR(400MHz,CDCl3):δ8.06(s,1H),6.58(s,1H),6.55(s,1H),5.85(d,J＝3.3Hz,2H),5.79–5.66(m,1H),5.04(s,1H),5.00–4.88(m,2H),3.77(d,J＝9.9Hz,1H),3.67(s,3H),3.21–3.02(m,2H),2.99–2.86(m,1H),2.65–2.53(m,2H),2.38(dd,J＝14.1,6.9Hz,1H),2.10(d,J＝16.0Hz,1H),2.05–1.98(m,2H),1.95–1.89(m,1H),1.78–1.71(m,1H),1.63(s,3H),1.59–1.47(m,1H),0.91–0.80(m,6H)ppm.HRMS-ESI(m/z):Calcd for C27H35N2O7[M+H]+499.2445.Found 499.2366.
化合物I-3-2：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率42％)。1H NMR(400MHz,CDCl3):δ6.60(s,1H),6.58(s,1H),5.93(d,J＝9.6Hz,1H),5.83(d,J＝19.6Hz,2H),5.06(s,1H),5.05–4.96(m,2H),3.81(s,1H),3.67(s,3H),3.35(s,1H),3.20–3.05(m,2H),2.94(d,J＝8.5Hz,1H),2.90–2.75(m,1H),2.63–2.48(m,3H),2.39(dd,J＝14.3,6.8Hz,1H),2.18–2.00(m,3H),1.89(d,J＝24.0Hz,4H),1.72(s,3H),1.66(d,J＝5.6Hz,3H),1.57(d,J＝6.1Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C29H39N2O7[M+H]+527.2758.Found 527.2679.
化合物I-3-3：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率30％)1H NMR(400MHz,CDCl3):δ7.60(s,1H),6.58(s,1H),6.55(s,1H),5.93(d,J＝9.7Hz,1H),5.84(dd,J＝8.9,1.6Hz,2H),5.04(s,1H),5.04–4.95 (m,1H),3.77(d,J＝9.7Hz,1H),3.67(s,3H),3.63(s,1H),3.22–3.03(m,2H),2.98–2.86(m,1H),2.63–2.52(m,2H),2.37(dd,J＝14.2,7.0Hz,1H),2.07(d,J＝15.9Hz,1H),2.04–1.83(m,4H),1.82–1.69(m,3H),1.65(s,6H),1.56(s,3H),1.53–1.36(m,2H)ppm.HRMS-ESI(m/z):Calcd for C29H39N2O7[M+H]+527.2758.Found 527.2679.
化合物I-3-5：柱层析PE:EA＝4:1,0.5％TEA，得到黄色无定形固体(收率46％)。1H NMR(400MHz,CDCl3):δ7.09(dd,J＝5.1,1.2Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.73(d,J＝2.4Hz,1H),6.58(s,1H),6.56(s,1H),5.99(d,J＝9.7Hz,1H),5.77(dd,J＝34.4,1.6Hz,2H),5.06(s,1H),3.87(s,1H),3.78(d,J＝9.7Hz,1H),3.67(s,3H),3.24–3.02(m,2H),2.99–2.83(m,2H),2.65–2.53(m,2H),2.55–2.42(m,1H),2.39(dd,J＝14.5,7.0Hz,1H),2.13(d,J＝18.6Hz,1H),2.10–1.95(m,3H),1.95–1.79(m,3H),1.82–1.68(m,4H),1.63(s,3H)ppm.HRMS-ESI(m/z):Calcd for C29H35N2O7S[M+H]+555.2166.Found 555.2087.
化合物I-3-5：柱层析PE:EA＝4:1,0.5％TEA，得到黄色无定形固体(收率45％)。1H NMR(400MHz,CDCl3):δ6.95(s,1H),6.84(d,J＝8.1Hz,1H),6.67(d,J＝8.1Hz,1H),6.57(s,1H),6.56(s,1H),5.99(d,J＝9.7Hz,1H),5.73(dd,J＝54.7,1.7Hz,2H),5.08(s,1H),4.53(t,J＝8.6Hz,2H),3.80(d,J＝9.8Hz,1H),3.70(s,3H),3.23–3.14(m,1H),3.16(t,J＝8.6,7.7Hz,2H),3.14–3.03(m,1H),3.00–2.87(m,1H),2.66–2.46(m,3H),2.38(dd,J＝14.2,7.0Hz,1H),2.22–2.08(m,1H),2.12(d,J＝17.4Hz,1H),2.08–1.95(m,2H),1.99(d,J＝17.4Hz,1H),1.96–1.84(m,2H),1.82–1.69(m,4H),1.66(s,3H)ppm.HRMS-ESI(m/z):Calcd for C33H39N2O8S[M+H]+591.2707.Found 591.2628.
化合物I-3-6：柱层析PE:EA＝4:1,0.5％TEA，得到黄色无定形固体(收率35％)。1H NMR(400MHz,CDCl3):δ6.94(s,1H),6.82(d,J＝8.1Hz,1H),6.68(d,J＝8.1Hz,1H),6.57(s,1H),6.57(s,1H),6.03(d,J＝9.8Hz,1H),5.77(dd,J＝28.7,1.5Hz,2H),5.07(s,1H),4.54(t,J＝8.7Hz,2H),3.79(d,J＝9.9Hz,1H),3.69(s,3H),3.65(s,1H),3.23–3.04(m,3H),3.19(t,J＝8.6,7.7Hz,2H),3.00–2.86(m,1H),2.65–2.48(m,4H),2.46(d,J＝17.5Hz,1H),2.36(dd,J＝14.1,6.9Hz,1H),2.28(dd,J＝25.2,12.5Hz,1H),2.19(d,J＝17.4Hz,1H),1.90(s,4H),1.82–1.69(m,2H),1.69–1.60(m,2H)ppm.HRMS-ESI(m/z):Calcd for C33H39N2O8S[M+H]+591.2707.Found 591.2628.
实施例20：醛肟类化合物的制备
通用操作：氩气保护下，-60℃下，向α-酮酯(1mmol)的CH2Cl2(15mL)溶液中滴入硫代烯醇硅醚(2mmol)，10min后，滴入BF3·OEt2(3mmol)，TLC板监测反应完全后，加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到硫酯中间体。
室温下，向硫酯的CH2Cl2(5mL)溶液中，加入Pd/C(0.1mmol)、Et3SiH(2.5mmol)，监测至反应完全。，加入饱和NaHCO3淬灭，硅藻土过滤，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到醛类似物。
室温下，将中间体醛(2mmol)溶于CH3CN/H2O(v/v＝9:1,5mL)中，搅拌下加入盐酸羟胺(2mmol)、乙酸钠(2.5mmol)，TLC板监测至反应完全。加入饱和NaHCO3淬灭，用CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到E/Z醛肟类似物。
参考上述方法，得到下列化合物：
化合物I-2-52：得到淡粉色无定形固体(收率98％)。1H NMR(400MHz,CDCl3):δ6.61(s,1H),6.52(s,1H),6.00(d,J＝9.8Hz,1H),5.86(dd,J＝6.5,1.7Hz,2H),5.04(s,1H),3.78(d,J＝9.8Hz,1H),3.67(s,3H),3.39(s,1H),3.15–3.03(m,2H),2.98–2.89(m,1H),2.61–2.55(m,2H),2.52(d,J＝16.0Hz,1H),2.36(dd,J＝14.1,6.8Hz,1H),2.22(s,3H),2.00(d,J＝16.0Hz,1H),1.94–1.86(m,1H),1.81–1.69(m,2H),1.51–1.34(m,3H),1.33–1.21(m,2H),0.99–0.92(m,1H),0.82(t,J＝6.4Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C28H38NO7S[M+H]+532.2370.Found 532.2291.
化合物I-2-53：得到淡粉色色无定形固体(收率90％)。1H NMR(400MHz,CDCl3):δ6.58(s,1H),6.50(s,1H),5.98(d,J＝9.8Hz,1H),5.82(dd,J＝6.5,1.7Hz,2H),5.69(tt,J＝13.1,5.1Hz,1H),5.03(s,1H),4.98–4.85(m,2H),3.76(d,J＝9.8Hz,1H),3.65(s,3H),3.41(s,1H),3.12–3.00(m,2H),2.97–2.83(m,1H),2.61–2.52(m,2H),2.50(d,J＝16.0Hz,1H),2.34(dd,J＝14.1,6.8Hz,1H),2.19(s,3H),2.11–2.02(m,1H),2.07(d,J＝16.0Hz,1H),1.93–1.75(m,3H),1.72(p,J＝5.9,4.8Hz,2H),1.51(tdd,J＝25.4,13.5,4.8Hz,2H)ppm.HRMS-ESI(m/z):Calcd for C24H34NO7[M+H]+516.2057.Found 516.1978.
化合物I-2-54：得到淡粉色无定形固体(收率82％)。1H NMR(400MHz,CDCl3):δ6.59(s,1H),6.50(s,1H),5.99(d,J＝9.8Hz,1H),5.83(d,J＝13.7Hz,2H),5.03(s,1H),5.02–4.96(m,1H),3.77(d,J＝9.8Hz,1H),3.65(s,3H),3.39(s,1H),3.16–3.01(m,2H),2.98–2.85(m,1H),2.62–2.52(m,2H),2.48(d,J＝15.9Hz,1H),2.35(dd,J＝14.2,6.8Hz,1H),2.21(s,3H),2.01–1.94(m,1H),1.98(d,J＝15.9Hz,1H),1.92–1.85(m,1H),1.74(dd,J＝13.7,7.9Hz,3H),1.64(s,3H),1.54(s,3H),1.52–1.35(m,3H)ppm.HRMS-ESI(m/z):Calcd for C29H38NO7S[M+H]+544.2370.Found 544.2291.
化合物I-2-55：得到粉色无定形固体(收率82％)。1H NMR(400MHz,CDCl3):δ7.10(dd,J＝5.1,1.3Hz,1H),6.90(dd,J＝5.1,3.4Hz,1H),6.73(d,J＝2.4Hz,1H),6.61(s,1H),6.54(s,1H),6.06(d,J＝9.8Hz,1H),5.82(dd,J＝24.8,1.6Hz,2H),5.08(s,1H),3.81(d,J＝9.8Hz,1H),3.68(s,3H),3.53(s,1H),3.12(ddd,J＝21.9,13.8,7.7Hz,2H),3.01–2.84(m,2H),2.66–2.51(m,4H),2.38(dd,J＝14.0,6.7Hz,1H),2.23(s,3H),2.11(d,J＝16.0Hz,1H),2.09–1.98(m,1H),1.98–1.83(m,2H),1.78(ddt,J＝17.6,8.9,4.7Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C29H34NO7S2[M+H]+572.1777.Found 572.1698.
化合物I-2-56：得到淡粉色无定形固体(收率89％)。1H NMR(400MHz,CDCl3):δ6.94(s,1H),6.82(d,J＝8.1Hz,1H),6.68(d,J＝8.1Hz,1H),6.58(s,1H),6.55(s,1H),6.06(d,J＝9.7Hz,1H),5.80(dd,J＝33.6,1.7Hz,2H),5.09(s,1H),4.53(t,J＝8.7Hz,2H),3.81(d,J＝9.8Hz,1H),3.70(s,3H),3.49(s,1H),3.16(t,J＝8.9Hz,2H),3.11(t,J＝6.1Hz,2H),3.01–2.86(m,1H),2.66–2.54(m,3H),2.52(d,J＝16.1Hz,1H),2.36(dd,J＝14.1,6.9Hz,1H),2.32–2.26(m,1H),2.23(s,3H),2.09(d,J＝16.1Hz,1H),2.07–1.98(m,1H),1.92(ddd,J＝12.1,7.6,4.5Hz,1H),1.83–1.61(m,4H)ppm.HRMS-ESI(m/z):Calcd for C33H38NO8S[M+H]+608.2319.Found 607.2240.
化合物I-2-57：柱层析PE:EA＝7:1,0.5％TEA，得到黄色无定形固体(收率49％)。1H NMR(400MHz,CDCl3):δ8.98(d,J＝2.9Hz,1H),6.60(s,1H),6.55(s,1H),5.98(d,J＝8.8Hz,1H),5.87(dd,J＝8.4,5.6Hz,2H),5.06(s,1H),3.78(d,J＝9.8Hz,1H),3.67(s,3H),3.31(s,1H),3.13–3.04(m,2H),2.94(ddd,J＝12.4,10.8,6.7Hz,1H),2.58(td,J＝9.3,7.3Hz,2H),2.36(dd,J＝13.9,6.7Hz,1H),2.29(dt,J＝17.0,2.7Hz,1H),2.06–2.01(m,1H),1.99(s,1H),1.90(ddd,J＝12.1,7.8,4.3Hz,1H),1.75(ddt,J＝9.5,8.1,5.0Hz,3H),1.67–1.62(m,1H),1.52–1.44(m,2H),1.12–1.01(m,1H),0.90–0.82(m,4H)ppm.HRMS-ESI(m/z):Calcd for C26H34NO7[M+H]+472.2336.Found 471.2257.
化合物I-2-58：柱层析PE:EA＝7:1,0.5％TEA，得到淡黄色无定形固体(收率51％)。1H NMR(400MHz,CDCl3):δ8.98(d,J＝2.9Hz,1H),6.59(s,1H),6.55(s,1H),5.98(d,J＝9.7Hz,1H),5.86(s,2H),5.06(s,1H),5.00(t,J＝7.2Hz,1H),3.79(d,J＝9.7Hz,1H),3.67(s,3H),3.37(s,1H),3.15–3.01(m,2H),2.97–2.89(m,1H),2.64–2.52(m,2H),2.36(dd,J＝14.0,6.7Hz,1H),2.27(dd,J＝17.1,3.1Hz,1H),2.10–1.95(m,3H),1.95–1.84(m,2H),1.84–1.70(m,4H),1.65(t,J＝2.3Hz,3H),1.56(s,3H)ppm.HRMS-ESI(m/z):Calcd for C28H36NO7[M+H]+498.2493.Found 498.2414.
化合物I-2-59：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率54％)。1H NMR(400MHz,CDCl3):δ9.00(d,J＝2.5Hz,1H),7.09(d,J＝5.2Hz,1H),6.92–6.83(m,1H),6.73(d,J＝3.4Hz,1H),6.58(s,1H),6.55(s,1H),6.02(d,J＝9.7Hz,1H),5.82(d,J＝9.8Hz,2H),3.79(d,J＝9.8Hz,1H),3.67(s,3H),3.43(s,1H),3.14–3.00(m,2H),2.97–2.83(m,2H),2.61-2.52(m,4H),2.41–2.28(m,2H),2.10–1.95(m,2H),1.94–1.82(m,3H),1.78–1.70(m,2H)ppm.HRMS-ESI(m/z):Calcd for C28H32NO7S[M+H]+526.1900Found 526.1821.
化合物I-2-60：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率62％)。1H NMR(400MHz,CDCl3):δ9.01(s,1H),6.96(s,1H),6.85(d,J＝8.2Hz,1H),6.68(d,J＝8.1Hz,1H),6.58(s,2H),6.05(d,J＝9.7Hz,1H),5.82(d,J＝18.7Hz,2H),5.11(s,1H),4.54(t,J＝8.6Hz,2H),3.82(d,J＝9.8Hz,1H),3.72(s,3H),3.43(s,1H),3.24–3.02(m,4H),3.01–2.87(m,1H),2.65–2.55(m,3H),2.41–2.25(m,2H),2.08–1.98(m,3H),1.98–1.85(m,1H),1.82–1.70(m,4H)ppm.HRMS-ESI(m/z):Calcd for C32H36NO8[M+H]+562.2442Found 562.2363.
化合物I-2-61：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率68％)。HRMS-ESI(m/z):Calcd for C27H36NO7[M+H]+486.2486Found 486.2480.
化合物I-2-62：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率65％)。HRMS-ESI(m/z):Calcd for C26H32NO7[M+H]+470.2173 Found 470.2170.
化合物I-3-7：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率42％)。1H NMR(400MHz,CDCl3):6.63–6.51(m,3H),5.96(d,J＝10.6Hz,1H),5.06(s,1H),3.79(d,J＝9.7Hz,1H),3.71(s,1H),3.68(s,3H),3.18–3.04(m,3H),2.94(td,J＝11.6,7.0Hz,1H),2.59(q,J＝9.4,8.8Hz,2H),2.38(dd,J＝14.3,6.9Hz,1H),2.14–1.98(m,3H),1.95–1.84(m,1H),1.82–1.70(m,3H),1.63–1.34(m,4H),1.01–0.88(m,1H),0.84(dd,J＝6.6,2.2Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C27H37N2O7[M+H]+501.2602.Found 501.2523.
化合物I-3-8：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率32％)。1H NMR(400MHz,CDCl3):δ8.11(s,1H),6.63(s,1H),6.59(s,1H),6.29(dd,J＝6.5,3.6Hz,1H),5.96(d,J＝9.7Hz,1H),5.88(q,J＝1.7Hz,2H),5.09(s,1H),3.82(d,J＝9.7Hz,1H),3.70(s,3H),3.20–3.06(m,3H),2.97(td,J＝11.5,6.8Hz,1H),2.66–2.57(m,2H),2.55(dd,J＝16.7,6.6Hz,1H),2.41(dd,J＝14.1,6.7Hz,1H),2.06–2.02(m,1H),1.92(ddd,J＝12.2,8.0,4.1Hz,1H),1.78(tq,J＝8.5,4.2,3.7Hz,2H),1.68(dd,J＝16.8,3.6Hz,1H),1.64–1.44(m,4H),0.96(td,J＝12.4,6.2Hz,1H),0.86(dd,J＝6.6,2.5Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C27H37N2O7[M+H]+501.2602.Found 501.2523.
化合物I-3-9：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率22％)。1H NMR(400MHz,CDCl3):δ6.57(dd,J＝6.8,3.2Hz,3H),5.95(d,J＝9.7Hz,1H),5.86(dd,J＝12.8,1.7Hz,2H),5.06(s,1H),5.02(t,J＝7.0Hz,1H),3.79(d,J＝9.7Hz,1H),3.67(s,3H),3.32(s,1H),3.10(ddd,J＝21.7,13.9,7.9Hz,2H),2.93(td,J＝11.6,6.9Hz,1H),2.63–2.53(m,2H),2.37(dd,J＝14.1,6.8Hz,1H),2.11–1.92(m,2H),1.89(ddd,J＝12.1,7.9,4.2Hz,1H),1.82–1.67(m,2H),1.65(s,3H),1.57(s,3H),1.54–1.39(m,1H),0.92–0.80(m,4H)ppm.HRMS-ESI(m/z):Calcd for C28H37N2O7[M+H]+513.2602.Found 513.2523.
化合物I-3-10：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率23％)。1H NMR(400MHz,CDCl3):δ6.60(s,2H),6.56(s,1H),6.27(dd,J＝6.5,3.7Hz,1H),5.93(d,J＝9.5Hz,1H),5.87–5.80(m,2H),5.07(s,1H),5.02(t,J＝7.9Hz,1H),3.79(d,J＝9.6Hz,1H),3.68(s,3H),3.16–3.03(m,2H),2.94(td,J＝11.5,6.8Hz,1H),2.63–2.54(m,2H),2.50(dd,J＝16.7,6.6Hz,1H),2.43–2.32(m,1H),2.10–1.98(m,1H),1.93–1.86(m,1H),1.83–1.68(m,2H),1.65(s,3H),1.57(s,3H),0.92–0.80(m,4H)ppm.HRMS-ESI(m/z):Calcd for C28H37N2O7[M+H]+513.2602.Found 513.2523.

化合物I-3-11：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率28％)。1H NMR(400MHz,CDCl3):δ6.59(s,1H),6.58(s,1H),6.53(dd,J＝7.9,4.2Hz,1H),5.95(d,J＝9.5Hz,1H),5.87(dd,2H),5.05(s,1H),3.79(d,J＝9.7Hz,1H),3.67(s,3H),3.29(s,1H),3.18–3.03(m,2H),2.94(td,J＝11.5,6.9Hz,1H),2.64–2.53(m,2H),2.37(dd,J＝14.1,6.8Hz,1H),2.14–1.98(m,3H),1.90(ddd,J＝12.1,8.1,4.1Hz,1H),1.76(ddt,J＝14.3,8.8,4.4Hz,4H),1.61–1.40(m,3H),0.92–0.80(m,4H)ppm.HRMS-ESI(m/z):Calcd for C26H35N2O7[M+H]+487.2445.Found 487.2366.
化合物I-3-12：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率35％)。1H NMR(400MHz,CDCl3):δ6.61(s,1H),6.56(s,1H),6.26(dd,J＝6.5,3.6Hz,1H),5.93(d,J＝9.8Hz,1H),5.86(d,J＝1.8Hz,2H),5.06(s,1H),3.79(d,J＝9.7Hz,1H),3.68(s,3H),3.13–3.05(m,2H),2.99–2.90(m,1H),2.64–2.48(m,3H),2.39(dd,J＝14.1,6.8Hz,1H),2.11–1.98(m,1H),1.95–1.84(m,1H),1.83–1.60(m,4H),1.61–1.44(m,2H),1.09–0.99(m,1H),0.91–0.80(m,5H)ppm.HRMS-ESI(m/z):Calcd for C26H35N2O7[M+H]+487.2445.Found 487.2366.
实施例21：肟酯类化合物的制备
通用操作：Ar氛下，0℃，向肟(1mmol)的CH2Cl2(5mL)溶液中滴入Et3N(3mmol)，然后滴入乙酸酐(1.2mmol)，滴加完毕后移至室温，TLC板监测至反应完全。加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到乙酸肟酯粗产物。
参考上述方法，得到如下化合物：
化合物I-3-13：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率87％)。HRMS-ESI(m/z):Calcd for C29H38N2O8[M+H]+543.2707.Found 543.2628.1H NMR(400MHz,CDCl3):δ6.82(dd,J＝8.8,3.8Hz,1H),6.53(d,J＝3.7Hz,2H),5.85(d,J＝8.8Hz,1H),5.81(dd,J＝18.3,1.6Hz,2H),5.01(s,1H),3.74(d,J＝9.7Hz,1H),3.64(s,1H),3.61(s,3H),3.05–2.97(m,4H),2.87(td,J＝11.5,6.8Hz,1H),2.57–2.49(m,2H),2.29(ddd,J＝18.0,14.2,7.8Hz,3H),2.06(s,3H),1.82(ddd,J＝14.9,10.6,4.4Hz,2H),1.70(dt,J＝13.1,7.4Hz,2H),1.55(td,J＝13.0,4.3Hz,1H),1.40(td,J＝13.5,13.1,5.1Hz,1H),0.88–0.82(m,1H),0.77(dd,J＝6.6,2.4Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C29H39N2O8[M+H]+543.2707.Found 543.2628.
化合物I-3-14：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率55％)。1H NMR(400MHz,CDCl3):δ6.89(dd,J＝8.8,3.8Hz,1H),6.60(s,1H),6.59(s,1H),5.92(d,J＝9.7Hz,1H),5.87(dd,J＝17.3,1.6Hz,2H),5.07(s,1H),3.80(d,J＝9.7Hz,1H),3.68(s,3H),3.13–3.06(m,2H),3.04(s,1H),2.98–2.89(m,1H),2.60(t,J＝8.4Hz,2H),2.43–2.29(m,2H),2.13(s,3H),2.10–1.97(m,2H),1.95–1.85(m,2H),1.80–1.70(m,3H),1.66–1.55(m,3H),1.47(td,J＝13.5,12.7,3.9Hz,1H),0.86(t,J＝7.1Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C28H37N2O8[M+H]+529.2551.Found 528.2472.
化合物I-3-15：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率49％)。1H NMR(400MHz,CDCl3):δ6.92(dd,J＝8.8,3.9Hz,1H),6.60(s,1H),6.58(s,1H),5.91(d,J＝9.7Hz,1H),5.86(dd,J＝9.7,1.6Hz,2H),5.08(s,1H),5.06–4.97(m,1H),3.81(d,J＝9.7Hz,1H),3.68(s,3H),3.14–3.03(m,2H),3.09(s,1H),2.92(td,J＝11.5,6.8Hz,1H),2.62–2.54(m,2H),2.42–2.26(m,2H),2.13(s,3H),2.10–1.97(m,2H),1.97–1.79(m,3H),1.81–1.71(m,3H),1.65(s,3H),1.56(s,3H),1.55–1.43(m,1H)ppm.HRMS-ESI(m/z):Calcd for C30H39N2O8[M+H]+555.2707.Found 555.2628.
实施例22：肟酯类化合物的制备
通用操作：Ar氛下，向肟(1mmol)的CH2Cl2(5mL)溶液中滴入Et3N(3mmol)，然后滴入酰氯(1.2mmol)，TLC板监测反应至完全。加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到肟酯粗产物。
参考上述方法，得到如下化合物：
化合物I-3-16：柱层析柱层析PE:EA＝5:1,0.5％TEA，得到淡黄色无定形固体(收率44％)。1H NMR(400MHz,CDCl3):δ6.58(d,J＝17.9Hz,2H),6.50(d,J＝17.5Hz,1H),6.22(ddd,J＝17.4,10.5,1.9Hz,1H),5.97–5.80(m,4H),5.03(s,1H),3.80(d,J＝8.8Hz,1H),3.66(s,3H),3.36(s,1H),3.11(dd,J＝23.9,8.5Hz,2H),2.92(q,J＝10.5Hz,1H),2.62–2.54(m,2H),2.39(d,J＝14.8Hz,1H),2.33(d,J＝16.9Hz,1H),2.09–1.96(m,1H),1.93–1.81(m,2H),1.79(d,J＝1.8Hz,3H),1.76–1.66(m,3H),1.55–1.48(m,1H),1.43(dt,J＝11.8,5.1Hz,1H),1.30–1.21(m,1H),0.97–0.87(m,1H),0.83(d,J＝6.7Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C31H41N2O8[M+H]+569.2864.Found 569.2785.
化合物I-3-17：柱层析PE:EA＝5:1,0.5％TEA，得到淡黄色无定形固体(收率57％)。1H NMR(400MHz,CDCl3):δ6.61(s,1H),6.56(s,1H),5.93(d,J＝9.7Hz,1H),5.85(dd,J＝13.7,1.5Hz,2H),5.03(s,1H),3.79(d,J＝9.7Hz,1H),3.66(s,3H),3.35(s,1H),3.21–3.04(m,2H),2.93(q,J＝11.2Hz,1H),2.67(p,J＝7.0Hz,1H),2.62–2.54(m,2H),2.38(dd,J＝14.2,6.9Hz,1H),2.30(d,J＝15.0Hz,1H),2.10–1.96(m,1H),1.93–1.86(m,1H),1.82(d,J＝15.0Hz,1H),1.75(s,3H),1.57–1.36(m,4H),1.23(dd,J＝7.0,1.2Hz,6H),1.18–1.06(m,1H),0.95–0.87(m,2H),0.83(dd,J＝6.6,2.7Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C32H45N2O8[M+H]+585.3177.Found 584.3098.
化合物I-3-18：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率87％)。1H NMR(400MHz,CDCl3):δ7.09(d,J＝5.1Hz,1H),6.90(dd,J＝5.1,3.5Hz,1H),6.73(t,J＝4.2Hz,1H),6.60(s,1H),6.56(s,1H),6.01(d,J＝9.3Hz,1H),5.79(d,J＝17.8Hz,2H),5.06(s,1H),3.81(d,J＝9.8Hz,1H),3.67(s,3H),3.53(s,1H),3.18(dt,J＝13.0,6.5Hz,1H),3.15–3.04(m,1H),3.00–2.79(m,2H),2.73–2.48(m,4H),2.40(dd,J＝14.2,6.9Hz,1H),2.33(d,J＝15.2Hz,1H),2.02(dd,J＝20.7,11.0Hz,2H),1.96–1.81(m,3H),1.63(s,1H),1.27–1.21(m,6H)ppm.HRMS-ESI(m/z):Calcd for C33H41N2O8S[M+H]+625.2581.Found 625.2505.
化合物I-3-19：柱层析PE:EA＝2:1,0.5％TEA，得到白色无定形固体(收率89％)。1H NMR(400MHz,CDCl3):δ6.95(s,1H),6.84(d,J＝8.1Hz,1H),6.67(d,J＝8.1Hz,1H),6.59(s,1H),6.58(s,1H),6.51(dd,J＝17.4,1.4Hz,1H),6.22(dd,J＝17.4,10.5Hz,1H),5.99(d,J＝9.7Hz,1H),5.91(dd,J＝10.5,1.5Hz,1H),5.75(dd,J＝40.8,1.6Hz,2H),5.08(s,1H),4.53(t,J＝8.6Hz,2H),3.82(d,J＝9.7Hz,1H),3.68(s,3H),3.46(s,1H),3.32–3.14(m,1H),3.16(t,J＝8.8Hz,2H),3.09(td,J＝8.5,5.1Hz,1H),2.93(td,J＝11.7,7.0Hz,1H),2.64–2.56(m,2H),2.49(td,J＝12.9,4.9Hz,1H),2.40(dd,J＝14.4,6.7Hz,1H),2.36(d,J＝17.4Hz,1H),2.19(td,J＝13.0,4.7Hz,1H),2.08–1.85(m,2H),1.96(d,J＝17.4Hz,1H),1.83(s,3H),1.80–1.65(m,4H)ppm.HRMS-ESI(m/z):Calcd for C36H41N2O9[M+H]+645.2810.Found 645.2734.
化合物I-3-20：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率38％)。1H NMR(400MHz,CDCl3):δ6.96(s,1H),6.84(d,J＝8.1Hz,1H),6.67(d,J＝8.1Hz,1H),6.58(d,J＝6.3Hz,2H),5.99(d,J＝9.7Hz,1H),5.76(dd,J＝33.8,1.6Hz,2H),5.08(s,1H),4.53(t,J＝8.6Hz,2H),3.83(d,J＝9.7Hz,1H),3.69(s,3H),3.44(s,1H),3.16(t,J＝8.8Hz,2H),3.13–3.04(m,2H),2.94(td,J＝11.5,6.9Hz,1H),2.72–2.54(m,3H),2.56–2.44(m,1H),2.40(dd,J＝13.7,7.2Hz,1H),2.33(d,J＝15.0Hz,1H),2.22(td,J＝12.9,4.5Hz,1H),2.08–1.98(m,1H),1.90(dd,J＝13.2,5.1Hz,2H),1.79(s,3H),1.74(dd,J＝12.7,5.4Hz,3H),1.68–1.48(m,1H),1.23(d,J＝7.0Hz,6H),1.20–1.08(m,2H)ppm.HRMS-ESI(m/z):Calcd for C37H45N2O9[M+H]+661.3120.Found 661.3122.
化合物I-3-21：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率30％)。1H NMR(400MHz,CDCl3):δ6.92(s,1H),6.82(d,J＝8.1Hz,1H),6.66(d,J＝8.1Hz,1H),6.59(d,J＝8.7Hz,2H),5.99(d,J＝9.6Hz,1H),5.74(dd,J＝54.6,1.6Hz,2H),5.12(s,1H),4.53(t,J＝8.7Hz,2H),3.85(d,J＝9.6Hz,1H),3.71(s,3H),3.15(t,J＝8.8Hz,2H),3.21–3.06(m,2H),3.05(s,1H),2.95(dt,J＝11.5,5.5Hz,1H),2.74(d,J＝13.7Hz,1H),2.67–2.52(m,3H),2.45–2.41(m,1H),2.38(dd,J＝13.7,7.2Hz,1H),2.15–1.98(m,2H),1.99–1.91(m,1H),1.90(s,3H),1.86–1.61(m,5H),1.16(dd,J＝15.8,7.0Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C37H45N2O9[M+H]+661.3120.Found,661.3122.
化合物I-3-22：柱层析PE:EA＝5:1,0.5％TEA，得到黄色无定形固体(收率89％)。1H NMR(400MHz,CDCl3):δ6.63-6.45(m,3H),6.14(dd,J＝17.3,10.5Hz,1H),5.96–5.83(m,3H),5.80(d,J＝11.5Hz,2H),5.06(s,1H),3.78(d,J＝9.6Hz,1H),3.65(s,3H),3.17–3.01(m,3H),3.00–2.87(m,1H),2.66–2.54(m,2H),2.42–2.29(m,2H),2.11–1.96(m,1H),1.95–1.82(m,1H),1.80–1.67(m,2H),1.66–1.51(m,2H),1.51–1.30(m,4H),0.87–0.77(m,6H)ppm.HRMS-ESI(m/z):Calcd for C30H39N2O8[M+H]+555.2707.Found 555.2628.
化合物I-3-23：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率43％)。1H NMR(400MHz,CDCl3):δ7.03(dd,J＝8.9,3.8Hz,1H),6.58(d,J＝7.0Hz,2H),5.91(d,J＝9.7Hz,1H),5.84(dd,J＝9.8,1.5Hz,2H),5.06(s,1H),3.79(d,J＝9.7Hz,1H),3.66(s,3H),3.12–3.03(m,3H),2.92(td,J＝11.5,6.8Hz,1H),2.63–2.53(m,4H),2.40–2.28(m,2H),1.89(ddd,J＝12.2,7.8,4.4Hz,1H),1.76(ddd,J＝17.9,11.8,5.5Hz,4H),1.59(td,J＝13.1,4.3Hz,1H),1.49–1.39(m,2H),1.20(dd,J＝7.0,1.5Hz,6H),0.89(ddd,J＝12.3,7.5,4.5Hz,1H),0.82(dd,J＝6.6,3.1Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C31H43N2O8[M+H]+571.3020.Found 571.2941.
化合物I-3-24：柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率43％)。1H NMR(400MHz,CDCl3):δ7.03(dd,J＝8.9,3.8Hz,1H),6.58(d,J＝7.0Hz,2H),5.91(d,J＝9.7Hz,1H),5.84(dd,J＝9.8,1.5Hz,2H),5.06(s,1H),3.79(d,J＝9.7Hz,1H),3.66(s,3H),3.12–3.03(m,3H),2.92(td,J＝11.5,6.8Hz,1H),2.63–2.53(m,4H),2.40–2.28(m,2H),1.89(ddd,J＝12.2,7.8,4.4Hz,1H),1.76(ddd,J＝17.9,11.8,5.5Hz,4H),1.59(td,J＝13.1,4.3Hz,1H),1.49–1.39(m,2H),1.20(dd,J＝7.0,1.5Hz,6H),0.89(ddd,J＝12.3,7.5,4.5Hz,1H),0.82(dd,J＝6.6,3.1Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C30H41N2O8[M+H]+557.2860.Found 557.2785.
化合物I-3-25：柱层析柱层析PE:EA＝5:1,0.5％TEA，得到白色无定形固体(收率87％)。1H NMR(400MHz,CDCl3):δ7.09(dd,J＝8.8,3.9Hz,1H),6.59(s,1H),6.59(s,1H),5.90(d,J＝5.1Hz,1H),5.85(dd,J＝1.6Hz,2H),5.08(s,1H),5.02(t,J＝6.8Hz,1H),3.81(d,J＝9.7Hz,1H),3.68(s,3H),3.08(q,J＝6.0Hz,3H),2.93(td,J＝11.5,7.0Hz,1H),2.61(dt,J＝13.9,7.0Hz,3H),2.38(dd,J＝14.0,6.7Hz,1H),2.31(dd,J＝14.8,8.8Hz,1H),2.10–1.97(m,1H),1.95–1.87(m,1H),1.82–1.71(m,4H),1.65(s,3H),1.56(s,3H),1.55–1.42(m,1H),1.22(dd,J＝7.0,1.3Hz,6H),0.85(d,J＝6.6,3.5Hz,2H)ppm.HRMS-ESI(m/z):Calcd for C32H43N2O8[M+H]+583.3020.Found 583.2941.
实施例23：肟酯类化合物的制备
通用操作：Ar氛下，向肟(1mmol)的CH2Cl2(2mL)溶液中滴入萘普生(1mmol)、EDCI(1.1mmol)、DMAP(0.2mmol)的CH2Cl2(2mL)，TLC板监测反应至完全。加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到肟酯粗产物。
参考上述方法，得到如下化合物：
化合物(I-3-26)：柱层析PE:EA＝4:1,0.5％TEA，得到淡黄色无定形固体(收率44％)。1H NMR(400MHz,CDCl3):δ7.70(d,J＝9.0Hz,3H),7.42(dd,J＝8.4,1.9Hz,1H),7.16–7.09(m,2H),6.56(s,1H),6.47(s,1H),5.90(d,J＝9.6Hz,1H),5.69(dd,J＝23.7,1.5Hz,2H),5.01(s,1H),3.91(s,3H),3.72(d,J＝8.9Hz,1H),3.64(s,3H),3.28(s,1H),3.15–3.03(m,2H),2.95–2.85(m,1H),2.61–2.53(m,2H),2.34(dd,J＝14.1,6.8Hz,1H),2.25(d,J＝15.0Hz,1H),2.04(s,3H),2.02–1.93(m,2H),1.92–1.81(m,2H),1.79–1.71(m,3H),1.63(d,J＝7.2Hz,3H),1.54–1.36(m,4H),0.82(dd,J＝6.6,2.7Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C42H51N2O9[M+H]+727.3594.Found 727.3516.
化合物I-3-27：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率45％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝9.1Hz,3H),7.43(d,J＝8.4Hz,1H),7.12(ddd,J＝15.9,12.3,3.8Hz,3H),6.89(dd,J＝5.1,3.4Hz,1H),6.73(d,J＝3.3Hz,1H),6.56(s,1H),6.48(s,1H),5.98(d,J＝9.7Hz,1H),5.65(dd,J＝55.3,1.5Hz,2H),5.04(s,1H),3.91(s,3H),3.75(s,1H),3.64(s,3H),3.51(s,1H),3.17–3.04(m,2H),2.98–2.80(m,2H),2.65–2.48(m,3H),2.37(dd,J＝14.1,6.7Hz,1H),2.28(d,J＝15.3Hz,1H),2.00(dd,J＝12.9,8.9Hz,1H),1.95–1.81(m,4H),1.81–1.70(m,3H),1.63(d,J＝7.2Hz,3H),1.57(s,3H)ppm.HRMS-ESI(m/z):Calcd for C43H47N2O9S[M+H]+767.2999.Found 767.2964.
化合物I-3-28：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率31％)。1H NMR(400MHz,CDCl3):δ7.68–7.62(m,3H),7.38(dd,J＝8.4,1.8Hz,1H),7.14–7.03(m,3H),6.86(dd,J＝5.2,3.4Hz,1H),6.60(d,J＝3.7Hz,1H),6.50(s,1H),6.49(s,1H),5.97(d,J＝9.5Hz,1H),5.73(dd,J＝53.8,1.6Hz,2H),5.08(s,1H),3.89(s,3H),3.76(d,J＝9.4Hz,1H),3.66(s,3H),3.53–3.43(m,1H),3.14–3.02(m,2H),2.92(dd,J＝11.2,7.0Hz,1H),2.87(s,1H),2.65–2.53(m,3H),2.52(d,J＝14.1Hz,1H),2.36–2.22(m,2H),2.02–1.98(m,1H),1.91(td,J＝12.4,11.9,5.2Hz,2H),1.78(s,3H),1.77–1.73(m,2H),1.70(d,J＝14.1Hz,2H),1.63(d,J＝7.1Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C43H47N2O9S[M+H]+767.2999.Found 767.2964.
化合物I-3-29：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率40％)。1H NMR(400MHz,CDCl3):δ7.70(d,J＝8.9Hz,2H),7.42(d,J＝8.6Hz,1H),7.17–7.08(m,2H),6.94(s,1H),6.83(d,J＝7.9Hz,1H),6.67(d,J＝8.1Hz,1H),6.52(d,J＝16.3Hz,2H),5.96(d,J＝9.7Hz,1H),5.71(s,1H),5.54(s,1H),5.06(s,1H),4.53(t,J＝8.6Hz,2H),3.91(s,3H),3.76(d,J＝9.8Hz,1H),3.66(s,3H),3.40(s,1H),3.15(t,J＝8.7Hz,2H),3.12–3.02(m,2H),2.91(td,J＝11.6,7.0Hz,1H),2.63–2.55(m,2H),2.53–2.42(m,1H),2.35(dd,J＝14.3,6.9Hz,1H),2.29(d,J＝15.0Hz,1H),2.26–2.14(m,1H),2.00(s,2H),1.94–1.70(m,6H),1.63(d,J＝7.1Hz,3H),1.59(s,3H)ppm.HRMS-ESI(m/z):Calcd for C47H51FN2O10[M+H]+803.3542.Found 803.3465.
化合物I-3-30：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率20％)。1H NMR(400MHz,CDCl3):δ7.64(d,J＝8.8Hz,2H),7.58(d,J＝8.5Hz,1H),7.34(d,J＝8.3Hz,1H),7.09(d,J＝9.0Hz,1H),7.04(s,1H),6.81(s,1H),6.73(d,J＝8.2Hz,1H),6.66(t,J＝7.2Hz,1H),6.50(dd,J＝12.3,2.5Hz,2H),5.98(d,J＝9.5Hz,2H),5.79(d,J＝10.4Hz,1H),5.58(s,1H),5.10(s,1H),4.53(t,J＝8.6Hz,2H),3.89(s,3H),3.78(d,J＝9.7Hz,1H),3.69(s,3H),3.21–3.05(m,4H),2.95–2.87(m,1H),2.85(s,1H),2.65–2.49(m,3H),2.32–2.20(m,2H),2.07–1.97(m,2H),1.93–1.88(m,1H),1.82(s,3H),1.79–1.72(m,3H),1.72–1.64(m,2H),1.61(d,J＝7.2Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C47H51FN2O10[M+H]+803.3542.Found 803.3465.
化合物I-3-31柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率20％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝8.2Hz,3H),7.44(d,J＝8.5Hz,1H),7.14(dd,J＝13.0,4.1Hz,2H),7.01(dd,J＝8.9,3.8Hz,1H),6.51(d,J＝10.7Hz,2H),5.93–5.88(m,1H),5.52(d,J＝22.8Hz,2H),5.05(s,1H),3.91(s,3H),3.77–3.72(m,1H),3.65(s,3H),3.12–2.98(m,3H),2.89(td,J＝11.4,6.9Hz,1H),2.57(q,J＝8.5Hz,2H),2.30(td,J＝14.8,7.8Hz,2H),2.08–1.95(m,1H),1.94–1.82(m,1H),1.74(ddd,J＝18.9,12.4,5.4Hz,4H),1.61(d,J＝7.1Hz,3H),1.50(ddd,J＝49.4,13.4,6.0Hz,3H),0.94–0.86(m,2H),0.83(dd,J＝6.7,3.1Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C41H49N2O9[M+H]+713.3439.Found 713.3360.
化合物I-3-32：柱层析PE:EA＝4:1,0.5％TEA，得到淡黄色无定形固体(收率54％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝8.2Hz,3H),7.44(d,J＝8.5Hz,1H),7.14(dd,J＝13.0,4.1Hz,2H),7.01(dd,J＝8.9,3.8Hz,1H),6.51(d,J＝10.7Hz,2H),5.93–5.88(m,1H),5.52(d,J＝22.8Hz,2H),5.05(s,1H),3.91(s,3H),3.77–3.72(m,1H),3.65(s,3H),3.12–2.98(m,3H),2.89(td,J＝11.4,6.9Hz,1H),2.57(q,J＝8.5Hz,2H),2.30(td,J＝14.8,7.8Hz,2H),2.08–1.95(m,1H),1.94–1.82(m,1H),1.74(ddd,J＝18.9,12.4,5.4Hz,4H),1.61(d,J＝7.1Hz,3H),1.50(ddd,J＝49.4,13.4,6.0Hz,3H),0.94–0.86(m,2H),0.83(dd,J＝6.7,3.1Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C40H47N2O9[M+H]+699.3203.Found 699.3280.
化合物I-3-33：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率58％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝8.6Hz,3H),7.43(dd,J＝8.4,1.8Hz,1H),7.18–7.06(m,3H),7.00(dd,J＝8.6,4.0Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.75–6.71(m,1H),6.52(d,J＝4.7Hz,2H),5.96(d,J＝9.6Hz,1H),5.46(dd,J＝46.8,1.5Hz,2H),5.08(s,1H),3.92(s,3H),3.77(d,J＝9.6Hz,1H),3.67(s,3H),3.14–3.00(m,3H),2.88(ddt,J＝17.7,13.6,5.8Hz,2H),2.62–2.52(m,3H),2.39–2.25(m,2H),2.09–1.95(m,2H),1.98–1.82(m,3H),1.84–1.70(m,3H),1.61(d,J＝7.1Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C42H45N2O9S[M+H]+753.2845.Found 753.2768.
化合物I-3-34：柱层析PE:EA＝2:1,0.5％TEA，得到淡黄色无定形固体(收率83％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝8.6Hz,3H),7.43(dd,J＝8.3,1.9Hz,1H),7.16–7.10(m,2H),7.04(dd,J＝8.7,4.0Hz,1H),6.95(s,1H),6.84(d,J＝8.8Hz,1H),6.67(d,J＝8.1Hz,1H),6.53(s,1H),6.51(s,1H),5.95(d,J＝9.6Hz,1H),5.48(dd,J＝48.8,1.6Hz,2H),5.09(s,1H),4.53(t,J＝8.7Hz,2H),3.92(s,3H),3.79(d,J＝9.7Hz,1H),3.69(s,3H),3.16(t,J＝8.7Hz,2H),3.11–3.02(m,2H),3.08(s,1H),2.90(td,J＝11.5,6.8Hz,1H),2.64–2.47(m,4H),2.36–2.20(m,4H),2.09–1.97(m,1H),1.93–1.85(m,1H),1.82–1.71(m,4H),1.61(d,J＝7.1Hz,3H)ppm.HRMS-ESI(m/z):Calcd for C46H49N2O10[M+H]+789.3385.Found 789.3309.
实施例24：酮肟醚类化合物的制备
通用操作：Ar氛下，向含有K2CO3(2mmol)的肟(1mmol)的DMF(2mL)溶液中滴入异戊基溴(1.2mmol)，TLC板监测反应至完全。加入饱和NaHCO3淬灭，Et2O萃取，合并有机相，依次用H2O、饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到酮肟醚粗产物。
参考上述方法，得到如下化合物：
化合物I-3-35：柱层析PE:EA＝7:1,0.5％TEA，得到淡黄色无定形固体(收率63％)。1H NMR(400MHz,CDCl3):δ6.59(s,1H),6.55(s,1H),5.93(d,J＝9.0Hz,1H),5.85(dd,J＝9.2,1.6Hz,2H),5.02(s,1H),3.76(d,J＝9.8Hz,1H),3.72(s,1H),3.66(s,3H),3.21–3.10(m,1H),3.13–3.02(m,1H),2.92(td,J＝11.6,7.1Hz,1H),2.63–2.52(m,2H),2.37(dd,J＝14.1,6.9Hz,1H),2.11–1.96(m,3H),1.94–1.82(m,2H),1.74(ddd,J＝17.1,8.7,4.6Hz,3H),1.61(s,3H),1.54–1.35(m,3H),1.34–1.22(m,5H),1.13(dt,J＝13.1,6.9Hz,1H),0.90–0.86(m,3H),0.83(dt,J＝6.6,3.4Hz,8H)ppm.HRMS-ESI(m/z):Calcd for C33H49N2O7[M+H]+585.3541.Found 584.3462.
通用操作：Ar氛下，向含有NaH(1.2mmol)的肟(1mmol)的DMF(2mL)溶液中滴入异戊基溴(1.2mmol)，TLC板监测反应至完全。加入半饱和NH4Cl淬灭，Et2O萃取，合并有机相，依次用H2O、饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到醛肟醚粗产物。
化合物I-3-36：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率66％)。1H NMR(400MHz,CDCl3):δ6.57(d,J＝4.4Hz,2H),6.23(dd,J＝6.7,3.5Hz,1H),5.92(d,J＝9.7Hz,1H),5.87(s,2H),5.06(s,1H),4.07(td,J＝7.0,2.2Hz,2H),3.79(d,J＝9.7Hz,1H),3.68(s,3H),3.15–3.06(m,2H),3.01(s,1H),2.98–2.89(m,1H),2.60(t,J＝8.3Hz,2H),2.50(dd,J＝16.7,6.7Hz,1H),2.37(dd,J＝14.1,6.7Hz,1H),2.03(t,J＝10.4Hz,1H),1.90(ddd,J＝12.2,8.1,4.1Hz,1H),1.79–1.59(m,6H),1.49(dq,J＝37.9,6.8Hz,6H),0.93(dd,J＝6.7,2.2Hz,6H),0.89(d,J＝6.7Hz,1H),0.84(dd,J＝6.6,2.2Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C32H47N2O7[M+H]+571.3384.Found 570.3305.
化合物I-3-37：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率35％)。1H NMR(400MHz,CDCl3)δ6.60(s,1H),6.58(s,1H),5.93(d,J＝9.8Hz,1H),5.86(d,J＝13.8Hz,2H),5.05(s,1H),4.20–4.01(m,1H),3.99(t,J＝7.0Hz,2H),3.79(d,J＝9.6Hz,1H),3.67(s,3H),3.19–3.04(m,2H),2.94(dd,J＝21.0,9.1Hz,1H),2.64–2.53(m,2H),2.38(dd,J＝13.7,6.7Hz,1H),2.15–1.97(m,2H),1.95–1.84(m,1H),1.83–1.69(m,3H),1.70–1.39(m,5H),1.27(h,J＝8.6,7.5Hz,6H),1.16–0.98(m,1H),0.90(d,J＝6.8Hz,6H),0.89–0.80(m,3H)ppm.HRMS-ESI(m/z):Calcd forC31H45N2O7[M+H]+557.3225.Found 557.3149.
化合物I-3-38：柱层析PE:EA＝3:1,0.5％TEA，得到淡黄色无定形固体(收率40％)。1H NMR(400MHz,CDCl3):δ7.10(dd,J＝5.2,1.2Hz,1H),6.90(dd,J＝5.2,3.4Hz,1H),6.74(d,J＝2.2Hz,1H),6.58(s,1H),6.58(s,1H),6.23(dd,J＝6.7,3.6Hz,1H),5.98(d,J＝9.6Hz,1H),5.83(dd,J＝26.4,1.7Hz,2H),5.09(s,1H),4.07(td,J＝7.0,2.4Hz,2H),3.82(d,J＝9.7Hz,1H),3.70(s,3H),3.19–3.05(m,3H),3.01–2.80(m,2H),2.66–2.49(m,4H),2.38(dd,J＝14.2,6.8Hz,1H),2.12–1.99(m,1H),1.97–1.85(m,3H),1.81–1.72(m,3H),1.73–1.61(m,3H),0.91(dd,J＝6.6,4.0Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C33H43N2O7S[M+H]+611.2789.Found 611.2713.
实施例25：氨基甲酸肟酯类化合物的制备
通用操作：Ar氛下，向肟(1mmol)的CH2Cl2(2mL)溶液中滴入环戊基氨基甲酸酯(1.2mmol)，反应12h。加入饱和NaHCO3淬灭，CH2Cl2萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥。旋蒸除去溶剂，得到氨基甲酸肟酯粗产物。
参考上述方法，得到如下化合物：
化合物I-3-39：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形体产物(收率32％)。1H NMR(400MHz,CDCl3):δ6.49(s,1H),6.42(s,1H),6.07(d,J＝7.2Hz,1H),5.96(d,J＝9.7Hz,1H),5.88(d,J＝1.6Hz,2H),5.05(s,1H),4.09(h,J＝6.9Hz,1H),3.71(d,J＝9.3Hz,1H),3.67(s,3H),3.30(s,1H),3.18–3.00(m,2H),2.90(td,J＝11.5,7.0Hz,1H),2.63–2.51(m,2H),2.34(dd,J＝14.1,7.0Hz,1H),2.27(d,J＝17.5Hz,1H),2.13(d,J＝17.5Hz,1H),2.11–1.93(m,4H),1.96–1.83(m,2H),1.85–1.74(m,2H),1.74(s,3H),1.72–1.51(m,6H),1.52–1.42(m,2H),1.41–1.28(m,1H),0.86(d,J＝6.6Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C34H48N3O8[M+H]+626.3438.Found 626.3363.
化合物I-3-40：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率41％)。1H NMR(400MHz,CDCl3):δ6.68(s,1H),6.63(s,1H),6.21(d,J＝7.4Hz,1H),5.97(d,J＝9.6Hz,1H),5.85(s,2H),5.08(s,1H),4.08(h,J＝6.8Hz,1H),3.85(d,J＝9.7Hz,1H),3.69(s,3H),3.21–2.99(m,4H),2.75–2.55(m,3H),2.13–1.89(m,6H),1.79(s,3H),1.73–1.53(m,6H),1.55–1.41(m,3H),1.43–1.30(m,4H),0.82(d,J＝6.6Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C34H48N3O8[M+H]+626.3438.Found 626.3363.
化合物(I-3-41)：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率32％)。1H NMR(400MHz,CDCl3):δ6.48(s,1H),6.42(s,1H),6.03(d,J＝1.7Hz,1H),5.97(d,J＝9.7Hz,1H),5.86(d,J＝1.7Hz,1H),5.86–5.68(m,1H),5.06(s,1H),5.05–4.90(m,2H),4.17–4.04(m,1H),3.69(d,J＝10.1Hz,1H),3.67(s,3H),3.31(d,J＝1.5Hz,1H),3.18–3.01(m,3H),2.97–2.85(m,1H),2.63–2.52(m,2H),2.34(dd,J＝13.6,6.3Hz,1H),2.30(d,J＝17.3Hz,1H),2.24–2.15(m,1H),2.18(d,J＝17.3Hz,1H),2.13–1.87(m,6H),1.85–1.76(m,2H),1.76(s,3H),1.75(s,1H),1.72–1.52(m,6H)ppm.HRMS-ESI(m/z):Calcd for C33H44N3O8[M+H]+610.3126.Found 610.3050.
化合物I-3-42：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率42％)。1H NMR(400MHz,CDCl3):δ6.48(s,1H),6.42(s,1H),6.03(s,1H),5.97(d,J＝9.7Hz,1H),5.86(s,1H),5.85–5.68(m,1H),5.05(s,1H),5.04–4.88(m,2H),4.08(dd,J＝8.4,4.9Hz,1H),3.69(d,J＝10.1Hz,1H),3.67(s,3H),3.41–3.27(m,1H),3.18–2.99(m,2H),2.98–2.81(m,1H),2.64–2.52(m,3H),2.40–2.25(m,2H),2.18(d,J＝17.3Hz,2H),2.12–1.94(m,4H),1.96–1.84(m,2H),1.87–1.75(m,2H),1.75(s,3H),1.76–1.69(m,1H),1.73–1.54(m,6H)ppm.HRMS-ESI(m/z):Calcd for C33H44N3O8[M+H]+610.3126.Found 610.3050.
化合物I-3-43：柱层析PE:EA＝3:1,0.5％TEA，得到淡黄色无定形固体(收率21％)。1H NMR(400MHz,CDCl3):δ7.09(dd,J＝5.2,1.2Hz,1H),6.89(dd,J＝5.2,3.4Hz,1H),6.73(d,J＝3.4Hz,1H),6.68(s,1H),6.63(s,1H),6.17(d,J＝7.4Hz,1H),6.01(d,J＝9.6Hz,1H),5.80(dd,J＝14.1,1.5Hz,2H),5.09(s,1H),4.07(h,J＝7.3Hz,1H),3.86(d,J＝9.6Hz,1H),3.67(s,3H),3.23(s,1H),3.17–3.07(m,2H),2.94(td,J＝11.6,6.8Hz,1H),2.89–2.76(m,1H),2.67(d,J＝14.2Hz,1H),2.66–2.53(m,3H),2.06–1.86(m,5H),1.81(s,3H),1.74(dd,J＝13.1,4.7Hz,2H),1.71–1.55(m,6H),1.53–1.40(m,2H),1.43–1.31(m,1H)ppm.HRMS-ESI(m/z):Calcd for C35H44N3O8S[M+H]+666.2680.Found 666.2771.
化合物I-3-44：柱层析PE:EA＝3:1,0.5％TEA，得到淡黄色无定形固体(收率18％)。1H NMR(400MHz,CDCl3):δ7.11(dd,J＝5.1,1.2Hz,1H),6.92(dd,J＝5.2,3.4Hz,1H),6.76(d,J＝2.2Hz,1H),6.49(s,1H),6.44(s,1H),6.06(d,J＝7.2Hz,1H),6.02(d,J＝1.7Hz,1H),5.86(d,J＝1.7Hz,1H),5.07(s,1H),4.10(h,J＝6.8Hz,1H),3.72(d,J＝9.7Hz,1H),3.65(s,3H),3.41(d,J＝1.6Hz,1H),3.18–3.01(m,2H),3.02–2.87(m,2H),2.70(td,J＝13.6,4.6Hz,1H),2.62–2.55(m,2H),2.35(dd,J＝14.4,7.0Hz,1H),2.22(d,J＝17.5Hz,1H),2.20(d,J＝17.5Hz,1H),2.11–1.95(m,4H),1.98–1.85(m,3H),1.86–1.78(m,2H),1.77(s,3H),1.73–1.55(m 6H)ppm.HRMS-ESI(m/z):Calcd for C35H44N3O8S[M+H]+666.2680.Found 666.2771.
化合物I-3-45：柱层析PE:EA＝3:1,0.5％TEA，得到淡黄色无定形固体(收率44％)。1H NMR(400MHz,CDCl3):δ6.94(s,1H),6.83(d,J＝8.1Hz,1H),6.66(d,J＝8.1Hz,1H),6.66(s,1H),6.62(s,1H),6.17(d,J＝7.4Hz,1H),6.00(d,J＝9.6Hz,1H),5.78(dd,J＝22.7,1.6Hz,2H),5.11(s,1H),4.53(t,J＝8.6Hz,2H),4.06(q,J＝6.9Hz,1H),3.86(d,J＝9.7Hz,1H),3.70(s,3H),3.20(s,1H),3.16(t,J＝8.5Hz,2H),3.15–3.04(m,2H),2.94(td,J＝11.5,6.9Hz,1H),2.70(d,J＝14.1Hz,1H),2.60(td,J＝14.5,6.9Hz,3H),2.49(td,J＝12.8,4.7Hz,1H),2.24(td,J＝13.7,13.2,3.9Hz,1H),2.10–1.95(m,2H),1.91(dt,J＝8.4,5.2Hz,2H),1.82(s,3H),1.82–1.71(m,2H),1.72–1.54(m,6H),1.53–1.40(m,3H)ppm.HRMS-ESI(m/z):Calcd for C39H48N3O9[M+H]+702.3388.Found 702.3312.
化合物I-3-46：柱层析PE:EA＝6:1,0.5％TEA，得到淡黄色无定形固体(收率38％)。1H NMR(400MHz,CDCl3):δ6.64(s,1H),6.60(s,1H),5.94(d,J＝9.7Hz,1H),5.91–5.88(m,2H),5.09(s,1H),3.81(d,J＝9.7Hz,1H),3.68(s,4H),3.34(s,1H),3.13–3.01(m,2H),3.01–2.89(m,2H),2.66–2.54(m,2H),2.38(dd,J＝13.6,6.3Hz,1H),2.10–2.01(m,2H),2.00–1.85(m,2H),1.80–1.71(m,4H),1.67–1.53(m,4H),1.47(dt,J＝13.2,6.5Hz,1H),1.40–1.23(m,4H),0.97–0.88(m,3H),0.85(dd,J＝6.6,4.5Hz,6H)ppm.HRMS-ESI(m/z):Calcd for C33H46N3O8[M+H]+612.3286.Found 612.3207.
实施例26：体外生物活性测试
供试细胞
人乳腺癌细胞MCF-7，肝癌细胞HepG2，肺腺癌细胞A549均购自中科院上海细胞库。人白血病细胞HL-60、人白血病细胞阿霉素耐药株HL-60/ADR、人胶质母细胞瘤细胞U-87MG购自上海传秋生物科技有限公司。人宫颈癌HeLa购自上海吉凯基因化学技术有限公司。人结肠癌细胞HCT-116、人脑微血管内皮细胞hCMEC/D3由天津尚德药缘科技股份有限公司保存。人结肠癌细胞Sw620、人结肠癌细胞LoVo由天津医科大学附属医院提供。
主要仪器与耗材
二氧化碳恒温细胞培养箱，美国Thermo Fisher公司；
倒置生物显微镜，重庆奥特光学仪器有限公司；
酶标仪，美国Thermo Fisher公司；
精密可调微量移液器，Eppendorf(德国)公司；
96孔细胞培养板，无锡耐思生命科技有限公司；
细胞培养皿，无锡耐思生命科技有限公司。
主要试剂
胎牛血清，以色列BI；
胰蛋白酶，Gibco公司；
双抗，Gibco公司；
DMEM培养基，以色列BI；
DMSO，天津渤化化学试剂有限公司；
MTT，上海源叶生物科技有限公司。
实验步骤如下：
细胞培养
人乳腺癌细胞MCF-7、肝癌细胞HepG2、肺腺癌细胞A549、人白血病细胞HL-60、人白血病细胞阿霉素耐药株HL-60/ADR、人胶质母细胞瘤细胞U-87MG、人宫颈癌细胞HeLa、人结肠癌细胞HCT-116、人结肠癌细胞Sw620、人结肠癌细胞LoVo、人脑微血管内皮细胞HCMEC/D3使用DMEM培养基培养。培养液是在培养基中加入了10％胎牛血清以及1％双抗(青霉素+链霉素)，培养环境为充入5％CO2，温度为37℃的培养箱；当细胞基本长满皿底(大约80％-90％)，进行传代培养。
配制工作液
MTT溶液的配制：称取MTT50mg，溶于10mL的磷酸缓冲液(PBS)中，分装，4℃避光保存，两周内有效。
供试药物的配置：取系列化合物用培养基稀释配成1mg/ml母液，临用前，精密吸取适量样品母液用培养基稀释成不同浓度梯度的工作液，如100μg/ml、10μg/ml、1μg/ml、0.1μg/ml、0.01μg/ml、0.001μg/ml等。
测定方法
1.取对数期细胞，消化、离心并重悬。加培养液调整细胞密度为1×105个/mL，每孔加入100微升配好的细胞悬液接种于96孔细胞培养板中，之后放置于细胞培养箱中培养。
2.在培养24h后，试验组分别加入2μl浓度为100μg/ml、10μg/ml、1μg/ml、0.1μg/ml、0.01μg/ml、0.001μg/ml的系列化合物，每个浓度设4个复孔，并设阳性对照组(依托泊苷)和空白对照组。
3.将96孔板分别培养48h后每孔加入20μl MTT溶液(浓度为5mg/ml)，在培养箱中继续培养4小时。
4.把96孔板从培养箱中取出，用微量移液器小心吸弃孔内培养基，并每孔加入150微升二甲基亚砜，震荡使结晶完全溶解，然后使用酶标仪在492nm波长条件下测定吸光度OD值。
5.试验连续重复三次，并按照下面的公式计算细胞抑制率：细胞抑制率(％)＝[1-试验组OD值/空白对照组OD)]×100％，并计算样品抑制细胞生长的半数抑制浓度IC50值。
试验结果显示，低于0.1v％DMSO溶剂对细胞影响可忽略，IC50值实验结果汇总于表1。
表1：实施例化合物的活性数据(IC50(nM))
以上对本发明示例性的实施方式进行了说明。但是，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所作出的任何修改、等同替换或改进等，均应涵盖在本发明的保护范围之内。

Claims (10)

  1. 式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物：
    其中，RS选自(RN)m-G-(CH2)n-或(RQ)m-G-(CH2)n-：
    RN代表包含氮原子的取代基，例如硝基、无取代或任选被一个、两个或更多个Ra取代的下列基团：-NR6R7、-NR6’-C(＝Y-R4)-NR6R7；
    每一个R6、R6’和R7相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R10C(＝O)-、R10C(＝O)O-、R10C(＝O)NH-、R10OC(＝O)-、R10NHC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
    RQ代表H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
    G代表化学键、C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；条件是当G不为化学键时，G连接的不同基团在G上取代的位置之间可以间隔1-10个原子，例如间隔1、2、3、4、5、6、7、8、9或10个原子；例如，当G为苯基时，其连接的不同基团在G上取代的位置之间可以间隔1、2、3、4或5个碳原子，例如所述不同基团在G上为邻位取代、间位取代和/或对位取代，优选为间位和/或对位取代；
    每一个m相同或不同，彼此独立地选自1以上的整数；
    每一个n相同或不同，彼此独立地选自1以上的整数；
    每一个Y相同或不同，彼此独立地选自O、S或N，条件是当Y选自O或S时，R4不存在；
    R1和R2相同或不同，彼此独立地选自H、C1-6烷基或卤素；
    R3选自R8、R8-O-、R8-S-；
    R4不存在，或选自H、无取代或任选被一个、两个或更多个Rd取代的下列基团：R8-O-、R8-S-、R9C(＝O)O-、R10OC(＝O)O-、R10NHC(＝O)-、R10NHC(＝O)O-、R10C(＝O)NH-；
    R5选自H或C1-6烷基；
    每一个Ra、Rb、Rc和Rd相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、氧代(＝O)，无取代或任选被一个、两个或更多个Re取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R11C(＝O)-、R11C(＝O)O-、R11C(＝O)NH-、R11OC(＝O)-、R11NHC(＝O)-、R11S(O)2-、R11S(O)2O-、R11OS(O)2-、R11S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
    每一个R8、R9、R10和R11相同或不同，彼此独立地选自H、C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R11’C(＝O)-、R11’C(＝O)O-、R11’C(＝O)NH-、R11’OC(＝O)-、R11’NHC(＝O)-、R11’S(O)2-、R11’S(O)2O-、R11’OS(O)2-、R11’S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
    每一个R11’、R12和R13相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    每一个Re和Rf相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、-NH2、氧代(＝O)，无取代或任选被一个、两个或更多个Rg取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基、R14C(＝O)-、R14C(＝O)O-、R14OC(＝O)-、R14S(O)2-、R14S(O)2O-、R14OS(O)2-、R14S(O)-；
    每一个R14相同或不同，彼此独立地选自C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    每一个Rg相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、-NH2、氧代(＝O)，C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-20烷基氧基、C2-20烯基氧基、C3-20环烷基氧基、C3-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-20烷基硫基、C2-20烯基硫基、C3-20环烷基硫基、C3-20环烯基硫基、3-20元杂环基硫基、C6-20芳基硫基、5-20元杂芳基硫基；
    任选地，所述C3-20环烷基或3-20元杂环基的一个、两个或更多碳原子可以任选地被氧取代以形成羰基。
  2. 如权利要求1所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中：
    G代表化学键、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基，例如化学键、C1-8烷基、C2-8烯基、苯基、萘基；
    m代表1～20的整数，优选1～10的整数；
    n代表1～20的整数，优选1～10的整数；
    卤素代表F、Cl、Br或I；
    Y选自O、N或S；
    R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基-O-、C2-8烯基-O-、C3-15环烷基-O-、C3-15环烯基-O-、3-15元杂环基-O-、C6-15芳基-O-、5-15元杂芳基-O-、C1-8烷基-S-、C2-8烯基-S-、C3-15环烷基-S-、C3-15环烯基-S-、3-15元杂环基-S-、C6-15芳基-S-、5-15元杂芳基-S-；
    R4不存在或选自H；
    RN代表硝基、无取代或任选被一个、两个或更多个Ra取代的下列基团：-NR6R7、-NH-C(＝Y-R4)-NR6R7；
    优选地，RN选自-NR6R7、-NH-C(＝O)-NR6R7、-NH-C(＝S)-NR6R7或-NH-C(＝NH)-NR6R7；
    或者，RN选自硝基、氨基，或邻位、间位和/或对位被硝基或氨基取代的苯基，其中所述氨基无取代或被一个、两个或更多个选自C1-8烷基羰基、C1-8烷基氧基羰基、C3-8环烷基羰基、C3-8环烷基氧基羰基、C6-10芳基羰基、C6-10芳基氧基羰基、C2-8烯基的取代基取代。
  3. 如权利要求1或2所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中：
    R6选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基；
    R7选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-20烷基氧基)硅基C1-20烷基、三(C1-20烷基)硅基。
    优选地，R6选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-8烷基氧基)硅基C1-8烷基、三(C1-8烷基)硅基；
    R7选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、R10C(＝O)-、R10C(＝O)O-、R10OC(＝O)-、R10S(O)2-、R10S(O)2O-、R10OS(O)2-、R10S(O)-、三(C1-8烷基氧基)硅基C1-8烷基、三(C1-8烷基)硅基；
    R10选自C1-8烷基、C2-8烯基、C3-10环烷基、C3-10环烯基、3-8元杂环基、C6-10芳基、5-10元杂芳基、NH2；
    每一个Ra和Rb相同或不同，彼此独立地选自卤素、-OH、-CN、-NO2、无取代或任选被一个、两个或更多个Rd取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、 5-15元杂芳基、C1-8烷基氧基、C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基、R11C(＝O)-、R11C(＝O)O-、R11OC(＝O)-、R11S(O)2-、R11S(O)2O-、R11OS(O)2-、R11S(O)-、-NR12R13、-NH-C(＝Y)-NR12R13；三(C1-20烷基氧基)硅基C1-20烷基；
    优选地，R7选自例如H、无取代或任选被一个、两个或更多个Re取代的下列基团：C1-8烷基、C3-8环烷基、C2-8烯基、三(C1-8烷基氧基)硅基C1-8烷基、苯基、联苯基、萘基；
    例如，R7选自H、无取代或任选被一个、两个或更多个Re取代的下列基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基、正庚基、环丙基、环丁基、环戊基、环己基、环庚基、烯丙基、苯基、
  4. 如权利要求1-3任一项所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中：
    RQ选自H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基氧基、C2-8烯基氧基、C3-15环烷基氧基、C3-15环烯基氧基、3-15元杂环基氧基、C6-15芳基氧基、5-15元杂芳基氧基、C1-8烷基硫基、C2-8烯基硫基、C3-15环烷基硫基、C3-15环烯基硫基、3-15元杂环基硫基、C6-15芳基硫基、5-15元杂芳基硫基；
    优选地，RQ选自H、卤素、-OH、-CN、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-6烷基、C2-6烯基、C3-10环烷基、C3-10环烯基、3-10元杂环基、C6-10芳基、5-10元杂芳基，例如无取代或任选被一个、两个或更多个Rc取代的下列基团：甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、三氟甲基-甲基、五氟乙基、苯基、萘基、噻吩基、二氢苯并呋喃基；
    R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、C1-8烷基-O-、C2-8烯基-O-、C3-15环烷基-O-、C3-15环烯基-O-、3-15元杂环基-O-、C6-15芳基-O-、5-15元杂芳基-O-、C1-8烷基-S-、C2-8烯基-S-、C3-15环烷基-S-、C3-15环烯基-S-、3-15元杂环基-S-、C6-15芳基-S-、5-15元杂芳基-S-；
    优选地，R3选自H、甲基、甲氧基、甲硫基；
    Y选自N。
  5. 如权利要求1-3任一项所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中：
    RQ选自H、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基；
    优选地，RQ选自无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-6烷基、C2-6烯基、C3-10环烷基、C3-10环烯基、3-10元杂环基、C6-10芳基、5-10元杂芳基，例如无取代或任选被一个、两个或更 多个Rc取代的下列基团：甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、噻吩基、二氢苯并呋喃基；
    R3选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基；
    R4选自无取代或任选被一个、两个或更多个Rd取代的下列基团：R8-O-、R8-S-、R9C(＝O)O-；
    每一个R8和R9相同或不同，彼此独立地选自H、C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、-NR12R13；
    每一个R12和R13相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基；
    优选地，R12选自H，R13选自无取代或任选被一个、两个或更多个Rf取代的下列基团：C1-8烷基、C2-8烯基、C3-15环烷基、C3-15环烯基、3-15元杂环基、C6-15芳基、5-15元杂芳基、-NR12R13，例如选自环戊基。
    优选地，R8选自H、-OH、丙烯酰基、异丁酰基、异戊基、
    R9选自C1-8烷基、C2-8烯基、NH2。
  6. 如权利要求1-5任一项所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中所述式(I)所示的化合物可以选自如下式(I-1)、(I-2)、(I-3)、(I-4)或(I-5)所示的化合物：
    其中，R6、R6’、R7、G、n、R3彼此独立地选自权利要求1-5任一项所述的定义，Y代表O、S或NH；
    其中，RQ、G、n、R3彼此独立地选自权利要求1-5任一项所述的定义；
    其中，RQ、G、n、R3、R4彼此独立地选自权利要求1-5任一项所述的定义；
    其中，R6、R7、G、n、R3彼此独立地选自权利要求1-5任一项所述的定义；
    其中，R6、R10、G、n、R3彼此独立地选自权利要求1-5任一项所述的定义。
  7. 如权利要求1所述的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物，其中所述式(I)所示的化合物选自下列化合物：
    其中，基团R、G、R4和n具有下表所述的定义：
    或者，所述式(I)所示的化合物选自下列化合物：
    其中，基团R、R3和n具有下表所述的定义：
    或者，所述式(I)所示化合物选自下列化合物：
    其中，基团R、R3和R8具有下表所述的定义：

  8. 权利要求1-7任一项所述式(I)所示化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物的制备方法，其中所述制备方法可以包括选自下列方法中的一种：
    方法(1)
    其中，R1、R2、R4、R5、Y具有上文所述的定义；
    R3选自R8-O-；
    所述步骤(1)在碱和R8-OH的存在下进行反应，制备式(I)化合物；
    方法(2)
    当式(I)化合物的取代基RS中包含氨基时，以相应的硝基化合物为底物，还原制备式(I)化合物；
    优选地，所述还原为在Zn和AcOH的存在下进行；
    方法(3)
    当式(I)化合物的取代基RS中包含酰基氨基时，以相应的氨基化合物为底物，通过酰化反应，制备式(I)化合物；
    方法(4)
    当式(I)化合物的取代基RS中包含脲基团时，以相应的氨基化合物为底物，通过与异氰酸酯类化合物反应，制备式(I)化合物；
    方法(5)
    当式(I)化合物的取代基RS中包含胍基团时，以相应的氨基化合物为底物，通过与腈胺、酰基腈胺或者不同取代的碳二亚胺类化合物反应，制备式(I)化合物；
    方法(6)
    其中，R1、R2、R3、R5具有上文所述的定义；
    R4选自羟基；
    Y选自N；
    所述步骤(1)在碱和盐酸羟胺的存在下进行反应，制备式(I)化合物；
    方法(7)
    其中，R1、R2、R3、R5具有上文所述的定义；
    R4选自R9C(＝O)O-；
    Y选自N；
    所述步骤(1)在碱和C1-20烷基-C(O)-O-C(O)-C1-20烷基的存在下进行反应，制备式(I)化合物；
    方法(8)
    其中，R1、R2、R3、R5具有上文所述的定义；
    R4选自R9C(＝O)O-；
    Y选自N；
    所述步骤(1)在碱和R9C(＝O)Cl或R9C(＝O)OH的存在下进行反应，制备式(I)化合物；
    方法(9)
    其中，R1、R2、R3、R5具有上文所述的定义；
    R4选自R8-O-；
    R8选自C1-20烷基、C2-20烯基、C3-20环烷基、C3-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    Y选自N；
    所述步骤(1)在碱和R8-L的存在下进行反应，制备式(I)化合物；
    L为离去基团，例如卤素，优选Br或I；
    方法(10)
    其中，R1、R2、R3、R5具有上文所述的定义；
    R4选自R10NHC(＝O)O-；
    Y选自N；
    所述步骤(1)在R10-N＝C＝O的存在下进行反应，制备式(I)化合物；
    任选地，所述制备方法还包括将制备得到的式(I)化合物与药学上可接受的酸或碱反应成盐的步骤。
  9. 一种药物组合物，其包含权利要求1-7任一项所述的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
  10. 权利要求1-7任一项所述的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物，药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种在制备药物中的用途，所述药物用于预防和/或治疗由不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答引起的疾病，或者伴有不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答的疾病的用途，特别地，所述疾病为例如血液肿瘤、实体瘤和/或它们的转移，如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头部和颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤、包括肾肿瘤、膀胱瘤和前列腺瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移；
    或者，所述药物用于抑制肿瘤细胞，其中所述肿瘤细胞选自血液肿瘤和/或实体瘤的肿瘤细胞，例如乳腺癌细胞、肝癌细胞、肺腺癌细胞、白血病细胞、白血病细胞阿霉素耐药株、胶质母细胞瘤细胞、宫颈癌细胞、结肠癌细胞和/或脑微血管内皮细胞；例如，所述肿瘤细胞选自人乳腺癌细胞MCF-7、肝癌细胞HepG2、肺腺癌细胞A549、人白血病细胞HL-60、人白血病细胞阿霉素耐药株HL-60/ADR、人胶质母细胞瘤细胞U-87MG、人宫颈癌细胞HeLa、人结肠癌细胞HCT-116、人结肠癌细胞Sw620、人结肠癌细胞LoVo和人脑微血管内皮细胞hCMEC/D3中的至少一种
    或者，所述药物用于治疗哺乳动物的过度增殖性病症，或用于抑制、阻断、降低、减少等细胞增殖和/或细胞分裂和/或引起凋亡；优选地，过度增殖性病症包括但不限于银屑病、瘢痕疙瘩和其它影响皮肤的增生、良性前列腺增生(BpH)、实体瘤例如乳腺癌、呼吸道癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌以及它们的远端转移；
    或者，所述病症还包括淋巴瘤、肉瘤和白血病。
PCT/CN2023/120776 2022-09-22 2023-09-22 三尖杉酯碱类衍生物及其药物组合物、制备方法和用途 WO2024061357A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN1474821A (zh) * 2000-10-17 2004-02-11 ����˹��ҩ�﹫˾ 新型粗榧生物碱、其制备方法和其在治疗癌症、白血病、包括耐受通常的化学治疗剂的寄生物在内的寄生物及作为反向治疗剂的应用
WO2009148654A2 (en) * 2008-03-03 2009-12-10 Sloan-Kettering Institute For Cancer Research Cephalotaxus esters, methods of synthesis, and uses thereof
WO2013023620A1 (zh) * 2011-08-18 2013-02-21 杭州本生药业有限公司 高三尖杉酯碱的胺化衍生物、及其制备方法和应用
CN106866690A (zh) * 2015-12-10 2017-06-20 南开大学 三尖杉酯类生物碱、其制备方法和用途

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Publication number Priority date Publication date Assignee Title
CN1474821A (zh) * 2000-10-17 2004-02-11 ����˹��ҩ�﹫˾ 新型粗榧生物碱、其制备方法和其在治疗癌症、白血病、包括耐受通常的化学治疗剂的寄生物在内的寄生物及作为反向治疗剂的应用
WO2009148654A2 (en) * 2008-03-03 2009-12-10 Sloan-Kettering Institute For Cancer Research Cephalotaxus esters, methods of synthesis, and uses thereof
WO2013023620A1 (zh) * 2011-08-18 2013-02-21 杭州本生药业有限公司 高三尖杉酯碱的胺化衍生物、及其制备方法和应用
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