Preparation and application of vinblastine derivative

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate of the compound, and application of the compound in cancer-related diseases such as acute myelogenous leukemia. The anti-proliferative activity of the synthesized vinblastine derivative on acute myelogenous leukemia cancer cells is obviously superior to that of vinblastine, and the vinblastine derivative can be used as a toxin molecule for development of antibody coupling drugs and has a very good anti-tumor effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound synthesis and pharmaceutical applications, and particularly to the preparation of vinblastine derivatives and their applications in medicine. Background Art

[0002] Acute myeloid leukemia is the most common subtype of leukemia in adults, characterized by rapid progression, difficult to cure, high recurrence rate, poor prognosis, with a mortality rate exceeding 80% and a 5-year survival rate less than 24%. Vinblastine and vincristine are dimeric monoterpene indole alkaloids of the Vinca class isolated from the plant Catharanthus roseus of the Apocynaceae family in the 1960s. They can inhibit tubulin polymerization and prevent spindle formation, thereby inducing apoptosis of cancer cells.

[0003] Clinically, vinblastine drugs are mainly used to treat bladder cancer, breast cancer, acute lymphoblastic leukemia, melanoma, and non-small cell lung cancer. These drugs are substrates of P-glycoprotein. When the drugs enter tumor cells, they are pumped out of the cells by highly expressed P-glycoprotein, resulting in tumor drug resistance and seriously affecting the treatment effect. In addition, in the preparation of derivatives, existing chemical synthesis methods have great limitations and are difficult to apply to the construction of a diverse vinblastine derivative library. Based on this, the present invention has developed a simple method for the diverse preparation of vinblastine derivatives, and through activity screening, derivatives with significantly better anti-proliferative activity against cancer cells such as acute myeloid leukemia than vinblastine have been discovered. The vinblastine derivatives prepared by the present invention, on the one hand, may overcome drug resistance and be used for the development of new anti-cancer drugs for the treatment of acute myeloid leukemia, etc.; on the other hand, they can be used as toxin molecules for the development of antibody-drug conjugates. Summary of the Invention

[0004] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a preparation method and application of vinblastine derivatives.

[0005] The purpose of the present invention is achieved by the following technical solutions: a vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and the vinblastine derivative is selected from the compounds represented by the general formula (I),

[0006]

[0007] wherein, R1, R2, R3 or R4 are each independently selected from H, deuterium, halogen, CN, COOH, NR a R b 、C(=O)NR a R b 、ORc , SR c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; and R1, R2, R3 and R4 are not simultaneously H;

[0008] R5 is selected from H, deuterium, halogen, OR c , SR c , CN, NR a R b , NHC(=O)NR a R b , NHC(=O)R c , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group;

[0009] R6 is selected from H, deuterium, formyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6A carbocyclic group, a 4-6 membered heterocyclic group, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic group optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group;

[0010] R7 is selected from H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic group optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group;

[0011] R8 is selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic group optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group;

[0012] R a 、R b or Rc Each independently selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclic group, 4-12 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group.

[0013] Furthermore, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (II),

[0014]

[0015] R1, R2 or R3 are each independently selected from H, deuterium, halogen, CN, COOH, NR a R b , C(=O)NR a R b , OR c , SR c , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(=O)C 1-4 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-4 alkyl, C(=O)OC 1-4 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; and R1, R2 and R3 are not simultaneously selected as H;

[0016] R a , R b or R c are each independently selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6a carbocyclic group, a 4- to 6-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents independently selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group.

[0017] Furthermore, R1, R2 or R3 are each independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NR a R b , C(=O)NR a R b , OR c , SR c , methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-benzene, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, wherein the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or pyridyl is optionally substituted with 1 to 4 substituents independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group; and R1, R2 and R3 are not simultaneously H;

[0018] R a , R b or R cEach independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, COOH, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group.

[0019] Furthermore, R1, R2 or R3 are each independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=O)NH2, OH, SH, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-isopropyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-benzene, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-benzene, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, OC(=O)CH3, OC(=O)CH2CH3, OC(=O)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl; and R1, R2 and R3 are not simultaneously selected as H.

[0020] Further, each of R1, R2 or R3 is independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=O)NH2, OH, SH, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-isopropyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-benzene, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-benzene, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, OC(=O)CH3, OC(=O)CH2CH3, OC(=O)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl; and R1, R2 and R3 do not simultaneously select H.

[0021] Further, each of R1, R2 or R3 is independently selected from H, F, Cl, Br, methyl, methoxy, ethyl, cyclopropyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy or monofluoromethoxy, and R1, R2 and R3 do not simultaneously select H.

[0022] Further, the vinblastine derivative is selected from one of the following structures:

[0023]

[0024] The present invention also provides a preparation method of the above vinblastine derivative. When R5 is selected as OH, it includes the following steps:

[0025]

[0026] (a) Compound A and compound B are subjected to a condensation reaction to obtain compound C;

[0027] (b) Compound C is subjected to a ring-closing reaction catalyzed by a copper catalyst to prepare compound D;

[0028] (c) Compound D is subjected to a reduction reaction to prepare compound E;

[0029] (d) Compound E and compound F are subjected to a reaction catalyzed by an iron catalyst to prepare the vinblastine derivative.

[0030] Further, in step (a), in the condensation reaction, the molar ratio of compound A to compound B is 1.2 to 2.0:1;

[0031] The reaction solvent for the condensation reaction is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, and tetrahydrofuran;

[0032] The chemical reagent for the condensation reaction is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, pivaloyl chloride, and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0033] The reaction temperature of the condensation reaction is 0 to 80 °C.

[0034] Further, in step (b), in the ring-closing reaction, the molar ratio of compound C to the chemical reagent is 1 to 2:2.7;

[0035] The solvent is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran;

[0036] In the ring-closing reaction, the chemical reagent is copper(I) iodide, tris(2-pyridylmethyl)amine, and 2,4,6-collidine, and the molar ratio of copper(I) iodide, tris(2-pyridylmethyl)amine, and 2,4,6-collidine is 0.3:0.4:2;

[0037] The reaction temperature of the ring-closing reaction is 20 to 110 °C.

[0038] Further, in step (c), in the reduction reaction, the molar ratio of compound D to the chemical reagent is 1 to 2:14;

[0039] The solvent is selected from one of dichloromethane, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran;

[0040] In the reduction reaction, the chemical reagent is selected from one of borane, tris(triphenylphosphine)rhodium(I) carbonyl hydride, carbonylbis(triphenylphosphine)iridium(I) chloride, lithium borohydride, and sodium borohydride;

[0041] The reaction temperature of the reduction reaction is 0 to 100 °C.

[0042] Further, in step (d), in the catalytic reaction, the molar ratio of compound E to compound F is 1:1.0 to 2.0;

[0043] The solvent is selected from one of trifluoroethanol, water, dichloromethane, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran;

[0044] The iron catalyst is selected from one of ferric chloride, iron oxalate, and ferric sulfate;

[0045] The reaction temperature of the catalytic reaction is 0 to 30 °C.

[0046] Furthermore, when the compound represented by the general formula (I) is selected from the compound represented by the general formula (II), the synthesis equation of the above vinblastine derivative is as follows (the synthesis method is the same as above (a) to (d)):

[0047]

[0048] The present invention also provides a method for treating cancer, including administering an effective dose of the above vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal to a cancer patient.

[0049] The present invention also provides the use of the above vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for the preparation of a drug for treating cancer.

[0050] Furthermore, the cancer includes leukemia, lymphoma, lung cancer, liver cancer, breast cancer, and pancreatic cancer.

[0051] The beneficial effects of the present invention are as follows: The vinblastine derivative synthesized in the present invention has significantly better anti-proliferative activity against cancer cells such as acute myeloid leukemia than vinblastine. It is worth mentioning that the anti-proliferative activities of derivatives G4, G5, G9, G10, G11, and G13 reach the picomolar level and can be used as toxin molecules for the development of antibody-drug conjugates, showing very good anti-tumor effects. Detailed Embodiments

[0052] The technical solutions of the present invention will be further described in detail below with reference to the accompanying drawings, but the protection scope of the present invention is not limited to the following.

[0053] Unless otherwise specified, the chemical reagents involved in the present invention are purchased from the reagent company and used directly, and the solvents are all domestic analytical grade without any purification treatment. The anhydrous and oxygen-free operations in the present invention are all performed using Schlenk technology under argon protection using a single row of tubes. The solvent drying method is based on "Purification of Laboratory Chemicals" (Armarego, WLF, Elsevier: Oxford, 2017). Dichloromethane and acetonitrile are heated and refluxed at normal pressure to remove water using calcium hydride. Tetrahydrofuran, ethylene glycol dimethyl ether, and ether are dried using a sodium / benzophenone system. Toluene is dried using sodium reflux. High-boiling point solvents such as dimethyl sulfoxide and N,N-dimethylformamide are soaked in molecular sieves to remove water. Color development methods of thin layer chromatography (TLC): fluorescence, iodine color development, phosphomolybdic acid, and alkaline potassium permanganate. Thin layer chromatography silica gel plates (0.2mm, HSGF254) were purchased from Yantai Jiangyou Silica Gel Development Co., Ltd. The 200–300 mesh silica gel used for column chromatography was from Anhui Liangchen Silica Source Materials Co., Ltd.

[0054] The NMR data were collected from Bruker AC-E 400, Agilent DD2-600 / 54 and Varian INOVA-400 / 54 instruments, using deuterated chloroform as solvent (7.26 as chemical shift reference for hydrogen spectrum and 77.0 as chemical shift reference for carbon spectrum), and tetramethylsilane (TMS) as internal standard. In the NMR data, s represents singlet, d represents doublet, t represents triplet, q represents quartet, and m represents multiplet. The coupling constant is represented by J in Hz. The infrared spectral data were measured using a Perkin Elmer Spectrum Two FT-IR spectrometer. The optical rotation data were collected from a Rudolph Research Analytical Autopol VI polarimeter. High-resolution mass spectral data were measured using a Bruker Apex IV FTMS or Thermo Scientific LTQ Orbitrap XL ESI mass spectrometer. The liquid chromatography-mass spectrometer used was an Agilent Technologies 6420 Triple Quad LC / MS.

[0055] Example 1 Preparation of Vinblastine Derivative G1

[0056]

[0057] Compound A1 (82.4 mg, 0.436 mmol, 1.2 equiv.) and compound B (99.5 mg, 0.363 mmol, 1.0 equiv.) were dissolved in dry dichloromethane (1.8 mL), and EDCI (83.6 mg, 0.436 mmol, 1.2 equiv.) was added at 0 °C. After reacting at room temperature for 2 h, the reaction was quenched by adding saturated aqueous NH4Cl solution. The mixture was extracted with dichloromethane (10 mL × 3), and then backwashed with saturated aqueous sodium bicarbonate solution (15 mL × 2). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 - 3:1 - 1:1) to give compound C1 (149 mg, 92%). TLC (petroleum ether / ethyl acetate 1:1, v / v): R f = 0.41; 1 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.16 (t, J = 7.11 Hz, 1H), 7.05 (d, J = 7.11 Hz, 0.53H), 7.02 (d, J = 7.11 Hz, 0.47H), 7.01 (s, 0.47H), 7.00 (s, 0.53H), 6.84 (d, J = 7.11 Hz, 0.53H), 6.80 (d, J = 7.11 Hz, 0.47H), 6.04 (m, 1H), 5.81 (d, J = 1.4 Hz, 0.53H), 4.87 (d, J = 1.4 Hz, 0.47H), 4.40 (d, J = 16.0 Hz, 0.47H), 4.10 (d, J = 16.0 Hz, 0.53H), 4.00 (d, J = 16.0 Hz, 0.53H), 3.93 (d, J = 16.0 Hz, 0.47H), 3.78 (s, 1.59H), 3.72 (s, 1.41H), 3.62–3.51 (m, 1H), 3.13–3.03 (m, 1H), 2.88–2.77 (m, 2H), 2.72 (s, 1.41H), 2.65 (s, 1.59H), 2.22–2.07 (m, 2H), 1.80–1.66 (m, 0.53H), 1.60–1.47 (m, 0.47H), 1.02 (t, J = 7.4 Hz, 1.59H), 0.80 (t, J = 7.4 Hz, 1.41H); 1313C NMR (100 MHz, CDCl3): δ 171.49, 171.24, 170.17, 169.81, 146.26, 144.43, 136.85, 130.66, 130.48, 127.73, 126.67, 126.11, 125.94, 123.29, 123.05, 122.25, 122.13, 121.33, 121.15, 110.12, 109.49, 109.47, 109.30, 61.30, 59.92, 54.69, 53.30, 53.23, 48.15, 47.43, 39.42, 39.28, 33.97, 33.35, 31.65, 30.84, 26.59, 25.60, 20.38, 20.34, 11.66, 10.82; IR (neat): ν max = 3275, 2962, 2935, 2879, 1737, 1634, 1418, 1260, 1082, 798 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 26 BrN2O3 + [M + H] + 445.1122, 447.1101, found 445.1119, 447.1101; Optical rotation: [α]25D = –43.6 (c = 0.30, CHCl3).

[0058] Compound C1 (149 mg, 0.334 mmol, 1.0 equiv.), tris(2-pyridylmethyl)amine (39.0 mg, 0.134 mmol, 0.4 equiv.) and copper(I) iodide (19.2 mg, 0.101 mmol, 0.3 equiv.) were dissolved in dry 1,2-dichloroethane (7.5 mL), and 2,4,6-trimethylpyridine (88.7 μL, 0.671 mmol, 2.0 equiv.) was added under argon protection. The reaction mixture was stirred at 60 °C for 1.5 h, then quenched with water (0.5 ml), diluted with dichloromethane (10 mL), and washed successively with 0.5 M HCl solution (3 × 5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered through diatomaceous earth, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 - 1:1) to give compound D1 (108 mg, 89%). TLC (petroleum ether / ethyl acetate 1:1, v / v): R f = 0.48; 11H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 6.7 Hz, 1H), 5.11 (s, 1H), 4.35 (d, J = 15.5 Hz, 1H), 4.22 (d, J = 15.5 Hz, 1H), 3.65 (s, 3H), 3.61–3.55 (m, 1H), 2.94 (d, J = 10.5 Hz, 1H), 2.89 (br.s, 1H), 2.73 (s, 3H), 2.69 (br.s, 1H), 2.35–2.17 (m, 2H), 1.76 (d, J = 13.2 Hz, 1H), 1.10 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.80, 173.23, 143.78, 135.33, 134.09, 130.71, 128.92, 125.86, 122.40, 122.21, 108.80, 104.58, 55.38, 53.63, 52.68, 50.90, 34.17, 33.89, 31.41, 26.89, 21.27, 11.36; IR (neat): ν max = 3230, 2922, 2854, 1739, 1627, 1439, 1255, 1080, 1017, 794 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 25 N2O3 + [M + H] + 365.1860, found 365.1855; Optical rotation: [α]25D = –6.4 (c = 0.16, CHCl3).

[0059] The solution of borane dimethyl sulfide (2.10 mL, 2.0 M, 4.20 mmol, 14.0 equiv.) was added to a solution of compound D1 (108 mg, 0.296 mmol, 1.0 equiv.) in tetrahydrofuran (5.4 mL) at 0 °C. The mixture was heated to 30 °C and stirred for 1 hour. Under ice bath conditions, methanol (4.0 mL) and hydrochloric acid methanol solution (5.4 mL, 4.0 M in MeOH) were added successively. The resulting mixture was stirred at 35 °C for 6 hours. Then, most of the solvent was removed by distillation under reduced pressure. Saturated aqueous sodium bicarbonate (10 ml) was added at 0 °C to adjust the pH to 9–10. Then, it was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous MgSO4, filtered, and concentrated. The obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1–1:1) to give compound E1 (87.9 mg, 84%). TLC (petroleum ether / ethyl acetate 1:1, v / v): R f = 0.15; 1 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.07 (dd, J = 8.1, 7.1 Hz, 1H), 6.85 (d, J = 7.1 Hz, 1H), 6.24 (d, J = 6.4 Hz, 1H), 4.82 (s, 1H), 4.22 (br.s, 1H), 3.73 (s, 3H), 3.66 (dd, J = 17.5, 9.0 Hz, 1H), 3.57–3.41 (m, 2H), 3.40–3.30 (m, 1H), 3.05 (br.s, 1H), 2.95 (d, J = 13.4 Hz, 1H), 2.87–2.75 (m, 2H), 2.66 (s, 3H), 2.24–2.11 (m, 1H), 1.94 (d, J = 13.3 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 171.37, 145.19, 135.54, 132.58, 130.42, 127.80, 125.60, 123.15, 122.58, 111.75, 109.15, 58.51, 58.04, 54.76, 53.39, 50.94, 35.60, 28.91, 26.74, 21.37, 21.03, 10.23; IR (neat): ν max = 3241, 2926, 2476, 1740, 1634, 1550, 1447, 1260, 1083, 750 cm -1; HRMS(ESI): m / z calcd. for C 22 H 27 N2O2 + [M+H] + 351.2068, found 351.2046; Optical rotation: [α]25D = +72.6 (c = 0.17, CHCl3).

[0060] Compound 2a (52.2 mg, 0.149 mmol, 1.0 equiv.), vindoline (68.0 mg, 0.149 mmol, 1.0 equiv.) and anhydrous iron(III) chloride (121 mg, 0.746 mmol, 5.0 equiv.) were dissolved in a mixed solution (1.0 ml trifluoroethanol and 5.0 mL 0.05 N hydrochloric acid), and stirred at 25 °C for 3 h. Then, an aqueous solution (1.60 mL) containing sodium borohydride (5.63 mg, 0.149 mmol, 1.0 equiv.) was added dropwise under an ice bath, and the reaction was maintained at this temperature for 30 min. Then, 12 ml concentrated ammonia water (28%–30%) was added to quench the reaction, and the mixture was extracted with a mixed solution of dichloromethane and methanol (DCM:MeOH = 10:1, 20 mL × 4). The organic layer was washed successively with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (CHCl3 / MeOH, 30:1–10:1) to obtain intermediate anhydrovinblastine. The intermediate (121 mg, 0.15 mmol, 1.0 equiv.) was dissolved in trifluoroethanol (0.72 ml), and slowly added dropwise to a mixed solution of iron(III) oxalate hexahydrate (2.18 g, 4.5 mmol, 30.0 equiv.) and water (323 ml) (bubbling air for 30 min). A 0.1 M hydrochloric acid solution was added under an ice bath to adjust the pH to 3–4. Under an ice bath, an aqueous solution (12.5 mL) of sodium borohydride (114 mg, 1.0 mmol, 20.0 equiv.) was slowly added dropwise. After stirring for 30 min, 2 ml concentrated ammonia water (28%–30%) was added to quench the reaction, and the pH was adjusted to 9–10. The mixture was extracted with a mixed solution of dichloromethane and methanol (DCM:MeOH = 10:1, 400 mL × 4). The organic layer was washed successively with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated by preparative thin layer chromatography (EA / MeOH / Et3N, 30:1:1) to obtain vinblastine derivative G1 (24.7 mg, 20%). TLC (EA / MeOH / Et3N 30:1:1, v / v): R f = 0.45; 11H NMR (400 MHz, CDCl3): δ 9.90 (s, 1H), 8.03 (s, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.0 Hz, 1H), 6.57 (s, 1H), 6.10 (s, 1H), 5.85 (dd, J = 10.1 3.9 Hz, 1H), 5.45 (s, 1H), 5.29 (d, J = 10.2 Hz, 1H), 4.01 (t, J = 14.0 Hz, 1H), 3.79 (s, 6H), 3.73 (s, 1H), 3.61 (s, 3H), 3.67–3.51 (m, 3H), 3.40–3.21 (m, 3H), 2.84 (s, 2H), 2.82 (s, 1H), 2.70 (s, 3H), 2.65 (s, 1H), 2.64 (s, 3H), 2.55–2.40 (m, 2H), 2.28–2.15 (m, 2H), 2.10 (s, 3H), 1.87–1.72 (m, 3H), 1.55–1.20 (m, 6H), 0.89 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.71, 171.69, 170.96, 157.92, 152.81, 135.50, 130.49, 129.98, 129.89, 124.63, 123.41, 122.94, 122.15, 121.13, 119.84, 119.57, 110.58, 108.83, 94.19, 83.27, 79.62, 76.39, 70.52, 65.43, 64.27, 55.79, 55.66, 55.63, 53.27, 52.46, 52.23, 50.21, 50.21, 48.81, 44.64, 42.64, 41.96, 38.30, 34.65, 34.65, 30.82, 28.78, 21.48, 21.14, 8.39, 6.77; IR (neat): ν max = 3464, 2925, 2853, 1734, 1613, 1456, 1229, 1035, 803, 732 cm -1 ; HRMS (ESI): m / z calcd. for C 47 H 61 N4O9 + [M + H] + 825.4434, found 825.4433; Optical rotation: [α]25D = +31.2 (c = 0.07, CHCl3).

[0061] Preparation of Vinblastine Derivative G2 in Example 2

[0062]

[0063] Refer to the preparation method of vinblastine derivative G1.

[0064] Intermediate C2: Yield 90%; 1 H NMR(400MHz,CDCl3):δ8.92(s,1H),7.05–6.92(m,2H),6.90(s,0.56H),6.83(s,0.44H),6.75–6.56(m,1H),6.11–5.87(m,1H),5.79(s,0.56H),5.01(s,0.44H),4.26(d,J=15.5Hz,0.44H),4.06(d,J=15.5Hz,0.56H),3.89(d,J=2.9Hz,1H),3.76(s,3H),3.63(d,J=9.4Hz,0.56H),3.55(d,J=11.5Hz,0.44H),3.21(dt,J=9.4,2.5Hz,0.56H),3.11(dt,J=11.5,2.5Hz,0.44H),2.92–2.65(m,2H),2.31–2.03(m,2H),2.02–1.87(m,0.56H),1.85–1.59(m,0.44H),1.01(t,J=7.4Hz,1.68H),0.89(t,J=7.4Hz,1.32H); 13 C NMR(100MHz,CDCl3):δ171.21,171.14,170.04,169.75,155.80,145.82,144.32,139.02,138.98,138.90,138.86,127.50,126.64,123.94,123.86,122.04,121.96,121.93,121.85,116.18,116.16,115.99,115.97,107.62,107.59,106.34,104.30,104.20,104.11,104.01,60.79,59.66,59.47,54.49,53.18,53.08,47.87,47.32,39.23,39.10,31.96,31.94,31.44,31.38,31.36,30.65,26.41,25.59,11.43,10.84;IR(neat):ν max= 3253, 2958, 1738, 1629, 1425, 1349, 1251, 1080, 1032, 749 cm -1 ; HRMS(ESI): m / z calcd. for C 21 H 23 BrFN2O3 + [M + H] + 449.0871, 451.0851, found 449.0873, 451.0854; Optical rotation: [α]25D = –49.3 (c = 1.2, CHCl3).

[0065] Intermediate D2: Yield 87%; 1 H NMR(400 MHz, CDCl3): δ 8.16 (s, 1H), 7.08–7.03 (m, 1H), 7.03–6.99 (m, 1H), 6.78–6.68 (m, 1H), 6.26 (d, J = 6.1 Hz, 1H), 5.10 (s, 1H), 4.29 (d, J = 15.5 Hz, 1H), 4.14 (d, J = 15.5 Hz, 1H), 3.67 (s, 3H), 3.57 (dd, J = 10.5, 2.9 Hz, 1H), 2.97–2.92 (m, 1H), 2.92–2.87 (m, 1H), 2.73–2.62 (m, 1H), 2.47–2.20 (m, 2H), 1.75 (d, J = 13.3 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H); 13 C NMR(100 MHz, CDCl3): δ 174.65, 173.04, 158.32, 155.86, 143.84, 137.62, 137.51, 134.61, 128.84, 122.97, 122.89, 116.44, 116.27, 106.81, 106.78, 105.55, 105.35, 102.59, 102.56, 55.46, 53.34, 52.78, 50.88, 33.74, 33.59, 33.54, 31.35, 26.89, 11.34; IR(neat): ν max = 3184, 2923, 1742, 1627, 1445, 1337, 1256, 1082, 1017, 796 cm -1 ; HRMS(ESI): m / z calcd. for C 21 H 22 FN2O3 + [M + H] +369.1609 found 369.1605; Optical rotation: [α]25D = –20.0 (c = 0.25, CHCl3).

[0066] Intermediate E2: Yield 80%; 1 H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.13–7.07 (m, 2H), 6.77 (ddd, J = 11.5, 6.0, 2.6 Hz, 1H), 6.24 (d, J = 5.7 Hz, 1H), 4.75 (s, 1H), 4.20–4.01 (m, 1H), 3.78 (s, 3H), 3.66–3.52 (m, 1H), 3.54–3.35 (m, 3H), 3.06 (br.s, 1H), 2.97–2.75 (m, 3H), 2.27–2.05 (m, 1H), 1.94 (d, J = 13.4 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 171.27, 158.15, 155.70, 145.35, 137.66, 137.55, 133.12, 127.40, 123.77, 123.69, 116.21, 116.04, 108.59, 108.56, 107.24, 107.20, 105.83, 105.64, 59.19, 56.57, 53.57, 52.93, 50.78, 36.50, 28.83, 26.76, 20.37, 20.33, 10.21; IR (neat): ν max = 3192, 2957, 2439, 1740, 1633, 1445, 1221, 1086, 1048, 745 cm -1 ; HRMS (ESI): m / z calcd. for C 21 H 24 FN2O2 + [M + H] + 355.1817, found 355.1812; Optical rotation: [α]25D = +78.8 (c = 0.19, CHCl3).

[0067] Vinblastine derivative G2: Yield 25%; 11H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 8.08 (s, 1H), 7.06–6.97 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.70 (dd, J = 11.8, 7.8 Hz, 1H), 6.50 (br.s, 1H), 6.09 (s, 1H), 5.86 (dd, J = 10.4, 4.4 Hz, 1H), 5.45 (s, 1H), 5.29 (d, J = 10.2 Hz, 1H), 3.95 (t, J = 14.0 Hz, 1H), 3.79 (s, 6H), 3.73 (s, 1H), 3.64 (s, 3H), 3.51–3.35 (m, 3H), 3.29–3.10 (m, 3H), 2.83 (s, 2H), 2.79 (s, 1H), 2.71 (s, 3H), 2.63 (s, 1H), 2.50–2.40 (m, 2H), 2.27 (d, J = 15.1 Hz, 1H), 2.22–2.13 (m, 1H), 2.10 (s, 3H), 1.93–1.71 (m, 3H), 1.50–1.20 (m, 6H), 0.89 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.68, 171.66, 170.96, 158.54, 157.94, 156.08, 152.82, 137.56, 137.45, 130.94, 129.89, 124.65, 123.32, 122.91, 117.72, 117.55, 106.60, 106.58, 94.16, 83.24, 79.64, 76.38, 69.34, 65.54, 56.36, 55.80, 55.51, 53.24, 52.53, 52.25, 50.31, 44.61, 42.63, 38.25, 34.51, 30.75, 21.14, 8.34, 6.80; IR (neat): ν max = 3461, 2926, 2849, 1735, 1617, 1502, 1435, 1229, 1039, 734 cm -1 ; HRMS (ESI): m / z calcd. for C 46 H 58 FN4O9 + [M + H] + 829.4183 found 829.4181; Optical rotation: [α]25D = +28.6 (c = 0.05, CHCl3).

[0068] Example 3 Preparation of Vinblastine Derivative G3

[0069]

[0070] Refer to the synthesis method of vinblastine derivative G1.

[0071] Intermediate C3: Yield 95%; 1 H NMR(400MHz,CDCl3): δ8.54(s,1H),7.09–6.98(m,1H),6.92(m,2H),6.49(d,J = 7.7Hz,0.54H),6.43(d,J = 7.7Hz,0.46H),6.01(d,J = 5.2Hz,0.54H),5.96(d,J = 5.2Hz,0.46H),5.78(s,0.46H),5.10(s,0.54H),4.67(d,J = 15.5Hz,0.54H),4.01–3.95(m,1H),3.94(d,J = 15.5Hz,0.46H),3.92(s,1.38H),3.84(s,1.62H),3.76(s,1.38H),3.71(s,1.62H),3.59(d,J = 9.4Hz,0.46H),3.51(d,J = 11.4Hz,0.54H),3.19(d,J = 9.4Hz,0.46H),3.05(d,J = 11.4Hz,0.54H),2.86–2.71(m,2H),2.23–1.96(m,2H),1.62(m,0.46H),1.34(m,0.54H),1.00(t,J = 7.4Hz,1.38H),0.69(t,J = 7.4Hz,1.62H); 13 C NMR(100MHz,CDCl3): δ172.29,171.74,170.10,169.84,154.49,154.47,145.90,144.70,137.73,137.48,126.86,126.43,122.51,122.36,122.08,121.88,117.71,116.87,109.00,108.43,104.82,104.71,99.14,99.12,60.94,59.80,59.27,55.05,54.97,54.38,53.04,47.84,47.43,39.23,39.15,32.78,32.03,31.44,30.60,26.33,24.91,11.32,10.50; IR(neat): ν max= 3199, 2950, 2877, 2833, 1737, 1629, 1420, 1246, 1081, 735; HRMS(ESI): m / z calcd. for C 22 H 26 BrN2O4 + [M + H] + 461.1071, 463.1050, found 461.1066, 463.1047; Optical rotation: [α]25D = –101 (c = 0.18, CHCl3).

[0072] Intermediate D3: Yield 86%; 1 H NMR(400 MHz, CDCl3): δ 8.33 (s, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 6.1 Hz, 1H), 5.10 (s, 1H), 4.53 (d, J = 15.5 Hz, 1H), 4.22 (d, J = 15.5 Hz, 1H), 3.82 (s, 3H), 3.63 (s, 3H), 3.53 (m, 1H), 2.91 (d, J = 10.4 Hz, 1H), 2.85–2.71 (m, 1H), 2.62 (d, J = 13.1 Hz, 1H), 2.25 (m, 2H), 1.65 (d, J = 13.1 Hz, 1H), 1.08 (t, J = 7.4 Hz, 3H); 13 C NMR(100 MHz, CDCl3): δ 175.55, 173.17, 154.70, 143.69, 136.64, 132.99, 128.76, 123.07, 117.03, 103.94, 103.87, 99.98, 55.43, 54.97, 53.27, 52.57, 50.78, 33.61, 33.47, 31.33, 26.82, 11.29; IR(neat): ν max = 3181, 2955, 2883, 2844, 1736, 1626, 1433, 1246, 1104, 732 cm -1 ; HRMS(ESI): m / z calcd. for C 22 H 25 N2O4 + [M + H] + 381.1809 found 381.1805; Optical rotation: [α]25D = –26.7 (c = 0.13, CHCl3).

[0073] Intermediate E3: Yield 81%; 1 H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.18 (d, J = 6.1 Hz, 1H), 4.72 (s, 1H), 4.05 (br.s, 1H), 3.87 (s, 3H), 3.73 (s, 3H), 3.72–3.58 (m, 2H), 3.46–3.30 (m, 2H), 2.98 (br.s, 1H), 2.90–2.66 (m, 3H), 2.24–2.04 (m, 1H), 1.88 (d, J = 13.7 Hz, 1H), 1.07 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 171.26, 154.48, 145.06, 136.67, 131.37, 127.39, 123.73, 116.71, 110.50, 104.33, 100.19, 58.93, 56.99, 55.04, 53.35, 53.21, 50.68, 36.08, 28.72, 26.59, 20.31, 10.12; IR (neat): ν max = 3219, 2953, 2476, 1730, 1510, 1438, 1250, 1105, 746, 663 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 27 N2O2 + [M + H] + 367.2017, found 367.2012; Optical rotation: [α]25D = +82.2 (c = 0.09, CHCl3).

[0074] Vinblastine derivative G3: Yield 23%; 11H NMR (400 MHz, CDCl3): δ 9.89 (s, 1H), 7.96 (s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.58 (s, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.09 (s, 1H), 5.85 (dd, J = 10.1, 3.9 Hz, 1H), 5.46 (s, 1H), 5.29 (d, J = 10.1 Hz, 1H), 3.98 (t, J = 14.1 Hz, 1H), 3.90–3.70 (m, 2H), 3.86 (s, 3H), 3.79 (s, 6H), 3.72 (s, 2H), 3.61 (s, 3H), 3.58–3.43 (m, 2H), 3.42–3.32 (m, 1H), 3.32–3.22 (m, 1H), 2.84 (s, 1H), 2.80 (s, 1H), 2.70 (s, 3H), 2.65 (s, 1H), 2.55–2.37 (m, 1H), 2.29–2.14 (m, 3H), 2.10 (s, 3H), 1.91–1.72 (m, 3H), 1.44–1.20 (m, 6H), 0.89 (t, J = 7.2 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.55, 171.63, 170.96, 157.80, 154.77, 152.86, 136.58, 129.81, 124.73, 123.01, 118.14, 103.87, 99.52, 94.12, 83.11, 79.65, 76.36, 68.73, 65.32, 55.75, 55.08, 53.24, 52.49, 52.22, 50.18, 50.07, 44.67, 42.59, 41.96, 38.21, 34.74, 30.74, 29.32, 21.14, 8.32, 6.71; IR (neat): ν max = 3465, 2926, 2846, 1997, 1736, 1614, 1503, 1233, 1038, 733 cm -1 ; HRMS (ESI): m / z calcd. for C 47 H 61 N4O 10 + [M + H] + 841.4383, found 841.4379; Optical rotation: [α]25D = +35.2 (c = 0.12, CHCl3).

[0075] Preparation of Vinblastine Derivative G4

[0076]

[0077] Refer to the synthesis method of vinblastine derivative G1.

[0078] Intermediate C4: Yield 92%; 1 H NMR(400MHz,CDCl3): δ8.23(s,1H),7.59(d,J=7.8Hz,0.54H),7.49(d,J=7.8,Hz,0.46H),7.12(s,0.46H),7.08(s,0.54H),7.06–6.97(m,1H),6.94–6.82(m,1H),6.00(t,J=7.1Hz,1H),5.77(s,0.46H),4.91(s,0.54H),4.14(d,J=15.6Hz,0.46H),3.94(d,J=15.6Hz,0.54H),3.80–3.70(m,1H),3.76(s,1.38H),3.74(s,1.62H),3.58(d,J=9.2Hz,0.46H),3.52(d,J=11.6Hz,0.54H),3.12(dt,J=9.2,2.7Hz,0.46H),3.06(dt,J=11.6,2.7Hz,0.54H),2.89–2.72(m,2H),2.26–2.02(m,2H),1.71–1.61(m,0.46H),1.44–1.31(m,0.54H),0.98(t,J=7.4Hz,1.38H),0.72(t,J=7.4Hz,1.62H); 13CNMR(100MHz,CDCl3):δ170.58,170.32,169.98,169.69,161.23,161.17,158.86,158.81,145.91,144.12,136.11,136.10,135.99,135.96,127.47,126.53,123.96,123.88,123.28,123.24,123.11,123.08,119.82,119.72,119.57,119.46,109.50,108.66,108.49,108.31,108.25,108.06,97.58,97.55,97.32,97.29,61.06,59.61,59.51,54.43,53.21,53.10,47.84,47.23,39.28,39.03,31.64,31.42,31.33,30.61,29.68,26.40,25.24,11.41,10.61; IR(neat):ν max = 3267,3058,2961,2930,2874,1737,1626,1424,1259,731cm -1 ; HRMS(ESI):m / z calcd.for C 21 H 22 FN2O3 + [M + H] + 369.1609,found 369.1606; Optical rotation: [α]25D = –69.7(c = 0.24,CHCl3).

[0079] Intermediate D4: Yield 85%; 1 H NMR(400MHz,CDCl3):δ8.20(s,1H),7.43(d,J = 7.7Hz,1H),7.00–6.79(m,2H),6.26(d,J = 6.1Hz,1H),5.09(s,1H),4.19(d,J = 15.5Hz,1H),3.72(d,J = 15.5Hz,1H),3.67(s,3H),3.60–3.49(m,1H)),2.94(d,J = 10.4Hz,1H),2.88(s,1H),2.66(d,J = 13.1Hz,1H),2.33–2.17(m,2H)),1.72(d,J = 11.9Hz,1H),1.10(t,J = 7.3Hz,3H); 1313C NMR (100 MHz, CDCl3): δ 174.45, 173.06, 161.24, 158.87, 135.13, 135.00, 134.80, 134.77, 143.83, 128.81, 124.05, 119.43, 119.33, 108.81, 108.57, 103.96, 97.33, 97.06, 55.74, 53.20, 52.73, 50.88, 33.63, 32.65, 31.42, 26.88, 11.33; IR (neat): ν max = 3251, 3058, 2958, 2924, 1737, 1628, 1451, 1426, 1249, 1129 cm -1 ; HRMS (ESI): m / z calcd. for C 21 H 22 FN2O3 + [M + H] + 369.1609, found 369.1606; Optical rotation: [α]25D = –25.5 (c = 0.26, CHCl3).

[0080] Intermediate E4: Yield 79%; 1 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.46–7.30 (m, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.87 (t, J = 8.8 Hz, 1H), 6.20 (br.s, 1H), 4.69 (s, 1H), 4.03 (br.s, 1H), 3.78 (s, 3H), 3.54–3.38 (m, 2H), 3.37–3.23 (m, 1H), 3.23–3.09 (m, 1H), 3.02 (br.s, 1H), 2.95–2.80 (m, 2H), 2.79–2.61 (m, 1H), 2.20–2.05 (m, 1H), 1.91 (d, J = 13.7 Hz, 1H), 1.07 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 171.11, 161.37, 158.99, 145.28, 135.32, 135.20, 133.47, 133.43, 127.27, 123.86, 118.95, 118.85, 109.43, 109.04, 108.79, 97.86, 97.60, 59.81, 55.95, 53.51, 52.22, 50.77, 36.36, 28.80, 26.62, 19.09, 10.14; IR (neat): νmax = 3195, 3058, 2959, 2396, 1739, 1457, 1260, 1230, 1084, 730 cm -1 ; HRMS(ESI): m / z calcd. for C 21 H 24 FN2O2 + [M + H] + 355.1817, found 355.1812; Optical rotation: [α]25D = +58.9 (c = 0.10, CHCl3).

[0081] Vinblastine derivative G4: Yield 21%; 1 1H NMR (400 MHz, CDCl3): δ 9.83 (s, 1H), 8.00 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.85 (t, J = 9.2 Hz, 1H), 6.77 (d, J = 9.5 Hz, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.87 (dd, J = 10.1, 3.9 Hz, 1H), 5.46 (s, 1H), 5.29 (d, J = 10.1 Hz, 1H), 3.92 (t, J = 14.1 Hz, 1H), 3.79 (s, 6H), 3.73 (s, 1H), 3.63 (s, 3H), 3.44–3.22 (m, 4H), 3.21–3.03 (m, 2H), 2.84 (s, 1H), 2.80 (s, 2H), 2.70 (s, 3H), 2.64 (s, 1H), 2.55–2.38 (m, 2H), 2.28 (d, J = 15.1 Hz, 1H), 2.20–2.12 (m, 1H), 2.11 (s, 3H), 1.93–1.75 (m, 3H), 1.53–1.39 (m, 2H), 1.39–1.28 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H); 1313C NMR(100MHz,CDCl3):δ174.87,171.67,170.94,161.32,158.95,158.02,152.70,134.81,134.68,131.43,129.90,125.95,124.62,123.37,122.80,119.25,119.15,119.06,119.00,107.74,96.89,96.63,94.14,83.30,79.63,76.37,69.41,65.60,55.79,55.61,53.23,52.44,52.24,50.36,44.57,42.63,38.32,34.43,34.20,30.75,21.14,8.34,6.84;IR(neat):ν max = 3463,2929,2879,1998,1736,1618,1500,1229,1037,733cm -1 ;HRMS(ESI):m / z calcd.for C 46 H 58 FN4O9 + [M+H] + 829.4183,found 829.4184;Optical rotation:[α]25D = +10.0(c = 0.10,CHCl3).

[0082] Example 5 Preparation of Vinblastine Derivative G5

[0083]

[0084] Refer to the synthesis method of vinblastine derivative G1.

[0085] Intermediate C5: Yield 92%; 11H NMR (400 MHz, CDCl3): δ 8.73 (s, 0.48H), 8.71 (s, 0.52H), 7.53 (d, J = 7.8 Hz, 0.52H), 7.43 (d, J = 7.8 Hz, 0.48H), 7.26 (d, J = 2.8 Hz, 0.52H), 7.22 (d, J = 2.8 Hz, 0.48H), 7.06 (dd, J = 8.4, 1.8 Hz, 0.48H), 7.02 (dd, J = 8.4, 1.8 Hz, 0.52H), 6.96 (d, J = 2.3 Hz, 0.52H), 6.92 (d, J = 2.3 Hz, 0.48H), 6.18–5.91 (m, 1H), 5.78 (d, J = 1.3 Hz, 0.48H), 4.91 (d, J = 1.3 Hz, 0.52H), 4.08 (d, J = 15.5 Hz, 0.52H), 3.95 (d, J = 15.5 Hz, 0.48H), 3.76 (s, 1.44H), 3.75 (s, 1.56H), 3.74–3.73 (m, 0.52H), 3.72–3.69 (m, 0.48H), 3.59 (dd, J = 9.3, 2.1 Hz, 0.48H), 3.54 (dd, J = 11.6, 2.1 Hz, 0.52H), 3.14 (dt, J = 11.6, 2.7 Hz, 0.48H), 3.07 (dt, J = 11.6, 2.7 Hz, 0.52H), 2.91–2.63 (m, 2H), 2.28–1.95 (m, 2H), 1.75 (m, 0.52H), 1.45 (m, 0.48H), 0.99 (t, J = 7.4 Hz, 1.44H), 0.76 (t, J = 7.4 Hz, 1.56H); 13 13C NMR (100 MHz, CDCl3): δ 170.64, 170.52, 169.93, 169.67, 145.80, 144.07, 136.53, 127.65, 127.78, 127.55, 126.61, 125.86, 125.82, 124.05, 123.81, 120.06, 119.89, 119.65, 119.41, 111.22, 111.18, 109.02, 108.23, 61.03, 59.60, 59.47, 54.50, 53.24, 53.12, 47.85, 47.24, 39.26, 39.03, 31.40, 31.36, 31.09, 30.59, 26.39, 25.37, 11.39, 10.67; IR (neat): ν max = 3258, 2959, 2930, 1738, 1628, 1429, 1259, 1079, 803, 755 cm-1 ; HRMS (ESI): m / z calcd. for C 21 H 23 BrClN2O3 + [M + H] + 465.0576, 467.0555, found 465.0573, 467.0551; Optical rotation: [α]25D = –65.9 (c = 0.77, CHCl3).

[0086] Intermediate D5: Yield 84%; 1 H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.24 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.26 (d, J = 6.1 Hz, 1H), 5.09 (s, 1H), 4.19 (d, J = 15.5 Hz, 1H), 3.72 (d, J = 15.5 Hz, 1H), 3.67 (s, 3H), 3.54 (dd, J = 10.4, 2.9 Hz, 1H), 2.94 (d, J = 10.4 Hz, 1H), 2.89 (br.s, 1H), 2.67 (d, J = 13.1 Hz, 1H), 2.36–2.12 (m, 2H), 1.73 (d, J = 13.1 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 174.33, 172.98, 143.83, 135.44, 135.19, 128.85, 128.38, 126.12, 120.73, 119.49, 110.70, 104.18, 55.72, 53.23, 52.78, 50.89, 33.64, 32.63, 31.40, 26.89, 11.34; IR (neat): ν max = 2922, 2854, 1741, 1623, 1453, 1257, 1193, 1080, 1017, 795 cm -1 ; HRMS (ESI): m / z calcd. for C 21 H 22 ClN2O3 + [M + H] + 385.1314, 387.1284, found 385.1309, 387.1285; Optical rotation: [α]25D = –40.0 (c = 0.25, CHCl3).

[0087] Intermediate E5: Yield 78%; 11H NMR (400 MHz, methanol-d4): δ 7.46 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 8.5, 1.9 Hz, 1H), 6.41–6.29 (m, 1H), 4.91 (d, J = 1.5 Hz, 1H), 3.93 (ddd, J = 15.0, 10.4, 4.4 Hz, 1H), 3.81 (s, 3H), 3.66 (ddd, J = 15.0, 10.4, 4.4 Hz, 1H), 3.47–3.38 (m, 1H), 3.39–3.27 (m, 3H), 3.26–3.10 (m, 2H), 2.93 (dt, J = 13.7, 4.6 Hz, 1H), 2.48–2.32 (m, 1H), 2.27–2.14 (m, 1H), 1.98 (dd, J = 13.7, 3.2 Hz, 1H), 1.13 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, methanol-d4): δ 171.66, 145.84, 137.62, 136.06, 129.93, 129.27, 127.50, 121.14, 120.05, 112.01, 110.26, 61.87, 56.37, 53.85, 52.57, 51.95, 36.11, 30.20, 26.95, 19.37, 10.58; IR (neat): ν max = 3233, 2922, 2853, 2468, 1736, 1457, 1259, 1085, 1016, 796 cm -1 ; HRMS (ESI): m / z calcd. for C 21 H 24 ClN2O2 + [M + H] + 371.1521, 373.1492, found 371.1516, 373.1493; Optical rotation: [α]25D = +66.5 (c = 0.20, CHCl3).

[0088] Vinblastine derivative G5: Yield 22%; 11H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 8.01 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.12–6.95 (m, 2H), 6.44 (br.s, 1H), 6.08 (s, 1H), 5.88 (dd, J = 10.1, 3.9 Hz, 1H), 5.42 (s, 1H), 5.29 (d, J = 10.1 Hz, 1H), 3.88 (t, J = 14.1 Hz, 1H), 3.84–3.74 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73 (s, 1H), 3.62 (s, 3H), 3.45–3.05 (m, 5H), 2.87 (s, 2H), 2.83 (s, 1H), 2.70 (s, 3H), 2.64 (s, 1H), 2.48–2.30 (m, 3H), 2.24–2.12 (m, 1H), 2.10 (s, 3H), 1.89–1.51 (m, 3H), 1.51–1.34 (m, 1H), 1.33–1.25 (m, 5H), 0.89 (t, J = 7.4 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.60, 171.63, 170.98, 157.94, 152.89, 135.22, 130.22, 129.78, 124.83, 123.08, 122.97, 122.60, 121.35, 119.23, 119.21, 110.44, 94.08, 83.15, 79.67, 76.35, 69.02, 65.34, 55.94, 55.79, 55.42, 53.26, 52.60, 52.25, 50.26, 44.64, 42.61, 38.19, 34.62, 30.73, 21.15, 8.33, 6.75; IR (neat): ν max = 3457, 3055, 2925, 1736, 1613, 1501, 1458, 1231, 1038, 731 cm -1 ; HRMS (ESI): m / z calcd. for C 46 H 58 ClN4O9 + [M + H] + 845.3887, 847.3858, found 845.3890, 847.3899; Optical rotation: [α]25D = +42.1 (c = 0.10, CHCl3).

[0089] Example 6 Preparation of Vinblastine Derivative G6

[0090]

[0091] Refer to the synthesis method of vinblastine derivative G1.

[0092] Intermediate C6: Yield 90%; 1 H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.39 (dd, J = 10.8, 7.7 Hz, 0.54H), 7.28 (dd, J = 10.8, 7.7 Hz, 0.46H), 7.14–7.02 (m, 2H), 6.10–5.91 (m, 1H), 5.77 (s, 0.46H), 4.90 (s, 0.54H), 4.05 (d, J = 15.8 Hz, 0.54H), 3.95 (d, J = 15.8 Hz, 0.46H), 3.77 (s, 3H), 3.74–3.64 (m, 1H), 3.60 (d, J = 9.2 Hz, 0.46H), 3.53 (d, J = 11.3 Hz, 0.54H), 3.15 (d, J = 9.2 Hz, 0.46H), 3.07 (d, J = 11.3 Hz, 0.54H), 2.90–2.74 (m, 2H), 2.27–2.02 (m, 2H), 1.81–1.69 (m, 0.54H), 1.50–1.37 (m, 0.46H), 0.99 (t, J = 7.4 Hz, 1.38H), 0.76 (t, J = 7.4 Hz, 1.62H); 13 C NMR (100 MHz, CDCl3): δ 170.36, 170.21, 169.91, 169.64, 145.86, 143.96, 131.16, 131.14, 131.06, 131.04, 127.67, 126.61, 124.65, 124.61, 124.47, 124.44, 122.61, 122.54, 109.34, 109.31, 109.30, 108.59, 108.58, 108.55, 108.53, 105.59, 105.39, 105.20, 99.20, 98.98, 61.03, 59.62, 59.45, 54.51, 53.27, 53.14, 47.87, 47.23, 39.31, 39.00, 31.42, 31.37, 31.10, 30.60, 26.39, 25.37, 11.36, 10.69; IR (neat): ν max = 3055, 2964, 1738, 1632, 1475, 1425, 1337, 1263, 846, 731 cm -1; HRMS(ESI): m / z calcd. for C 21 H 22 BrF2N2O3 + [M + H] + 467.0777, 469.0756, found 467.0772, 469.0753; Optical rotation: [α]25D = –62.7 (c = 0.26, CHCl3).

[0093] Intermediate D6: Yield 84%; 1 H NMR(400 MHz, CDCl3): δ 8.20 (s, 1H), 7.24 (dd, J = 10.4, 7.5 Hz, 1H), 7.01 (dd, J = 10.4, 6.5 Hz, 1H), 6.26 (d, J = 6.8 Hz, 1H), 5.08 (s, 1H), 4.18 (d, J = 15.5 Hz, 1H), 3.67 (s, 3H), 3.62 (d, J = 15.5 Hz, 1H), 3.54 (dd, J = 10.5, 2.8 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H), 2.89 (br.s, 1H), 2.67 (d, J = 13.1 Hz, 1H), 2.35–2.15 (m, 2H), 1.72 (d, J = 13.1 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H); 13 C NMR(100 MHz, CDCl3): δ 174.21, 172.92, 149.42, 149.26, 147.94, 147.79, 147.02, 146.86, 145.56, 145.42, 143.80, 135.96, 135.92, 130.14, 130.04, 128.86, 122.92, 122.84, 105.42, 105.23, 104.18, 104.17, 104.14, 104.13, 98.96, 98.74, 55.71, 53.26, 52.80, 50.88, 33.66, 32.71, 31.38, 26.88, 11.33; IR(neat): ν max = 3269, 3065, 2962, 1742, 1632, 1472, 1429, 1259, 855, 733 cm -1 ; HRMS(ESI): m / z calcd. for C 21 H 21 F2N2O3 + [M + H] +387.1515, found 387.1511; Optical rotation: [α]25D = –22.7 (c = 0.32, CHCl3).

[0094] Intermediate E6: Yield 78%; 1 H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.18 (dd, J = 10.8, 7.8 Hz, 1H), 7.00 (dd, J = 10.8, 6.6 Hz, 1H), 5.95–5.89 (m, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.53 (ddd, J = 14.4, 10.7, 3.9 Hz, 1H), 3.36 (dt, J = 14.4, 4.5 Hz, 1H), 3.23 (ddd, J = 16.4, 10.7, 4.5 Hz, 1H), 2.94–2.59 (m, 5H), 2.41–2.20 (m, 1H), 2.18–2.02 (m, 1H), 1.75 (d, J = 10.7 Hz, 1H), 1.06 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 173.99, 149.33, 149.05, 148.89, 147.66, 147.52, 146.66, 146.50, 145.30, 145.15, 137.86, 137.82, 129.80, 129.70, 124.44, 124.37, 123.53, 110.85, 110.83, 110.80, 110.79, 105.06, 104.87, 98.60, 98.38, 62.00, 55.45, 52.71, 52.48, 48.95, 38.68, 30.62, 26.13, 21.41, 10.61; IR (neat): ν max = 3457, 3364, 2960, 2883, 1714, 1472, 1354, 1264, 845, 734 cm -1 ; HRMS (ESI): m / z calcd. for C 21 H 23 F2N2O2 + [M + H] + 373.1723, found 373.1718; Optical rotation: [α]25D = +28.6 (c = 0.22, CHCl3).

[0095] Vinblastine derivative G6: Yield 20%; 11H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.19 (dd, J = 10.8, 7.6 Hz, 1H), 6.85 (dd, J = 10.5, 6.5 Hz, 1H), 6.50 (s, 1H), 6.09 (s, 1H), 5.89 (dd, J = 10.1, 3.9 Hz, 1H), 5.46 (s, 1H), 5.30 (d, J = 10.1 Hz, 1H), 3.90 (t, J = 14.0 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77–3.72 (m, 1H), 3.74 (s, 1H), 3.63 (s, 3H), 3.40 (dd, J = 16.3, 5.2 Hz, 1H), 3.30 (td, J = 9.4, 4.5 Hz, 1H), 3.27–3.13 (m, 2H), 2.83 (s, 1H), 2.80 (s, 1H), 2.78 (s, 1H), 2.71 (s, 3H), 2.61 (s, 1H), 2.51–2.39 (m, 2H), 2.32–2.23 (m, 1H), 2.23–2.13 (m, 1H), 2.11 (s, 3H), 1.92–1.71 (m, 2H), 1.67–1.59 (m, 2H), 1.52–1.26 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.81, 171.65, 170.97, 158.00, 152.75, 147.28, 146.99, 145.07, 144.94, 132.80, 132.65, 129.84, 129.71, 124.67, 123.28, 122.84, 120.54, 105.23, 105.05, 98.39, 98.17, 94.09, 83.26, 79.63, 76.34, 69.37, 65.66, 64.34, 55.80, 55.73, 55.66, 53.20, 52.51, 52.26, 50.49, 50.42, 44.56, 42.61, 38.25, 34.45, 34.18, 30.69, 21.13, 8.32, 6.82; IR (neat): ν max = 3464, 2926, 2879, 1734, 1471, 1353, 1229, 1036, 807, 733 cm -1 ; HRMS (ESI): m / z calcd. for C 46 H 57 F2N4O9 + [M + H] +847.4089, found 847.4091; Optical rotation: [α]25D = +33.2 (c = 0.18, CHCl3).

[0096] Example 17 Preparation of Vinblastine Derivative G7

[0097]

[0098] Refer to the synthesis method of vinblastine derivative G1.

[0099] Intermediate C7: Yield 88%; 1 H NMR (400 MHz, CDCl3): δ8.43 (s, 0.48H), 8.39 (s, 0.52H), 7.01 (d, J = 2.4 Hz, 0.48H), 6.95 (d, J = 2.4 Hz, 0.52H), 6.91–6.76 (m, 2H), 6.04 (dt, J = 6.3, 1.8 Hz, 1H), 5.78 (d, J = 1.6 Hz, 0.48H), 5.06 (d, J = 1.6 Hz, 0.52H), 4.39 (d, J = 16.0 Hz, 0.48H), 4.01 (d, J = 16.0 Hz, 0.52H), 4.00 (d, J = 2.1 Hz, 1.56H), 3.97 (d, J = 2.1 Hz, 1.44H), 3.94 (d, J = 6.7 Hz, 1H), 3.77 (s, 1.44H), 3.76 (s, 1.56H), 3.60 (dd, J = 9.4, 2.0 Hz, 0.48H), 3.53 (dd, J = 11.5, 2.0 Hz, 0.52H), 3.21 (dt, J = 9.4, 2.6 Hz, 0.48H), 3.10 (dt, J = 11.5, 2.8 Hz, 0.52H), 2.92–2.76 (m, 2H), 2.33–2.09 (m, 2H), 1.95–1.85 (m, 0.48H), 1.80–1.68 (m, 0.52H), 1.00 (t, J = 7.4 Hz, 1.44H), 0.86 (t, J = 7.4 Hz, 1.56H); 1313C NMR (100 MHz, CDCl3): δ 171.55, 171.36, 170.01, 169.79, 149.92, 147.61, 145.92, 144.57, 139.98, 139.93, 139.86, 139.81, 134.01, 133.98, 127.30, 126.56, 124.68, 124.49, 120.92, 120.88, 120.82, 120.78, 111.96, 111.81, 111.72, 111.57, 109.22, 109.16, 108.51, 108.45, 106.22, 106.13, 106.03, 105.95, 61.49, 61.43, 61.26, 61.19, 60.96, 59.86, 59.47, 54.58, 53.13, 53.08, 47.89, 47.30, 39.35, 39.15, 32.05, 31.50, 31.46, 30.71, 26.36, 25.52, 11.25, 10.72; IR (neat): ν max = 3283, 2961, 1736, 1632, 1506, 1430, 1344, 1258, 1071, 972, 732 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 25 BrFN2O4 + [M + H] + 478.0903, 479.0976, found 479.0971, 481.0918; Optical rotation: [α]25D = –64.5 (c = 0.27, CHCl3).

[0100] Intermediate D7: Yield 97%; 11H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 6.92 (dd, J = 11.9, 8.7 Hz, 1H), 6.84 (dd, J = 8.8, 3.6 Hz, 1H), 6.31–6.22 (m, 1H), 5.10 (s, 1H), 4.34 (d, J = 15.8 Hz, 1H), 4.22 (d, J = 15.8 Hz, 1H), 4.07 (d, J = 2.0 Hz, 3H), 3.67 (s, 3H), 3.57 (dd, J = 10.5, 2.9 Hz, 1H), 2.94 (d, J = 10.4 Hz, 1H), 2.89 (br.s, 1H), 2.68 (d, J = 13.2 Hz, 1H), 2.33–2.22 (m, 2H), 1.74 (d, J = 14.2 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, DMSO): δ 174.12, 171.58, 149.49, 147.46, 142.40, 137.29, 133.55, 133.55, 128.88, 128.88, 120.01, 110.70, 106.99, 102.39, 102.33, 61.52, 61.47, 55.28, 52.75, 52.45, 50.43, 32.61, 30.64, 26.07, 11.13; IR (neat): ν max = 3247, 2919, 2851, 1717, 1627, 1449, 1260, 1075, 798, 735, 660 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 24 FN2O4 + [M + H] + 399.1715, found 399.1708; Optical rotation: [α]25D = –45.4 (c = 0.15, CHCl3).

[0101] Intermediate E7: Yield 87%; 11H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.92–6.77 (m, 2H), 5.92 (d, J = 5.0 Hz, 1H), 4.21–4.16 (m, 1H), 3.98 (d, J = 1.6 Hz, 3H), 3.71 (s, 3H), 3.60–3.44 (m, 2H), 3.38–3.25 (m, 2H), 2.87–2.79 (m, 2H), 2.77–2.67 (m, 2H), 2.38–2.20 (m, 1H), 2.15–2.01 (m, 1H), 1.83–1.73 (m, 1H), 1.05 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 173.94, 150.69, 149.02, 148.37, 140.57, 140.45, 137.36, 132.79, 129.48, 123.84, 122.13, 111.82, 111.76, 111.63, 111.39, 105.49, 105.40, 61.72, 61.66, 61.16, 55.64, 53.73, 52.40, 50.27, 38.32, 30.63, 26.18, 21.96, 10.63; IR (neat): ν max = 3372, 2958, 2850, 1721, 1506, 1440, 1336, 1262, 1077, 978, 867, 733 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 26 FN2O3 + [M + H] + 385.1922, found 385.1920; Optical rotation: [α]25D = +22.4 (c = 0.15, CHCl3).

[0102] Vinblastine derivative G7: Yield 22%; 11H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 7.92 (s, 1H), 6.93 (dd, J = 12.6, 8.7 Hz, 1H), 6.66 (dd, J = 8.8, 3.2 Hz, 1H), 6.33 (s, 1H), 6.09 (s, 1H), 5.89 (dd, J = 10.1, 3.9 Hz, 1H), 5.41 (s, 1H), 5.31 (d, J = 10.1 Hz, 1H), 4.05 (d, J = 3.0 Hz, 3H), 3.94 (t, J = 14.7 Hz, 1H), 3.83–3.74 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (s, 1H), 3.66 (s, 3H), 3.41–3.11 (m, 5H), 3.00 (d, J = 14.2 Hz, 1H), 2.88 (s, 1H), 2.84 (s, 1H), 2.72 (s, 3H), 2.65 (s, 1H), 2.61–2.52 (m, 1H), 2.36 (d, J = 15.1 Hz, 1H), 2.25–2.11 (m, 2H), 2.10 (s, 3H), 1.90–1.26 (m, 10H), 0.94 (t, J = 7.4 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.22, 171.58, 171.03, 157.74, 153.11, 149.45, 147.90, 140.45, 132.71, 130.57, 129.67, 124.97, 123.22, 122.70, 121.25, 104.79, 104.73, 94.09, 82.97, 79.70, 76.34, 68.44, 65.27, 61.15, 61.09, 57.35, 55.77, 55.08, 53.27, 52.69, 52.24, 50.18, 49.94, 44.75, 44.51, 42.59, 38.07, 35.88, 34.98, 31.90, 30.68, 22.67, 21.15, 8.34, 6.61; IR (neat): ν max = 3446, 2930, 2852, 1737, 1614, 1503, 1437, 1371, 1262, 1238, 1038, 979, 897, 730 cm -1 ; HRMS (ESI): m / z calcd. for C 47 H 60 FN4O 10 + [M + H] +859.4288, found 859.4280; Optical rotation: [α]25D = +33.8 (c = 0.08, CHCl3).

[0103] Example 8 Preparation of Vinblastine Derivative G8

[0104]

[0105] Refer to the synthesis method of vinblastine derivative G1.

[0106] Intermediate C8: Yield 87%; 1 H NMR (400 MHz, CDCl3): δ 8.53 (s, 0.45H), 8.44 (s, 0.55H), 6.85 (s, 1H), 6.60 (dd, J = 9.3, 2.0 Hz, 0.55H), 6.55 (dd, J = 9.3, 2.0 Hz, 0.45H), 6.30 (dd, J = 11.7, 2.0 Hz, 0.55H), 6.20 (dd, J = 11.7, 2.0 Hz, 0.45H), 6.05 (d, J = 4.5 Hz, 0.45H), 5.99 (d, J = 4.5 Hz, 0.55H), 5.78 (s, 0.45H), 5.04 (s, 0.55H), 4.53 (d, J = 15.7 Hz, 0.45H), 3.95 (d, J = 16.8 Hz, 0.55H), 3.91 (br.s, 1H), 3.89 (s, 1.65H), 3.81 (s, 1.35H), 3.77 (s, 1.35H), 3.73 (s, 1.65H), 3.62 (dd, J = 9.3, 2.0 Hz, 0.45H), 3.51 (dd, J = 11.5, 2.0 Hz, 0.55H), 3.21 (dt, J = 9.4, 2.6 Hz, 0.45H), 3.05 (dt, J = 11.4, 2.8 Hz, 0.55H), 2.89–2.74 (m, 2H), 2.22–2.08 (m, 2H), 1.79–1.62 (m, 0.55H), 1.49–1.35 (m, 0.45H), 1.01 (t, J = 7.4 Hz, 1.35H), 0.75 (t, J = 7.3 Hz, 1.65H); 1313C NMR (100 MHz, CDCl3): δ 171.94, 171.57, 170.08, 169.82, 161.59, 161.47, 159.25, 159.13, 154.75, 154.63, 154.51, 146.08, 144.68, 136.85, 136.70, 136.55, 136.40, 127.06, 126.43, 122.21, 122.18, 121.95, 121.91, 113.65, 113.49, 109.33, 108.68, 90.69, 90.58, 90.43, 90.32, 90.23, 90.08, 89.94, 89.79, 61.01, 59.81, 59.36, 55.36, 55.34, 54.49, 53.10, 53.07, 47.92, 47.42, 39.36, 39.22, 32.46, 31.91, 31.79, 31.53, 30.68, 26.39, 25.15, 22.67, 14.10, 11.34, 10.60; IR (neat): ν max = 3393, 3017, 2958, 1746, 1627, 1453, 1282, 1215, 1024, 967, 751 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 25 BrFN2O4 + [M + H] + 479.0976, 481.0956, found 479.0971, 481.0911; Optical rotation: [α]25D = –60.5 (c = 0.43, CHCl3).

[0107] Intermediate D8: Yield 80%; 1 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 6.54 (dd, J = 8.9, 2.0 Hz, 1H), 6.32–6.21 (m, 2H), 5.07 (s, 1H), 4.44 (d, J = 15.9 Hz, 1H), 4.18 (d, J = 15.9 Hz, 1H), 3.88 (s, 3H), 3.66 (s, 3H), 3.56 (dd, J = 10.5, 2.9 Hz, 1H), 2.98–2.84 (m, 2H), 2.66 (dt, J = 13.3, 3.1 Hz, 1H), 2.26 (q, J = 7.4 Hz, 2H), 1.73 (dd, J = 13.5, 1.7 Hz, 1H), 1.09 (t, J = 7.4 Hz, 3H); 1313C NMR (100 MHz, DMSO): δ 174.38, 171.81, 160.46, 158.13, 154.49, 154.36, 142.50, 136.08, 135.92, 134.76, 134.73, 128.85, 112.89, 102.58, 90.44, 90.29, 90.18, 90.00, 55.63, 55.32, 52.63, 52.41, 50.51, 32.99, 32.72, 30.71, 26.11, 11.16; IR (neat): ν max = 2924, 2855, 2400, 1744, 1713, 1623, 1440, 1258, 1211, 1084, 1018, 798 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 24 FN2O4 + [M + H] + 399.1715, found 399.1713; Optical rotation: [α]25D = –25.5 (c = 0.16, CHCl3).

[0108] Intermediate E8: Yield 81%; 1 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 6.52 (d, J = 9.0 Hz, 1H), 6.27 (d, J = 11.9 Hz, 1H), 5.92 (d, J = 6.1 Hz, 1H), 4.18 (s, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 3.58–3.45 (m, 2H), 3.41–3.22 (m, 2H), 2.88–2.78 (m, 2H), 2.76–2.64 (m, 2H), 2.38–2.22 (m, 1H), 2.16–2.01 (m, 1H), 1.76 (dd, J = 13.6, 3.3 Hz, 1H), 1.06 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.14, 161.41, 159.06, 155.20, 155.08, 149.06, 135.64, 135.49, 134.75, 134.71, 123.79, 114.55, 111.85, 90.51, 90.23, 89.93, 89.67, 61.10, 55.45, 55.31, 53.78, 52.33, 50.32, 38.44, 30.67, 26.16, 22.55, 10.61; IR (neat): ν max= 3367,2926,2850,1716,1622,1602,1448,1345,1258,1205,1079,1017,965,800,754 cm -1 ; HRMS(ESI): m / z calcd. for C 22 H 26 FN2O3 + [M + H] + 385.1922, found 385.1922; Optical rotation: [α]25D = +20.1 (c = 0.32, CHCl3).

[0109] Vinblastine derivative G8: Yield 23%; 1 1H NMR(400 MHz, CDCl3): δ 9.77 (s, 1H), 7.93 (s, 1H), 6.55 (s, 1H), 6.37 (dd, J = 9.1, 2.3 Hz, 1H), 6.24 (dd, J = 11.9, 2.1 Hz, 1H), 6.09 (d, J = 2.6 Hz, 1H), 5.86 (dd, J = 10.2, 5.1 Hz, 1H), 5.47 (d, J = 2.5 Hz, 1H), 5.28 (d, J = 10.0 Hz, 1H), 3.95 (t, J = 14.2 Hz, 1H), 3.85–3.79 (m, 1H), 3.84 (d, J = 2.4 Hz, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.72 (s, 1H), 3.62 (s, 3H), 3.46–3.32 (m, 3H), 3.34–3.21 (m, 1H), 3.11–3.00 (m, 1H), 2.82 (s, 1H), 2.78 (s, 2H), 2.69 (s, 3H), 2.60 (s, 1H), 2.48–2.35 (m, 1H), 2.25–2.12 (m, 3H), 2.10 (s, 3H), 1.95–1.75 (m, 3H), 1.50–1.11 (m, 6H), 0.87 (t, J = 7.4 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H); 1313C NMR (100 MHz, CDCl3): δ 174.90, 171.73, 170.89, 161.50, 159.14, 157.99, 155.39, 155.27, 152.63, 135.68, 135.53, 129.96, 129.19, 129.15, 124.51, 123.63, 122.85, 121.16, 118.36, 114.83, 94.22, 89.90, 89.72, 89.61, 89.47, 83.38, 79.58, 76.43, 76.38, 69.60, 65.85, 64.34, 56.37, 55.78, 55.55, 55.31, 53.20, 52.31, 52.21, 50.63, 50.45, 48.02, 44.48, 42.67, 41.38, 38.33, 34.37, 30.78, 29.96, 21.09, 8.35, 6.85; IR (neat): ν max = 3346, 2959, 2855, 1737, 1614, 1505, 1451, 1307, 1230, 1092, 1020, 799, 752 cm -1 ; HRMS (ESI): m / z calcd. for C 47 H 60 FN4O 10 + [M + H] + 859.4288, found 859.4284; Optical rotation: [α]25D = +31.4 (c = 0.14, CHCl3).

[0110] Example 9 Preparation of Vinblastine Derivative G9

[0111]

[0112] Refer to the synthesis method of vinblastine derivative G1.

[0113] Intermediate C9: Yield 87%; 11H NMR (400 MHz, CDCl3): δ 8.71 (s, 0.49H), 8.60 (s, 0.51H), 6.83 (d, J = 2.3 Hz, 0.49H), 6.81 (d, J = 2.3 Hz, 0.51H), 6.72 (dd, J = 10.1, 5.8 Hz, 0.49H), 6.67 (dd, J = 10.1, 5.8 Hz, 0.51H), 6.12–6.03 (m, 1H), 5.79 (d, J = 1.4 Hz, 0.49H), 5.02 (d, J = 1.4 Hz, 0.51H), 4.29 (d, J = 16.2 Hz, 0.51H), 4.02 (d, J = 2.6 Hz, 1.47H), 4.00 (d, J = 2.6 Hz, 1.53H), 3.99 (d, J = 16.2 Hz, 0.49H), 3.89 (d, J = 16.2 Hz, 0.49H), 3.83 (d, J = 16.2 Hz, 0.51H), 3.78 (s, 1.47H), 3.77 (s, 1.53H), 3.64 (dd, J = 9.4, 2.1 Hz, 0.49H), 3.53 (dd, J = 11.5, 2.1 Hz, 0.49H), 3.23 (dt, J = 9.4, 2.7 Hz, 0.51H), 3.12 (dt, J = 11.5, 2.7 Hz, 0.51H), 2.92–2.78 (m, 2H), 2.26–2.12 (m, 2H), 2.05–1.90 (m, 0.51H), 1.90–1.74 (m, 0.49H), 1.02 (t, J = 7.4 Hz, 1.47H), 0.91 (t, J = 7.4 Hz, 1.53H); 13 13C NMR (100 MHz, CDCl3): δ 171.40, 171.36, 169.98, 169.75, 150.12, 149.99, 146.00, 144.58, 131.18, 131.12, 131.05, 131.00, 127.43, 126.59, 124.27, 124.25, 124.01, 123.98, 116.01, 109.25, 109.20, 108.54, 108.49, 93.62, 93.51, 93.40, 93.29, 61.45, 61.38, 61.30, 61.23, 60.99, 59.86, 59.51, 54.68, 53.18, 53.11, 47.93, 47.30, 39.44, 39.22, 31.86, 31.55, 31.34, 30.75, 26.39, 25.69, 11.25, 10.80; IR (neat): ν max= 3246,2959,2930,1739,1632,1511,1463,1427,1257,1154,911,799,755 cm -1 ; HRMS(ESI): m / z calcd. for C 22 H 24 BrF2N2O4 + [M + H] + 497.0882, found 497.0885; Optical rotation: [α]25D = –59.4 (c = 0.31, CHCl3).

[0114] Intermediate D9: Yield 81%; 1 H NMR(400 MHz, DMSO-d6): δ 11.15 (s, 1H), 6.94 (dd, J = 10.4, 6.1 Hz, 1H), 6.26 (dd, J = 6.7, 1.9 Hz, 1H), 5.15 (s, 1H), 4.43 (d, J = 15.4 Hz, 1H), 3.98 (d, J = 1.6 Hz, 3H), 3.88 (d, J = 15.4 Hz, 1H), 3.57 (s, 3H), 3.41–3.35 (m, 1H), 2.88 (br.s, 1H), 2.72 (dt, J = 10.4, 1.9 Hz, 1H), 2.63 (ddd, J = 13.1, 4.2, 2.2 Hz, 1H), 2.27–2.03 (m, 2H), 1.49 (dd, J = 13.1, 1.7 Hz, 1H), 1.02 (t, J = 7.4 Hz, 3H); 13 C NMR(100 MHz, DMSO-d6): δ 174.38, 171.96, 149.11, 148.97, 146.74, 146.61, 142.79, 141.06, 141.00, 137.42, 137.39, 131.05, 130.92, 129.31, 115.93, 103.00, 102.95, 94.54, 94.32, 62.23, 62.18, 55.64, 53.12, 52.89, 50.84, 32.98, 32.88, 31.05, 26.47, 11.53; IR(neat): ν max = 3242,2927,1738,1630,1429,1257,1087,1021,913,798 cm -1 ; HRMS(ESI): m / z calcd. for C 22 H 23 F2N2O4 + [M + H] +417.1620, found 417.1619; Optical rotation: [α]25D = –38.5 (c = 0.20, CHCl3).

[0115] Intermediate E9: Yield 75%; 1 H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 6.72 (dd, J = 9.8, 5.8 Hz, 1H), 5.98–5.88 (m, 1H), 4.20 (s, 1H), 4.03 (d, J = 2.1 Hz, 3H), 3.73 (s, 3H), 3.63–3.53 (m, 1H), 3.51–3.41 (m, 1H), 3.35–3.24 (m, 2H), 2.93–2.77 (m, 2H), 2.77–2.66 (m, 2H), 2.40–2.25 (m, 1H), 2.19–2.00 (m, 1H), 1.77 (d, J = 10.8 Hz, 1H), 1.06 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 171.21, 150.46, 150.36, 148.85, 148.75, 145.32, 141.54, 141.48, 139.90, 139.80, 138.32, 138.22, 133.29, 133.27, 130.20, 130.11, 127.58, 115.73, 110.83, 110.79, 93.45, 93.30, 61.68, 61.63, 59.07, 57.27, 53.72, 53.59, 50.87, 36.10, 28.89, 26.78, 19.93, 10.23; IR (neat): ν max = 3190, 2929, 1740, 1633, 1510, 1461, 1380, 1259, 1093, 1018, 918, 799, 753 cm -1 ; HRMS (ESI): m / z calcd. for C 22 H 25 F2N2O3 + [M + H] + 403.1828, found 403.1829; Optical rotation: [α]25D = +46.2 (c = 0.33, CHCl3).

[0116] Vinblastine derivative G9: Yield 21%; 11H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 6.53 (dd, J = 9.8, 5.6 Hz, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 5.89 (dd, J = 10.2, 4.6 Hz, 1H), 5.42 (s, 1H), 5.29 (d, J = 10.2 Hz, 1H), 4.07 (d, J = 2.8 Hz, 3H), 3.91 (t, J = 14.3 Hz, 1H), 3.83–3.74 (m, 1H), 3.79 (s, 6H), 3.74 (s, 1H), 3.65 (s, 3H), 3.61–3.51 (m, 2H), 3.44–3.11 (m, 3H), 2.92 (br.s, 1H), 2.86 (s, 1H), 2.82 (s, 1H), 2.71 (s, 3H), 2.60 (s, 1H), 2.55–2.45 (m, 1H), 2.38–2.24 (m, 1H), 2.21–2.10 (m, 2H), 2.10 (s, 3H), 1.93–1.25 (m, 10H), 0.92 (t, J = 7.5 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 174.75, 171.68, 170.95, 157.93, 152.78, 142.04, 141.95, 140.21, 140.05, 137.86, 137.70, 130.92, 129.99, 129.85, 124.65, 123.36, 122.98, 117.08, 94.13, 92.50, 92.28, 89.81, 83.27, 79.62, 79.60, 76.37, 76.34, 69.33, 65.84, 65.69, 61.35, 61.27, 56.64, 55.79, 55.54, 55.39, 53.21, 53.17, 52.47, 52.44, 52.24, 50.63, 50.48, 50.38, 44.53, 42.64, 38.25, 38.22, 34.54, 30.75, 30.71, 21.10, 8.33, 6.79; IR (neat): ν max = 3454, 2927, 1736, 1614, 1503, 1461, 1255, 1022, 952, 799, 751 cm -1 ; HRMS (ESI): m / z calcd. for C 47 H 59 F2N4O 10 + [M + H] +877.4194, found 877.4184; Optical rotation value: [α]25D = –34.2 (c = 0.14, CHCl3).

[0117] Example 10 Biological Activity Test

[0118] Acute myeloid leukemia cells MV-4-11 and THP-1 were purchased from ATCC, and OCI-AML2, OCI-AML3, and MOLM-13 were purchased from Nanjing Kebai Biotechnology Co., Ltd. The cell culture medium was 1640 + 10% FBS, and the cells were cultured in an incubator at 37°C with 5% CO2. The anti-proliferative activity of the compound was evaluated by the CCK-8 assay. A certain number of cells were seeded in a 96-well plate, and then different concentrations of the compound were added, and the plate was placed in the incubator and incubated for another 24 h. CCK-8 solution was added at 10% of the total volume of the medium in the well, mixed evenly, and incubated in the incubator for 0.5 - 4 hours. The absorbance value at a wavelength of 450 nm was read using a microplate reader. GraphPad prism 8.0 software was used to determine the linear regression parameters and calculate the IC 50 value.

[0119] The experimental results are shown in the following table:

[0120] IC 50 value

[0121]

[0122] Structures of the control compounds vinblastine and vincristine:

[0123]

[0124] Conclusion: The vinblastine derivatives of the present invention have significant anti-proliferative activity against acute myeloid leukemia cells MV-4-11, THP-1, OCI-AML2, OCI-AML3, and MOLM-13, and are more active than the control compounds vinblastine and vincristine.

[0125] The above are only the preferred embodiments of the present invention. It should be understood that the present invention is not limited to the forms disclosed herein, should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications, and environments, and can be changed within the scope of the concept described herein through the above teachings or the technology or knowledge in the relevant field. Any changes and modifications made by those skilled in the art without departing from the spirit and scope of the present invention shall fall within the protection scope of the appended claims of the present invention.

Claims

1. A vinblastine derivative or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, characterized in that, The vinblastine derivative is selected from the compounds represented by the general formula (I), In the formula, R1, R2, R3 or R4 are each independently selected from H, deuterium, halogen, CN, COOH, NR a R b , C(=O)NR a R b , OR c , SR c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy group, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy group, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; and R1, R2, R3 and R4 are not simultaneously selected as H; R5 is selected from H, deuterium, halogen, OR c , SR c , CN, NR a R b , NHC(=O)NR a R b , NHC(=O)R c , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; R6 is selected from H, deuterium, formyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group; R7 is selected from H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; R8 is selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=O)C 1-6 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; R a , R b or R c each independently selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclic group, 4- to 12-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group.

2. The vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 1, characterized in that, The compounds represented by the general formula (I) are selected from the compounds represented by the general formula (II), R1, R2, or R3 is independently selected from H, deuterium, halogen, CN, COOH, NR a R b , C(=O)NR a R b , OR c , SR c , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(=O)C 1-4 alkyl, C(=O)-C 3-6 carbocyclic group, C(=O)-(4-6 membered heterocyclic group), OC(=O)C 1-4 alkyl, C(=O)OC 1-4 alkyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group; and R1, R2, and R3 are not simultaneously H; R a 、R b or R c is independently selected from H, deuterium, halogen, OH, NH2, CN, C(=O)NH2, COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents independently selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group.

3. The vinblastine derivative according to claim 2, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that, R1, R2, or R3 is independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NR a R b , C(=O)NR a R b , OR c , SR c , methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-benzene, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or pyridyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group; and R1, R2, and R3 are not simultaneously H; R a 、R b or R c are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, COOH, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group.

4. The vinblastine derivative according to claim 3, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that, R1, R2 or R3 are each independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=O)NH2, OH, SH, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-isopropyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-phenyl, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-phenyl, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, OC(=O)CH3, OC(=O)CH2CH3, OC(=O)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl; and R1, R2 and R3 do not simultaneously select H.

5. The vinblastine derivative according to claim 4, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that, Each of R1, R2 or R3 is independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=O)NH2, OH, SH, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-isopropyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-benzene, C(=O)CH3, C(=O)CH2CH3, C(=O)CH(CH3)2, C(=O)-cyclopropyl, C(=O)-cyclobutyl, C(=O)-cyclopentyl, C(=O)-cyclohexyl, C(=O)-benzene, C(=O)OCH3, C(=O)OCH2CH3, C(=O)OCH(CH3)2, OC(=O)CH3, OC(=O)CH2CH3, OC(=O)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl; and R1, R2 and R3 do not simultaneously select H.

6. The vinblastine derivative according to claim 5, or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that Each of R1, R2 or R3 is independently selected from H, F, Cl, Br, methyl, methoxy, ethyl, cyclopropyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy or monofluoromethoxy, and R1, R2 and R3 do not simultaneously select H.

7. The vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 6, characterized in that, The vinblastine derivative is selected from one of the following structures:

8. The preparation method of the vinblastine derivative according to claim 1, characterized in that, When R5 is selected as OH, the following steps are included: (a) Compound A and compound B are subjected to a condensation reaction to obtain compound C; (b) Compound C is subjected to a ring-closing reaction catalyzed by a copper catalyst to prepare compound D; (c) Compound D is subjected to a reduction reaction to prepare compound E; (d) Compound E and compound F are subjected to a reaction catalyzed by an iron catalyst to prepare the vinblastine derivative.

9. The preparation method according to claim 8, characterized in that, In step (a), in the condensation reaction, the molar ratio of compound A to compound B is 1.2 - 2.0:1; The reaction solvent for the condensation reaction is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, toluene and tetrahydrofuran; The chemical reagent for the condensation reaction is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, pivaloyl chloride and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; The reaction temperature of the condensation reaction is 0 - 80 °C.

10. The preparation method according to claim 8, characterized in that, In step (b), in the ring-closing reaction, the molar ratio of compound C to the chemical reagent is 1 - 2:2.7; The solvent is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, 1,4-dioxane and tetrahydrofuran; In the ring-closing reaction, the chemical reagents are copper(I) iodide, tris(2-pyridylmethyl)amine, and 2,4,6-trimethylpyridine, and the molar ratio of copper(I) iodide, tris(2-pyridylmethyl)amine, and 2,4,6-trimethylpyridine is 0.3:0.4:2; The reaction temperature of the ring-closing reaction is 20 to 110 °C.

11. The preparation method according to claim 8, characterized in that, In step (c), in the reduction reaction, the molar ratio of compound D to the chemical reagent is 1 to 2:14; The solvent is selected from one of dichloromethane, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran; In the reduction reaction, the chemical reagent is selected from one of borane, tris(triphenylphosphine)rhodium(I) carbonyl hydride, iridium(I) chloride bis(triphenylphosphine), lithium borohydride, and sodium borohydride; The reaction temperature of the reduction reaction is 0 to 100 °C.

12. The preparation method according to claim 8, characterized in that, In step (d), in the catalytic reaction, the molar ratio of compound E to compound F is 1:1.0 to 2.0; The solvent is selected from one of trifluoroethanol, water, dichloromethane, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran; The iron catalyst is selected from one of iron(III) chloride, iron(III) oxalate, and iron(III) sulfate; The reaction temperature of the catalytic reaction is 0 to 30 °C.

13. A method for treating cancer, characterized in that, Comprising administering to a cancer patient an effective dose of the vinblastine derivative or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal according to any one of claims 1-6.

14. A method for treating cancer according to claim 13, characterized in that, The types of cancer include leukemia, lymphoma, lung cancer, liver cancer, breast cancer, and pancreatic cancer.

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