Preparation of vinblastine derivative and use thereof

Abstract

A compound as shown in general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, and the use thereof in cancer-related diseases such as acute myeloid leukemia. The synthesized vinblastine derivative has an antiproliferative activity against acute myeloid leukemia cancer cells that is significantly superior to that of vinblastine, can be used as a toxin molecule in the development of antibody-drug conjugates, and has a great anti-tumor effect.

Description

Preparation and application of vinblastine derivatives TECHNICAL FIELD

[0001] The present application relates to the technical field of organic compound synthesis and medical application, in particular to a preparation of vinblastine derivatives and application thereof in medicine. BACKGROUND

[0002] Acute myeloid leukemia is the most common subtype of leukemia in adults, which has the characteristics of rapid progression, difficult cure, high recurrence rate and poor prognosis, with a mortality rate of more than 80% and a 5-year survival rate of less than 24%. Vinblastine and vincristine are Vinca monoterpenoid indole alkaloid dimers isolated from the plant Catharanthus roseus in the 1960s, which can induce apoptosis of cancer cells by inhibiting microtubulin polymerization and preventing spindle formation.

[0003] In clinical practice, vinblastine drugs are mainly used for the treatment of bladder cancer, breast cancer, acute lymphoblastic leukemia, melanoma and non-small cell lung cancer. The drugs are substrates of P-glycoprotein, and when the drugs enter tumor cells, they are pumped out of the cells by highly expressed P-glycoprotein, thereby affecting the treatment effect due to drug resistance of the tumor. In addition, in the preparation of derivatives, the existing chemical synthesis method has great limitations and is difficult to be applied to the construction of a diversified vinblastine derivative library. Based on this, the present application develops a simple and convenient method for the preparation of vinblastine derivatives, and through active screening, a derivative with an anti-proliferative activity obviously better than that of vinblastine on cancer cells such as acute myeloid leukemia is found. The vinblastine derivative prepared by the present application can overcome drug resistance and be used for the development of new drugs for the treatment of acute myeloid leukemia and other cancers, and can be used as a toxin molecule for the development of antibody conjugated drugs. SUMMARY

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

[0005] The purpose of the present application is achieved by the following technical solution: a vinblastine derivative or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the vinblastine derivative being selected from the compounds shown in general formula (I),

[0006] 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 , 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OH, C(=O)OR 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl; and said R1, R2, R3and R4are not simultaneously selected as H;

[0007] R5is selected from the group consisting of 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OH, C(=O)OR 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl;

[0008] R6is selected from the group consisting of H, deuterium, formyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 substituted by substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OC

[0009] R7is selected from the group consisting of 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, which alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 substituted by substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OC

[0010] R8is selected from the group consisting of 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, which alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OC 1-6 alkyl, C 1-6 alkoxy, C 3-6 substituted by substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C(=O)OC

[0011] R a , R b or Rc each independently selected from H, deuterium, halogen, OH, NH2, CN, C(=0)NH2, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=0)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=0)NH2, C

[0012] Further, the compound of Formula (I) is selected from the group consisting of compounds of Formula (II),

[0013] each of R1, R2, or R3is independently selected from H, deuterium, halogen, CN, COOH, NR a R b , C(=0)NR a R b , OR c , SR c , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(=0)C 1-4 alkyl, C(=0)-C 3-6 carbocyclyl, C(=0)-(4-6 membered heterocyclyl), OC(=0)C 1-4 alkyl, C(=0)OC 1-4 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=0)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, halogen, OH, NH2, CN, C(=0)NH2, C

[0014] R a , R b , or R c each independently selected from H, deuterium, halogen, OH, NH2, CN, C(=0)NH2, COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is selected from 1 to 4 of deuterium, halogen, OH, NH2, CN, C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of carbocyclic groups and 4-6 membered heterocyclic groups.

[0015] Furthermore, R1, R2, or R3 are each independently selected from H, deuterium, F, Cl, Br, I, CN, COOH, and 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, aziridine, pyrrole Alkyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, wherein the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, aziridine, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl or pyridinyl group is selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituents of carbocyclic groups and 4-6 membered heterocyclic groups; and R1, R2, and R3 do not simultaneously choose H;

[0016] R a R b or R ceach independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, NH2, CN, C(=0)NH2, COOH, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=0)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=0)NH2, C

[0017] Further, each of R1, R2, or R3is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=0)NH2, OH, SH, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-i-propyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-benzene, C(=0)CH3, C(=0)CH2CH3, C(=0)CH(CH3)2, C(=0)-cyclopropyl, C(=0)-cyclobutyl, C(=0)-cyclopentyl, C(=0)-cyclohexyl, C(=0)-benzene, C(=0)OCH3, C(=0)OCH2CH3, C(=0)OCH(CH3)2, OC(=0)CH3, OC(=0)CH2CH3, OC(=0)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=0)NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl; and R1, R2, and R3are not simultaneously selected as H. Further, each of R1, R2, or R3is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=0)NH2, OH, SH, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-i-propyl, O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O-benzene, C(=0)CH3, C(=0)CH2CH3, C(=0)CH(CH3)2, C(=0)-cyclopropyl, C(=0)-cyclobutyl, C(=0)-cyclopentyl, C(=0)-cyclohexyl, C(=0)-benzene, C(=0)OCH3, C(=0)OCH2CH3, C(=0)OCH(CH3)2, OC(=0)CH3, OC(=0)CH2CH3, OC(=0)CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=0)NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl; and R1, R2, and R3are not simultaneously selected as H.

[0018] Further, each of R1, R2or R3is 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, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-i-propyl, 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 R1, R2and R3are not simultaneously selected as H.

[0019] Further, each of R1, R2or R3is independently selected from H, F, Cl, Br, methyl, methoxy, ethyl, cyclopropyl, i-propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy or monofluoromethoxy, and R1, R2and R3are not simultaneously selected as H.

[0020] Further, the vinblastine derivative is selected from one of the following structures:

[0021] The present application also provides a preparation method of the above-mentioned vinblastine derivative, when R5is selected as OH, comprising the following steps:

[0022] (a) Compound A and Compound B are condensed to obtain Compound C;

[0023] (b) Compound C is prepared by a ring-closing reaction catalyzed by a copper catalyst to obtain Compound D;

[0024] (c) Compound D is prepared by a reduction reaction to obtain Compound E;

[0025] (d) Compound E and Compound F are reacted by a reaction catalyzed by an iron catalyst to obtain the vinblastine derivative.

[0026] Further, in step (a), in the condensation reaction, the molar ratio of Compound A to Compound B is 1.2-2.0:1;

[0027] The reaction solvent of the condensation reaction is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, toluene and tetrahydrofuran;

[0028] The chemical reagent of the condensation reaction is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, trimethylacetyl chloride and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0029] The reaction temperature of the condensation reaction is 0-80℃.

[0030] Further, in step (b), the molar ratio of compound C and the chemical reagent in the ring-closing reaction is 1-2:2.7;

[0031] The solvent is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, 1,4-dioxane and tetrahydrofuran;

[0032] In the ring-closing reaction, the chemical reagent is cuprous iodide, tris(2-pyridylmethyl)amine and 2,4,6-trimethylpyridine, and the molar ratio of cuprous iodide, tris(2-pyridylmethyl)amine and 2,4,6-trimethylpyridine is 0.3:0.4:2;

[0033] The reaction temperature of the ring-closing reaction is 20-110℃.

[0034] Further, in step (c), the molar ratio of compound D and the chemical reagent in the reduction reaction is 1-2:14;

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

[0036] The chemical reagent in the reduction reaction is selected from one of borane, tris(triphenylphosphine)carbonylhydridocobalt, carbon bis(triphenylphosphine)chloro iridium, lithium borohydride and sodium borohydride;

[0037] The reaction temperature of the reduction reaction is 0-100℃.

[0038] Further, in step (d), the molar ratio of compound E and compound F in the catalytic reaction is 1:1.0-2.0;

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

[0040] The iron catalyst is selected from one of ferric chloride, iron oxalate and iron sulfate;

[0041] The reaction temperature of the catalytic reaction is 0-30℃.

[0042] Furthermore, when the compound represented by general formula (I) is selected from the compound represented by general formula (II), the synthetic equation for the above-mentioned vincristine derivative is as follows (the synthetic method is the same as described above in (a) to (d)):

[0043] The present invention also provides a method for treating cancer, comprising administering to a cancer patient an effective dose of the above-mentioned vincristine derivative or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

[0044] The present invention also provides an application of the above-mentioned vincristine derivatives or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics in the preparation of cancer treatment drugs.

[0045] Furthermore, the cancers include leukemia, lymphoma, lung cancer, liver cancer, breast cancer, and pancreatic cancer.

[0046] The beneficial effects of this invention are: the vinblastine derivatives synthesized in this invention exhibit significantly better antiproliferative activity against cancer cells such as acute myeloid leukemia than vinblastine. It is worth mentioning that derivatives G4, G5, G9, G10, G11, and G13 demonstrate antiproliferative activity at the picomolar level, making them suitable as toxin molecules for the development of antibody-drug conjugates, exhibiting excellent antitumor effects. Detailed Implementation

[0047] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings, but the scope of protection of the present invention is not limited to the following description.

[0048] Unless otherwise specified, all chemical reagents used in this invention were purchased directly from reagent companies, and all solvents were domestically produced analytical grade without any purification treatment. All anhydrous and oxygen-free operations in this invention were performed using the Schlenk technique under argon protection in single-row tubes. Solvent drying methods followed the guidelines in *Purification of Laboratory Chemicals* (Armarego, WLF, Elsevier: Oxford, 2017). Dichloromethane and acetonitrile were dehydrated by reflux with calcium hydride at atmospheric pressure. Tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether were dried using a sodium / benzophenone system. Toluene was dried by reflux with sodium. High-boiling-point solvents such as dimethyl sulfoxide and N,N-dimethylformamide were dehydrated by soaking in molecular sieves. Thin-layer chromatography (TLC) was performed using fluorescence, iodine staining, phosphomolybdic acid, and basic potassium permanganate. The 0.2mm, HSGF254 silica gel plates for TLC were purchased from Yantai Jiangyou Silica Gel Development Co., Ltd. The 200–300 mesh silica gel used in column chromatography was sourced from Anhui Liangchen Silicon Source Materials Co., Ltd.

[0049] NMR data were acquired using Bruker AC-E 400, Agilent DD2-600 / 54, and Varian INOVA-400 / 54 instruments, with deuterated chloroform as the solvent (7.26 ppm for 1H NMR and 77.0 ppm for 1C NMR), and tetramethylsilane (TMS) as the internal standard. In the NMR data, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, and m represents a multiplet. The coupling constant is expressed in J, in Hz. Infrared spectroscopy data were measured using a Perkin Elmer Spectrum Two FT-IR spectrometer. Optical rotation data were acquired using a Rudolph Research Analytical Autopol VI polarimeter. High-resolution mass spectrometry data were measured using a Bruker Apex IV FTMS or a Thermo Scientific LTQ Orbitrap XL ESI mass spectrometer. Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent Technologies 6420 Triple Quad LC / MS.

[0050] Example 1: Preparation of vincristine derivative G1

[0051] 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 hours, the reaction was quenched with saturated NH4Cl aqueous solution, extracted with dichloromethane (10 mL × 3), and backwashed with saturated sodium bicarbonate aqueous solution (15 mL × 2). The organic phases were combined, dried over anhydrous MgSO4, filtered, concentrated under reduced pressure, and the 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; 1H NMR (400 MHz, CDC13): 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); 13 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -43.6 (c = 0.30, CHCl3).

[0052] Compound C1 (149 mg, 0.334 mmol, 1.0 equiv.), tris(2-pyridylmethyl)amine (39.0 mg, 0.134 mmol, 0.4 equiv.) and cuprous 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), washed with 0.5 M HC1 solution (3 x 5 mL) and brine (5 mL) successively. The organic layer was dried over MgS04, filtered through celite and concentrated under reduced pressure. The resulting crude 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): Rf= 0.48;1H NMR (400 MHz, CDC13): 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). f 1 H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v​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: [a]25D= -6.4 (c = 0.16, CHCl3).

[0053] Borane dimethyl sulfide solution (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, and the mixture was heated to 30 °C and stirred for 1 h. Methanol (4.0 mL) and hydrochloric acid in methanol (5.4 mL, 4.0 M in MeOH) were added successively under ice-bath conditions. The resulting mixture was stirred at 35 °C for 6 h. Then, most of the solvent was removed by distillation under reduced pressure. Saturated aqueous sodium bicarbonate solution (10 ml) was added at 0 °C, and the pH was adjusted to 9-10. Then, it was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (25 mL), dried over anhydrous MgS04, 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 H NMR (400 MHz, CDC13): 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); 13C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +72.6 (c = 0.17, CHCl3).

[0054] Compound 2a (52.2 mg, 0.149 mmol, 1.0 equiv.), vindoline (68.0 mg, 0.149 mmol, 1.0 equiv.) and anhydrous ferric 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 hours. Then, a solution of sodium borohydride (5.63 mg, 0.149 mmol, 1.0 equiv.) in water (1.60 mL) was added dropwise under ice bath and kept at this temperature for 30 minutes. Then, 12 ml of concentrated ammonia (28% - 30%) was added to quench, extracted with a mixed solution of dichloromethane and methanol (DCM:MeOH = 10:1, 20 mL x 4), and the organic layer was washed 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 an intermediate anhydrovinblastine. This 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) (air was bubbled for 30 min), and 0.1 M hydrochloric acid solution was added under ice bath to adjust the pH to 3 - 4. A solution of sodium borohydride (114 mg, 1.0 mmol, 20.0 equiv.) in water (12.5 mL) was added dropwise slowly under ice bath, and after stirring for 30 min, 2 ml of concentrated ammonia (28% - 30%) was added to quench, and the pH was adjusted to 9 - 10, extracted with a mixed solution of dichloromethane and methanol (DCM:MeOH = 10:1, 400 mL x 4). The organic layer was washed 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): Rf = 0.45; f = 0.45; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +31.2 (c = 0.07, CHCl3).

[0055] Example 2 Preparation of Vinblastine Derivative G2

[0056] Reference is made to the method of preparation of Vinblastine Derivative G1.

[0057] Intermediate C2: Yield 90%; 1 H NMR (400 MHz, CDC13): δ 8.92 (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 = 15.5 Hz, 0.44H), 4.06 (d, J = 15.5 Hz, 0.56H), 3.89 (d, J = 2.9 Hz, 1H), 3.76 (s, 3H), 3.63 (d, J = 9.4 Hz, 0.56H), 3.55 (d, J = 11.5 Hz, 0.44H), 3.21 (dt, J = 9.4, 2.5 Hz, 0.56H), 3.11 (dt, J = 11.5, 2.5 Hz, 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 = 7.4 Hz, 1.68H), 0.89 (t, J = 7.4 Hz, 1.32H); 13 C NMR (100 MHz, CDC13): δ 171.21, 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): v 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: [a]25D= -49.3 (c = 1.2, CHCl3).

[0058] Intermediate D2: Yield 87%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= -20.0 (c = 0.25, CHCl3).

[0059] Intermediate E2: Yield 80%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= +78.8 (c = 0.19, CHCl3).

[0060] Vinblastine derivative G2: Yield 25%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +28.6 (c = 0.05, CHCl3).

[0061] Example 3 Preparation of Vinblastine Derivative G3

[0062] Reference is made to the synthesis of vinblastine derivative G1.

[0063] Intermediate C3: Yield 95%; 1 H NMR (400 MHz, CDC13): δ 8.54 (s, 1H), 7.09 - 6.98 (m, 1H), 6.92 (m, 2H), 6.49 (d, J = 7.7 Hz, 0.54H), 6.43 (d, J = 7.7 Hz, 0.46H), 6.01 (d, J = 5.2 Hz, 0.54H), 5.96 (d, J = 5.2 Hz, 0.46H), 5.78 (s, 0.46H), 5.10 (s, 0.54H), 4.67 (d, J = 15.5 Hz, 0.54H), 4.01 - 3.95 (m, 1H), 3.94 (d, J = 15.5 Hz, 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 = 9.4 Hz, 0.46H), 3.51 (d, J = 11.4 Hz, 0.54H), 3.19 (d, J = 9.4 Hz, 0.46H), 3.05 (d, J = 11.4 Hz, 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 = 7.4 Hz, 1.38H), 0.69 (t, J = 7.4 Hz, 1.62H); 13 C NMR (100 MHz, CDC13): δ 172.29, 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): v 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: [a]25D= -101 (c = 0.18, CHCl3).

[0064] Intermediate D3: Yield 86%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= -26.7 (c = 0.13, CHCl3).

[0065] Intermediate E3: Yield 81 %; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= +82.2 (c = 0.09, CHCl3).

[0066] Vincamine derivative G3: Yield 23 %; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +35.2 (c = 0.12, CHCl3).

[0067] Example 4 Preparation of Vinblastine Derivative G4

[0068] Reference is made to the synthesis of Vinblastine Derivative G1.

[0069] Intermediate C4: Yield 92%; 1 H NMR (400 MHz, CDC13): δ 8.23 (s, 1H), 7.59 (d, J = 7.8 Hz, 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 = 7.1 Hz, 1H), 5.77 (s, 0.46H), 4.91 (s, 0.54H), 4.14 (d, J = 15.6 Hz, 0.46H), 3.94 (d, J = 15.6 Hz, 0.54H), 3.80 - 3.70 (m, 1H), 3.76 (s, 1.38H), 3.74 (s, 1.62H), 3.58 (d, J = 9.2 Hz, 0.46H), 3.52 (d, J = 11.6 Hz, 0.54H), 3.12 (dt, J = 9.2, 2.7 Hz, 0.46H), 3.06 (dt, J = 11.6, 2.7 Hz, 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 = 7.4 Hz, 1.38H), 0.72 (t, J = 7.4 Hz, 1.62H); 13C NMR (100 MHz, CDC13): δ 170.58, 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): v max = 3267, 3058, 2961, 2930, 2874, 1737, 1626, 1424, 1259, 731 cm -1 ; HRMS (ESI): m / z calcd for C 21 H 22 FN2O3 + [M+H] + 369.1609, found 369.1606; optical rotation: [a]25D= -69.7 (c = 0.24, CHCI3).

[0070] Intermediate D4: Yield 85%; 1 H NMR (400 MHz, CDC13): δ 8.20 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.00 - 6.79 (m, 2H), 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), 3.60 - 3.49 (m, 1H)), 2.94 (d, J = 10.4 Hz, 1H), 2.88 (s, 1H), 2.66 (d, J = 13.1 Hz, 1H), 2.33 - 2.17 (m, 2H)), 1.72 (d, J = 11.9 Hz, 1H), 1.10 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -25.5 (c = 0.26, CHCI3).

[0071] Intermediate E4: Yield 79%; 1 H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): vmax = 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: [a]25D= +58.9 (c = 0.10, CHCl3).

[0072] Vincamine derivative G4: Yield 21%; 1 H NMR (400 MHz, CDC13): 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); 13C NMR (100 MHz, CDC13): δ 174.87, 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): v max = 3463, 2929, 2879, 1998, 1736, 1618, 1500, 1229, 1037, 733 cm -1 ; HRMS (ESI): m / z calcd for C 46 H 58 FN4O9 + [M+H] + 829.4183, found 829.4184; optical rotation: [a]25D= +10.0 (c = 0.10, CHCl3).

[0073] Example 5. Preparation of vinblastine derivative G5

[0074] The synthesis method of vinblastine derivative G1 was referred to.

[0075] Intermediate C5: Yield 92%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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).

[0076] Intermediate D5: Yield 84%; 1 H NMR (400MHz, CDCl3): δ8.10(s,1H),7.44(d,J=7.7Hz,1H),7.24(s,1H),7.09(d,J=7.7H z,1H),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),3.54(dd,J=10.4,2.9Hz,1H),2.94(d,J=10.4Hz,1H),2.89(br.s,1H),2 .67(d,J=13.1Hz,1H),2.36–2.12(m,2H),1.73(d,J=13.1Hz,1H),1.10(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.33,172.98,143.83,135.44,135.19,128.85,128.38,126.12,120.73,1 19.49,110.70,104.18,55.72,53.23,52.78,50.89,33.64,32.63,31.40,26.89,11.34;IR(neat):ν max =2922,2854,1741,1623,1453,1257,1193,1080,1017,795cm -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).

[0077] Intermediate E5: Yield 78%;1 H 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 C 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): v 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: [a]25D= +66.5 (c = 0.20, CHCl3).

[0078] Vincamine derivative G5: Yield 22%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +42.1 (c = 0.10, CHCl3).

[0079] Example 6 Preparation of Vinblastine Derivative G6

[0080] Reference is made to the synthesis of vinblastine derivative G1.

[0081] Intermediate C6: Yield 90%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v max = 3055, 2964, 1738, 1632, 1475, 1425, 1337, 1263, 846, 731 cm -1 ; HRMS (ESI): m / z calcd for C 21 H22 BrF2N2O3 + [M+H] + 467.0777, 469.0756, found 467.0772, 469.0753; optical rotation: [a]25D= -62.7 (c = 0.26, CHCl3).

[0082] Intermediate D6: Yield 84%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= -22.7 (c = 0.32, CHCl3).

[0083] Intermediate E6: Yield 78%; 1 H NMR (400 MHz, CDC13): 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, CDC13): 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): v 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: [a]25D= +28.6 (c = 0.22, CHCl3).

[0084] Vinblastine derivative G6: Yield 20%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +33.2 (c = 0.18, CHCl3).

[0085] Example 17 Preparation of Vinblastine Derivative G7

[0086] The synthesis of Vinblastine Derivative G1 was used as a reference.

[0087] Intermediate C7: Yield 88%; 1 H NMR (400 MHz, CDC13): δ 8.43 (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); 13C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -64.5 (c = 0.27, CHCl3).

[0088] Intermediate D7: Yield 97%; 1H NMR (400 MHz, CDC13): 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 C 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): v 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: [a]25D= -45.4 (c = 0.15, CHCl3).

[0089] Intermediate E7: Yield 87%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +22.4 (c = 0.15, CHCl3).

[0090] Vincamine derivative G7: Yield 22%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +33.8 (c = 0.08, CHCl3).

[0091] Example 8 Preparation of vinblastine derivative G8

[0092] Reference is made to the synthesis of vinblastine derivative G1.

[0093] Intermediate C8: Yield 87%; 1 H NMR (400 MHz, CDC13): 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); 13C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -60.5 (c = 0.43, CHCI3).

[0094] Intermediate D8: Yield 80%; 1 H NMR (400 MHz, CDC13): 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); 13C 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): v 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: [a]25D= -25.5 (c = 0.16, CHCl3).

[0095] Intermediate E8: Yield 81%; 1 H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= +20.1 (c = 0.32, CHCl3).

[0096] Vinblastine derivative G8: Yield 23%; 1 H NMR (400 MHz, CDC13): 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); 13C NMR (100 MHz, CDC13): 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): v max = 3346 1, 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: [a]25D= +31.4 (c = 0.14, CHCl3).

[0097] Example 9. Preparation of vinblastine derivative G9

[0098] The synthesis was performed according to the procedure described for vinblastine derivative Gl.

[0099] Intermediate C9: Yield 87%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -59.4 (c = 0.31, CHCl3).

[0100] 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): v 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: [a]25D= -38.5 (c = 0.20, CHCI3).

[0101] Intermediate E9: Yield 75%; 1 H NMR (400 MHz, CDCI3): δ 7.63 (s, 1 H), 6.72 (dd, J = 9.8, 5.8 Hz, 1 H), 5.98 - 5.88 (m, 1 H), 4.20 (s, 1 H), 4.03 (d, J = 2.1 Hz, 3 H), 3.73 (s, 3 H), 3.63 - 3.53 (m, 1 H), 3.51 - 3.41 (m, 1 H), 3.35 - 3.24 (m, 2 H), 2.93 - 2.77 (m, 2 H), 2.77 - 2.66 (m, 2 H), 2.40 - 2.25 (m, 1 H), 2.19 - 2.00 (m, 1 H), 1.77 (d, J = 10.8 Hz, 1 H), 1.06 (t, J = 7.3 Hz, 3 H); 13 C NMR (100 MHz, CDCI3): 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): v 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: [a]25D= +46.2 (c = 0.33, CHCI3).

[0102] Vinblastine derivative G9: Yield 21%; 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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): v 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: [a]25D= -34.2 (c = 0.14, CHCl3).

[0103] Example 10 Biological activity test

[0104] Acute myeloid leukemia cells MV-4-11, THP-1 were purchased from ATCC, OCI-AML2, OCI-AML3, MOLM-13 were purchased from Nanjing Kebai Biotechnology Co., Ltd. The cell culture medium was 1640 + 10% FBS, and the culture was carried out in a 37°C, 5% CO2 incubator. The anti-proliferative activity of the compound was evaluated by CCK-8 assay. A certain amount of cells were inoculated in a 96-well plate, then different concentrations of compounds were added, and incubated in an incubator for 24h. Add CCK-8 solution to 10% of the total volume of the culture medium in the well, mix well, and incubate in the incubator for 0.5-4h. The absorbance value at 450nm wavelength was read by a microplate reader. GraphPad prism 8.0 software was used to determine the linear regression parameters and calculate the IC 50 value.

[0105] The experimental results are shown in the following table:

[0106] IC 50 value of AML cell inhibition

[0107] The structures of the control compounds vinblastine and vincristine:

[0108] Conclusion: The vinblastine derivative of the present application has obvious anti-proliferative activity on acute myeloid leukemia cells MV-4-11, THP-1, OCI-AML2, OCI-AML3, MOLM-13, and its activity is stronger than that of the control compounds vinblastine and vincristine.

[0109] The above only describes the preferred embodiments of the present application, and it should be understood that the present application is not limited to the forms disclosed herein, and should not be considered as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the concepts described herein, by the above-mentioned teaching or related art or knowledge. Any modification and change made by those skilled in the art without departing from the spirit and scope of the present application should be within the protection scope of the appended claims of the present application.

Claims

1. A vinblastine derivative or a stereoisomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, characterized in that, said vinblastine derivative is selected from the group consisting of compounds of general formula (I), wherein each of R1, R2, R3, or R4is 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl 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 carbocyclyl, 4-6 membered heterocyclyl; and said R1, R2, R3, and R4are not simultaneously selected as H; R5is 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, which alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl 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 carbocyclyl, 4-6 membered heterocyclyl; R6is selected from H, deuterium, formyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl 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 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=O)NH2, C R7is 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl 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 carbocyclyl, 4-6 membered heterocyclyl; R8is selected from H, deuterium, halogen, OH, NH2, CN, C(=0)NH2, COOH, NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C(=0)C 1-6 alkyl, C(=0)-C 3-6 carbocyclyl, C(=0)-(4-6 membered heterocyclyl), OC(=0)C 1-6 alkyl, C(=0)OC 1-6 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C(=0)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl; R a , R b , or R c are 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 carbocyclyl, 4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with from 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 carbocyclyl, 4-6 membered heterocyclyl.

2. The vinblastine derivative according to claim 1, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, characterized in that, The compounds of general formula (I) are selected from the group consisting of compounds of general formula (II), R1, R2or R3are 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 carbocyclyl, C(=O)-(4-6 membered heterocyclyl), OC(=O)C 1-4 alkyl, C(=O)OC 1-4 alkyl, C 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl 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 carbocyclyl, 4-6 membered heterocyclyl; and R1, R2and R3are not simultaneously selected as H; 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 3-6 carbocyclyl, 4-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with from 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 carbocyclyl, 4-6 membered heterocyclyl.

3. The vinblastine derivative of claim 2, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein R1, R2or R3are each independently selected from the group consisting of 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, i-propyl, ethenyl, 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, pyridinyl, optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C(=O)OH, C(=O)OR 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl; and R1, R2and R3are not simultaneously selected as H; R a , R b , or R c are each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, COOH, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, said methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl being optionally substituted with from 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl, 4-6 membered heterocyclyl.

4. The vinblastine derivative of claim 3, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein R1, R2, or R3are each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, COOH, NH2, C(=O)NH2, OH, SH, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-i-propyl, 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, pyridinyl, optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2, CN, C(=O)NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl; and R1, R2, and R3are not simultaneously selected as H.

5. The vinblastine derivative of claim 4, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein R1, R2or R3are each 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, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, O-methyl, O-ethyl, O-n-propyl, O-i-propyl, 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, pyridinyl; and R1, R2and R3are not simultaneously selected as H.

6. The vinblastine derivative of claim 5, or a stereoisomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein: R1, R2or R3are each independently selected from H, F, Cl, Br, methyl, methoxy, ethyl, cyclopropyl, i-propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, or monofluoromethoxy, and R1, R2and R3are not simultaneously selected as H.

7. The vinblastine derivative of claim 6, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein The vinblastine derivative is selected from one of the following structures:

8. A process for the preparation of the vinblastine derivative of claim 1, characterized in that, when R5is selected from OH, including the step of: (a) Compound A and Compound B are condensed to obtain Compound C; (b) Compound C is prepared by a copper catalyst catalyzed ring-closing reaction to obtain Compound D; (c) Compound D is prepared by a reduction reaction to obtain Compound E; (d) Compound E and Compound F are reacted by an iron catalyst catalyzed reaction to obtain 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 of the condensation reaction is selected from one of dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, and tetrahydrofuran; the chemical reagent of the condensation reaction is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, trimethylacetyl 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 cuprous iodide, tris(2-pyridylmethyl)amine and 2,4,6-trimethylpyridine, and the molar ratio of cuprous 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 20-110°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 and the chemical reagent is 1-2:14; 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)carbonylhydridocobalt, carbon bis(triphenylphosphine)chloro iridium, lithium borohydride and sodium borohydride; The reaction temperature of the reduction reaction is 0-100°C.

12. The method of claim 8, wherein, In step (d), in the catalytic reaction, the molar ratio of compound E and compound F is 1:1.0-2.0; 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 ferric chloride, iron oxalate and iron sulfate; The reaction temperature of the catalytic reaction is 0-30°C.

13. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-12. The method comprises administering to a cancer patient an effective dose of the vinblastine derivative or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-6.

14. The method of treating cancer according to claim 13, wherein, The types of cancer include leukemia, lymphoma, lung cancer, liver cancer, breast cancer and pancreatic cancer. The types of cancer include leukemia, lymphoma, lung cancer, liver cancer, breast cancer and pancreatic cancer.

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