CN109879888A - A kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and application - Google Patents

A kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and application Download PDF

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CN109879888A
CN109879888A CN201910258529.6A CN201910258529A CN109879888A CN 109879888 A CN109879888 A CN 109879888A CN 201910258529 A CN201910258529 A CN 201910258529A CN 109879888 A CN109879888 A CN 109879888A
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staurosporine
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CN109879888B (en
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王立平
朱伟明
李明朋
许言超
左明星
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Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
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Abstract

The invention discloses a kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and applications；Such compound is reacted and is made by sulphur acylation reaction, with iodomethane salt-forming reaction, substitution reaction and dehydration cyclization with staurosporine or halogenated staurosporine；Compound disclosed in this invention has very strong selective inhibitory activity to the acute myelocytic cells strain MV4-11 that Flt3-ITD is mutated；It is weak to human peripheral blood mononuclear cell's PBMC inhibiting effect, the drug of the prevention and treatment leukaemia of high-efficiency low-toxicity can be developed as.

Description

A kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and application
Technical field
The invention belongs to drug fields, and in particular to a kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and Using.
Background technique
Cancer is first of the cause of the death of China's various diseases, and morbidity and mortality are also continuing to increase.According to statistics, 2015 There are 429.2 ten thousand cancer new cases, 281.4 ten thousand cancer mortality cases in year China, daily there are about 1.2 Wan Renxin cancer strickens, 0.75 ten thousand people die of cancer；Compared with 2010, Chinese cancer morbidity and the death rate have increased separately about 39% within 2015 With 44%, the 22% and 27% of global cancer new cases and death is accounted for respectively.Leukaemia is ten kinds of high-incidence cancers of China male One of disease, and disease incidence (W. Chen, R. Zheng, P. D. Baade, et al. Cancer in rising trend Statistics in China, 2015. CA:Cancer J. Clin. 2016,66:115-132).
The morbidity of acute leukemia is very fast, and patient is difficult to carry out bone-marrow transplantation in a short time, and drug therapy is that most have at present The method of effect.Wherein, acute myelogenous leukemia (Acute myeloid leukemia, AML) is a kind of myeloide white thin The leukemia of born of the same parents' abnormality proliferation.3 (the Fms-like Tyrosine of FMS sample tyrosine kinase of the AML patient's body of 17-34% Kinase-3, Flt3) height expression (AYH Leung, CH Man, YL Kwong. FLT3 inhibition:a moving and evolving target in acute myeloid leukaemia. Leukemia. 2013, 27: 260–268)。 Fu Ruide carbazole alkali first (Fradcarbazole A) is a kind of from Fei Shi streptomycete mutant strain (Streptomyces fradiae Micro indole carbazole Alkaloid (P Fu, YB Zhuang, the Y Wang, PP obtained in tunning 007M135) Liu, X. Qi, K. Gu, D. Zhang, WM Zhu. New Indolocarbazoles from a Mutant Strain of the Marine-Derived Actinomycete Streptomyces fradiae 007M135, Organic Letter. 2012,14:6194-6197)；The novelty of its structure and preferable tumor cytotoxic activity obtain Researcher's concern is obtained, applicant is by synthesizing Fu Ruide carbazole alkali first and its 3 analogues, 3 analogs Show preferable tumor cytotoxic activity and molecular targeted (PKC- β) inhibiting effect (LP Wang, XG Mei, C Wang, WM Zhu. Biomimetic semi-synthesis of fradcarbazole A and its analogues. Tetrahedron 2015,71:7990-7997).
The present invention synthesizes new Fu Ruide carbazole alkali Class A compound as skeleton using staurosporine.Staurosporine derivative rice Successful listing (2017 year April 28 day be approved by the FDA in the United States) of the appropriate woods of diindyl (midostaurin) as treatment AML, is established Such compound can be used as the basis of anti-leukemia medicine research and development.It therefore may using the compound that staurosporine is synthesized as skeleton There is strong inhibitory activity to acute myelocytic cells.
Summary of the invention
The object of the present invention is to provide a kind of Fu Ruide carbazole alkali Class A compound and preparation method thereof and the compounds The application being used to prepare in the drug of prevention or treatment leukaemia.
It the purpose of the present invention and solves its technical problem underlying and adopts the following technical solutions to realize: a kind of Fu Ruide Carbazole alkali Class A compound, the compound based on staurosporine or halogenated staurosporine be made, structural formula be (I) Formula:
(I)；
Wherein, R1 are as follows:-H or halogen, R2 are as follows:-H, halogen or methoxyl group；
The compound producing step include: sulphur acylation reaction, with iodomethane salt-forming reaction, substitution reaction and dehydration cyclization react, Specifically:
(1) R1When selected from-H, the preparation method comprises the following steps: staurosporine (Ia) is dissolved in methylene chloride, triethylamine is then added, and N, N '-thiocarbonyldiimidazole carries out sulphur acylation reaction；Then in acetonitrile solvent, compound (Ib) is obtained at salt with iodomethane；? Substitution reaction, which is carried out, with indolecthanamine in N,N-dimethylformamide solvent obtains compound (Ic)；In dichloromethane solvent, Fu Ruide carbazole alkali Class A compound (I) is obtained with dehydration cyclization is carried out under trifluoroacetic anhydride and ethyl alcohol effect；
(2) R1When selected from halogen, the preparation method comprises the following steps: by staurosporine in methanol or dichloromethane solvent with halogenated succinimide acyl Imines carries out halogenating reaction, obtains halogenated staurosporine；Halogenated staurosporine (Ia) is dissolved in methylene chloride again, three second are then added Amine, with N, N '-thiocarbonyldiimidazole carries out sulphur acylation reaction；Then in acetonitrile solvent, compound is obtained at salt with iodomethane (Ib)；Substitution reaction, which is carried out, with indolecthanamine in N,N-dimethylformamide solvent obtains compound (Ic)；In methylene chloride In solvent, Fu Ruide carbazole alkali Class A compound is obtained with dehydration cyclization is carried out under trifluoroacetic anhydride and ethyl alcohol effect, it is described Synthetic technology route is as shown in Figure 2.
The wherein R1Selected from-H, Cl, Br, R2Selected from-H, F, Cl, Br ,-OMe.
Application of the Fu Ruide carbazole alkali Class A compound in the drug of preparation prevention or treatment leukaemia.It is described Compound be used as drug when, can directly use or be used in the form of pharmaceutical composition, which contains 0.1-99% compound, remaining is pharmaceutical carrier or excipient.
The present invention has obvious advantages and beneficial effects compared with the existing technology.From the above technical scheme, this hair Bright compound has very strong selective inhibitory activity to the acute myelocytic cells strain MV4-11 that Flt3-ITD is mutated；To people Peripheral blood mononuclear cells PBMC inhibiting effect is weak；It can be developed as the drug of the prevention and treatment leukaemia of high-efficiency low-toxicity.
Detailed description of the invention
Fig. 1 is the structural diagrams of Fu Ruide carbazole alkali Class A compound.
Fig. 2 is synthesis Fu Ruide carbazole alkali Class A compound route.
Fig. 3 is the structural formula of compound 1-14.
Specific embodiment
The preparation of 1 compound 1 of embodiment
Under argon gas protection, 100 mL methylene chloride of staurosporine (1.86 g, 4.0 mmol) are dissolved, are added at room temperature 10 mL triethylamines andN,N'-thiocarbonyldiimidazole (1.3 g, 8.0 mmol), ambient temperature overnight reaction.Reaction solution pours into 100 In mL ice water, methylene chloride is extracted, and is concentrated after the dry organic phase of anhydrous sodium sulfate, silica gel column chromatography separation, methylene chloride: first Alcohol=20:1 (v/v) affords 3 '-N1.9 g of (the thio formyl of 1- imidazoles) staurosporine, yield 82%, ESI-MSm/z 599.2 [M + Na]+.Under argon gas protection, by 3 '-N(the thio formyl of 1- imidazoles) staurosporine (1.9 g, 3.30 mmol) It is dissolved in 200 mL acetonitriles, is added iodomethane (2.0 mL, 33.0 mmol), react at room temperature 24 hours.Reaction solution is directly dense Contracting, with 200 mL petroleum ethers: methylene chloride=4:1(v/v) mixed solution wash it is pure up to compound 3 '-N(1- imidazoles sulphur For formyl) 1.7 g of iodomethane salt of the imidazole fragment of staurosporine, yield 72%, ESI-MSm/z 591.2 [M - I]+。 Under argon gas protection, in 100 mL, two mouthfuls of reaction flasks, 400 mg 5- flutamines (2.25 mmol), 15 mL tetrahydro furans are added It mutters dissolution, is added 0.5 mL triethylamine, at 10 DEG C plus di-tert-butyl dicarbonate (488 mg, 2.25 mmol), 10 DEG C of reaction 1h, Water is added to terminate reaction, ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: acetic acid second Ester (v/v 3:1) elutes to obtain white powder productN[2- (3- (5- fluoro indole)) ethyl] t-butyl carbamate (486 mg, Yield 83%).1H NMR (400 MHz, DMSO-d 6) δ 10.91 (s, 1H, NH), 7.21-7.33 (m, 3H, ArH), 6.87-6.92 (m, 2H, ArH, NH), 3.14-3.19 (m, 2H, CH2), 2.76 (t, J = 7.4 Hz, 2H, CH2), 1.37 (s, 9H, 3×CH3); 13C NMR (100 MHz, DMSO-d 6) δ 156.6 (d, 1 J C-F = 230.6 Hz), 155.6, 132.9, 127.6 (d, 3 J C-F = 9.7 Hz), 124.8, 112.3 (d, 3 J C-F = 9.7 Hz), 112.2(d, 4 J C-F = 4.5 Hz), 109.0 (d, 2 J C-F = 25.2 Hz), 103.0 (d, 2 J C-F = 25.2 Hz),77.5, 40.8, 28.3 (3×C), 25.4; ESI-MS m/z 301.0 [M + Na]+.In 100 mL two In mouth reaction flask, it is addedN[2- (3- (5- fluoro indole)) ethyl] t-butyl carbamate (100 mg, 0.31 mmol) is with 11 mL THF/H2O (10:1) dissolution, DDQ(144 mg, 0.64 mmol are added at 0 DEG C), react 2 hours at this temperature, instead It answers liquid to pour into 100 mL ethyl acetate, colourless, ethyl acetate layer anhydrous sodium sulfate is washed till with saturated sodium bicarbonate solution It is concentrated after drying, silica gel column chromatography separation, petroleum ether: ethyl acetate (v/v 2:1) elutesN[2- oxygen subunit -2- (3- (5- Fluoro indole)) ethyl] t-butyl carbamate (70 mg, yield 67%).1H NMR (600 MHz, DMSO-d 6) δ 8.47 (s, 1H, ArH), 7.81-7.84 (m, 1H, ArH), 7.48-7.51 (m, 1H, ArH), 7.06-7.10 (m, 1H, ArH), 7.03 (t, J = 5.9 Hz, 1H, NH), 4.28 (d, J = 5.9 Hz, 2H, CH2), 1.40 (s, 9H, 3×CH3); 13C NMR (150 MHz, DMSO-d 6) δ 190.9, 158.6 (d, 1 J C-F = 235.5 Hz), 156.0, 134.9, 133.0, 126.0 (d, 3 J C-F = 10.8 Hz), 114.1(d, 4 J C-F = 4.0 Hz), 113.5 (d, 3 J C-F = 10.8 Hz), 111.1 (d, 2 J C-F = 26.0 Hz), 106.0 (d, 2 J C-F = 26.0 Hz),77.9, 46.8, 28.3 (3×C); ESI-MS m/z 315.0 [M + Na]+.It willN[2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl] t-butyl carbamate (300 mg, 0.95 mmol) dissolves with 5 mL trifluoroacetic acids, at 10 DEG C Reaction one hour, addition benzene (5 mL × 3 time) are azeotroped off trifluoroacetic acid and obtainN[2- oxygen subunit -2- (3- (5- fluorine Indoles)) ethyl] 185 mg of trifluoroacetic acid ammonium, yield 72%.3'-N(the thio formyl of 1- imidazoles) staurosporine imidazole fragment Iodomethane salt (121 mg, 0.17 mmol) is dissolved in 5 mL DMF, be added 0.5 mL triethylamine andN[2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl] trifluoroacetic acid ammonium (147 mg, 0.51 mmol), it reacts at room temperature 24 hours.Reaction solution is with 10 The dilution of mL ethyl acetate is concentrated after anhydrous sodium sulfate is dry with the salt pickling of 1N.Half preparation HPLC separation, MeOH:H2O =9:1 (v/v) affords 3 '-N-[N(2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl) aminothio formyl] cross spore 61 mg of alkali, yield 51%.1H NMR (600 MHz, DMSO-d 6) δ 12.15 (s, 1H, NH), 9.29 (d, J = 7.9 Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.06 (d, J = 7.7 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.94 (brs, 1H, NH), 7.85 (dd, J = 9.8, 2.4 Hz, 1H, ArH), 7.75 (d, J = 8.2 Hz, 1H, ArH), 7.48-7.54 (m, 3H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.31 (t, J = 7.4 Hz, 1H, ArH), 7.08-7.12 (m, 2H, ArH, H-1’), 5.92 (brs, 1H, H-3’), 4.95-5.05 (m, 4H, H-7, H-3’’), 4.53 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.87 (s, 3H, 4'-OCH3), 2.71-2.76 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.27-2.33 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 172.0, 158.6 (d, 1 J C-F = 233.5 Hz), 139.1, 136.4, 134.8, 133.0, 132.8, 129.1, 126.0 (d, 3 J C-F = 10.0 Hz), 125.7, 125.4, 125.1, 125.0, 123.8, 122.7, 121.5, 120.4, 119.5, 119.4, 115.3, 114.3 (d, 4 J C-F = 4.2 Hz), 114.2, 113.9, 113.5 (d, 3 J C-F = 10.0 Hz), 111.1 (d, 2 J C-F = 24.0 Hz), 109.2, 106.0 (d, 2 J C-F = 24.0 Hz), 95.0, 82.9, 82.4, 60.4, 54.3, 51.9, 45.5, 32.8, 29.6, 27.7; ESI-MS m/z 723.2 [M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, It is added 3 '-N-[N(2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl) aminothio formyl] and staurosporine (55 mg, 0.079 Mmol), 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol are added, are added 400 at 0 DEG CµL trifluoroacetic anhydride is reacted 1 hour Afterwards plus water terminates reaction, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9: 1 (v/v) affords 5 ' ' '-fluorine Fu Ruide carbazole alkali first (compound 1) 34 mg, yield 63%.1H NMR (600 MHz, DMSO-d 6) δ 11.46 (s, 1H, NH), 9.32 (d, J = 7.8 Hz, 1H, ArH), 8.62 (s, 1H, NH), 8.06 (d, J = 8.0 Hz, 1H, ArH), 8.02 (d, J = 8.0 Hz, 1H, ArH), 7.66-7.68 (m, 2H, ArH), 7.54-7.58 (m, 2H, ArH), 7.44-7.51 (m, 3H, ArH), 7.35 (t, J = 7.2 Hz, 1H, ArH), 7.31 (t, J = 7.3 Hz, 1H, ArH), 7.08 (t, J = 7.2 Hz, 1H, ArH), 7.04 (t, J = 8.4 Hz, 1H, H-1’), 4.96-5.01 (m, 3H, H-7, H-3’), 4.49 (s, 1H, H-4’), 2.89 (s, 3H, 3'-NCH3), 2.85-2.88 (m, 1H, H-2’a), 2.71 (s, 3H, 4'- OCH3), 2.43 (s, 3H, 6'-CH3), 2.38-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.9, 167.5, 157.4 (d, 1 J C-F = 232.7 Hz), 138.8, 136.3, 134.1, 133.2, 132.7, 129.3, 125.7, 125.4, 125.1, 125.0, 124.9 (d, 3 J C-F = 9.5 Hz), 124.9, 123.8, 122.7, 121.5, 120.4, 119.9, 119.5, 119.4, 115.2, 114.2, 113.6, 113.1 (d, 3 J C-F = 9.8 Hz), 110.1(d, 2 J C-F = 24.1 Hz), 109.0, 107.2 (d, 4 J C-F = 4.9 Hz), 104.0 (d, 2 J C-F = 24.1 Hz), 94.8, 82.5, 82.4, 60.2, 53.2, 45.5, 34.5, 29.3, 27.1; HRESI-MS m/z 683.2236 [M + H]+ (calcd for C39H32N6O3FS, 683.2235)。
The preparation of 2 compound 2 of embodiment
Under argon gas protection, in 100 mL, two mouthfuls of reaction flasks, 5- chloramine (300 mg, 1.55 mmol) are added with 15 mL tetra- The dissolution of hydrogen furans is added 0.5 mL triethylamine, adds di-tert-butyl dicarbonate (349 mg, 1.60 mmol) at 10 DEG C, and 10 DEG C anti- 1h is answered, water is added to terminate reaction, ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: second Acetoacetic ester (v/v 3:1) elutes to obtain white powder productN[2- (3- (5- chloro-indole)) ethyl] t-butyl carbamate (411 Mg, yield 90%).1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H, NH), 7.53 (d, J = 1.5 Hz, 1H, ArH), 7.24 (d, J = 8.6 Hz, 1H, ArH), 7.12 (dd, J = 8.6, 1.5 Hz, 1H, ArH), 7.00 (s, 1H, ArH), 4.65 (brs, 1H, NH), 3.35-3.44 (m, 2H, CH2), 2.88 (t, J = 6.4 Hz, 2H, CH2), 1.44 (s, 9H, 3×CH3); 13C NMR (150 MHz, CDCl3) δ156.0, 134.7, 128.5, 125.1, 123.4, 122.3, 118.3, 112.9, 112.2, 79.3, 41.0, 28.4(3×C), 25.6; ESI-MS m/z 317.0 [M + Na]+.In 100 mL, two mouthfuls of reaction flasks, it is addedN[2- (3- (5- chloro-indole)) Ethyl] 11 mL THF/H of t-butyl carbamate (380 mg, 1.29 mmol)2O (10:1) dissolves, and DDQ is added at 0 DEG C (586 mg, 2.58 mmol) react 2 hours at this temperature, and reaction solution pours into 100 mL ethyl acetate, uses saturated carbon Sour hydrogen sodium solution be washed till it is colourless, ethyl acetate layer with anhydrous sodium sulfate it is dry after be concentrated, silica gel column chromatography separation, petroleum ether: second Acetoacetic ester (v/v 1:1) elutesN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] t-butyl carbamate (268 mg, Yield 67%).1H NMR (600 MHz, DMSO-d 6) δ 12.16 (s, 1H, NH), 8.47 (s, 1H, ArH), 8.14 (s, 1H, ArH), 7.51 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.03 (t, J = 5.9 Hz, 1H, NH), 4.28 (d, J = 5.9 Hz, 2H, CH2), 1.40 (s, 9H, 3×CH3) ; 13C NMR (150 MHz, DMSO-d 6) δ 190.9, 156.0, 134.9, 134.7, 126.5, 126.5, 122.9, 120.2, 113.8, 113.5, 77.9, 46.8, 28.2(3×C); ESI-MS m/z 331.0 [M + Na ]+.It willN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] t-butyl carbamate (230 mg, 0.75 mmol) is with 5 ML trifluoroacetic acid dissolves, and reacts one hour at 10 DEG C, and addition benzene (5 mL × 3 time) is azeotroped off trifluoroacetic acid and obtainsN202 mg of [2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] trifluoroacetic acid ammonium, yield 88%.3'-N(1- imidazoles is thio Formyl) the iodomethane salt (200 mg, 0.28 mmol) of staurosporine imidazole fragment is dissolved in 5 mL DMF, triethylamine is added 0.5 mL andN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] trifluoroacetic acid ammonium (85 mg, 0.28 mmol), room temperature is anti- It answers 24 hours.Reaction solution is diluted with 10 mL ethyl acetate, with the salt pickling of 1N, is concentrated after anhydrous sodium sulfate is dry.Half Prepare HPLC separation, MeOH:H2O=9:1 (v/v) affords 3 '-N-[N(2- oxygen subunit -2- (3- (5- chloro-indole)) second Base) aminothio formyl] 81 mg of staurosporine, yield 40%.1H NMR (600 MHz, DMSO-d 6) δ 12.22 (s, 1H, NH), 9.30 (d, J = 7.9 Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.59 (s, 1H, ArH), 8.17 (d, J = 2.0 Hz, 1H, ArH), 8.05 (t, J = 10.3 Hz, 1H, ArH), 7.99 (t, J = 9.6 Hz, 1H, ArH), 7.95 (brs, 1H, NH), 7.74 (d, J = 8.3 Hz, 1H, ArH), 7.54 (d,J = 8.6 Hz, 1H, ArH), 7.47-7.50 (m, 2H, ArH), 7.36 (t, J = 7.5 Hz, 1H, ArH), 7.31 (t, J = 7.5 Hz, 1H, ArH), 7.26 (dd, J = 8.6, 2.0 Hz, 1H, ArH), 7.09 (t,J = 7.7 Hz, 1H, H-1’), 5.83 (brs, 1H, H-3’), 4.94-5.07 (m, 4H, H-7, H-3’’), 4.53 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.87 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.27-2.33 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.9, 139.1, 136.3, 134.9, 134.6, 132.7, 129.1, 126.6, 126.5, 125.7, 125.4, 125.0, 124.9, 123.8, 122.9, 122.7, 121.4, 120.3, 120.3, 119.5, 119.4, 115.3, 115.2, 114.2, 113.9, 113.8, 109.1, 95.0, 82.9, 82.3, 60.4, 54.3, 51.9, 45.5, 32.9, 29.5, 27.7; ESI-MS m/z 739.2 [M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, it is added 3 '-N-[N(2- oxygen subunit -2- (3- (5- chloro-indole)) second Base) aminothio formyl] staurosporine (60 mg, 0.084 mmol), 6 mL methylene chloride are added and 200 μ L ethyl alcohol are molten It solves, is added 400 at 0 DEG CµL trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, methylene chloride extraction, anhydrous sodium sulfate It is concentrated after drying, half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords 5 ' ' ' (change of-chlorine Fu Ruide carbazole alkali first Close object 2) 29 mg, yield 49%.1H NMR (600 MHz, DMSO-d 6) δ 11.57 (s, 1H, NH), 9.32 (d, J = 7.8 Hz, 1H, ArH), 8.63 (s, 1H, NH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.03 (d,J = 8.5 Hz, 1H, ArH), 7.80 (s, 1H, ArH), 7.68 (brs, 1H, ArH), 7.58 (brs, 1H, ArH), 7.47-7.51 (m, 3H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.32 (t, J = 7.5 Hz, 1H, ArH), 7.18-7.20 (m, 1H, ArH), 7.09 (t, J = 7.4 Hz, 1H , H-1’), 4.97- 5.01 (m, 3H, H-7, H-3’), 4.50 (s, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.85-2.90 (m, 1H, H-2’a), 2.71 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.39-2.43 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.9, 167.7, 138.7, 136.3, 135.0, 134.5, 132.7, 129.2, 125.9, 125.7, 125.4, 125.1, 125.0, 124.6, 124.3, 123.8, 122.7, 121.9, 121.5, 120.3, 119.5(2×C), 119.4, 118.2, 115.2, 114.1, 113.6 (2×C), 109.0, 106.8, 94.8, 82.5, 82.4, 60.2, 53.2, 45.4, 34.5, 29.2, 27.1; HRESI-MSm/z 699.1940[M + H]+ (calcd for C39H32N6O3ClS, 699.1940 )。
Embodiment 3: the preparation of compound 3
Under argon gas protection, in 100 mL, two mouthfuls of reaction flasks, 5- bromoamine (300 mg, 1.26 mmol) are added with 15 mL tetra- The dissolution of hydrogen furans is added 0.5 mL triethylamine, adds di-tert-butyl dicarbonate (285 mg, 1.31 mmol) at 10 DEG C, and 10 DEG C anti- 1h is answered, water is added to terminate reaction, ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: second Acetoacetic ester (v/v 3:1) elutes to obtain white powder productN[2- (3- (5- bromo indole)) ethyl] t-butyl carbamate (359 Mg, yield 84%).1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H, NH), 7.73 (d, J = 1.5 Hz, 1H, ArH), 7.27-7.30 (m, 1H, ArH), 7.25 (d, J = 8.6 Hz, 1H, ArH), 7.02 (s, 1H, ArH), 4.69 (brs, 1H, NH), 3.37-3.47 (m, 2H, CH2), 2.92 (t, J = 6.6 Hz, 2H, CH2), 1.48 (s, 9H, 3×CH3); 13C NMR (150 MHz, CDCl3) δ156.0, 135.0, 129.2, 124.8, 123.3, 121.4, 112.9, 112.6 (2×C), 79.3, 41.0, 28.4(3×C), 25.6; ESI- MS m/z 361.0 [M + Na]+.In 100 mL, two mouthfuls of reaction flasks, it is addedN[2- (3- (5- bromo indole)) ethyl] amino 11 mL THF/H of t-butyl formate (100 mg, 0.296 mmol)2O (10:1) dissolves, and DDQ(134 mg is added at 0 DEG C, 0.592 mmol), it reacts 2 hours at this temperature, reaction solution pours into 100 mL ethyl acetate, molten with saturated sodium bicarbonate Liquid be washed till it is colourless, ethyl acetate layer with anhydrous sodium sulfate it is dry after be concentrated, silica gel column chromatography separation, petroleum ether: ethyl acetate (v/v 1:1) is elutedN[2- oxygen subunit -2- (3- (5- bromo indole)) ethyl] t-butyl carbamate (61 mg, yield 58%)。1H NMR (600 MHz, DMSO-d 6) δ 8.45 (s, 1H, ArH), 8.30 (d, J = 1.5 Hz, 1H, ArH), 7.46 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.6, 1.5 Hz, 1H), 7.03 (t, J = 5.9 Hz, 1H, NH), 4.29 (d, J = 5.9 Hz, 2H, CH2), 1.40 (s, 9H, 3×CH3); 13C NMR (150 MHz, DMSO-d 6) δ 190.9, 156.0, 135.1, 134.5, 127.2, 125.4, 123.3, 114.6, 114.3, 113.4, 77.9, 46.8, 28.2(3×C); ESI-MS m/z 375.0 [M + Na]+.It willN[2- oxygen is sub- Base -2- (3- (5- bromo indole)) ethyl] t-butyl carbamate (61 mg, 0.17 mmol) 5 mL trifluoroacetic acids dissolution, It is reacted one hour at 10 DEG C, addition benzene (5 mL × 3 time) is azeotroped off trifluoroacetic acid and obtainsN[2- oxygen subunit -2- (3- (5- bromo indole)) ethyl] 56 mg of trifluoroacetic acid ammonium, yield 94%.3'-N(the thio formyl of 1- imidazoles) staurosporine imidazoles portion Point iodomethane salt (185 mg, 0.26 mmol) be dissolved in 5 mL DMF, be added 0.5 mL of triethylamine andN[2- oxygen is sub- Base -2- (3- (5- bromo indole)) ethyl] trifluoroacetic acid ammonium (180 mg, 0.52 mmol), it reacts at room temperature 24 hours.Reaction solution It is diluted with 10 mL ethyl acetate, with the salt pickling of 1N, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3 '-N-[N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio first Acyl] 91 mg of staurosporine, yield 46%.1H NMR (600 MHz, DMSO-d 6) δ 12.22 (s, 1H, NH), 9.29 (d, J = 7.9 Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.56 (s, 1H, ArH), 8.31 (s, 1H, ArH), 8.05 (d, J = 7.7 Hz, 1H, ArH), 8.00 (d, J = 8.5 Hz, 1H, ArH), 7.95 (brs, 1H, NH), 7.74 (d, J = 8.3 Hz, 1H, ArH), 7.48-7.50 (m, 3H, ArH), 7.35- 7.38 (m, 2H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.08 (t, J = 7.7 Hz, 1H, H- 1’), 5.90 (brs, 1H, H-3’), 4.92-5.06 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H- 4’), 2.94 (s, 3H, 3'-NCH3), 2.87 (s, 3H, 4'-OCH3), 2.70-2.74 (m, 1H, H-2’a), 2.35 (s, 3H, 6'-CH3), 2.26-2.32 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.3, 182.5, 172.0, 139.1, 136.4, 135.2, 134.5, 132.8, 129.1, 127.3, 125.7, 125.5, 125.4, 125.1, 124.9, 123.8, 123.3, 122.7, 121.5, 120.4, 119.5, 119.4, 115.3, 114.6, 114.4, 114.2, 113.9, 113.7, 109.2, 95.0, 82.9, 82.4, 60.5, 54.3, 51.9, 45.5, 32.9, 29.7, 27.7; ESI-MS m/z 783.2[M + Na]+.Under argon gas protection, In 25 two mouthfuls of mL reaction flasks, it is added 3 '-N-[N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio formyl] ten Word spore alkali (42 mg, 0.055 mmol) is added 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol, is added 400 at 0 DEG CµL Trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords 5 ' ' '-bromine Fu Ruide carbazole alkali first (compound 3) 28 mg, yield 69%。1H NMR (600 MHz, DMSO-d 6) δ 11.58 (s, 1H, NH), 9.32 (d, J = 3.0 Hz, 1H, ArH), 8.62 (s, 1H, NH), 8.06 (d, J = 7.4 Hz, 1H, ArH), 8.02 (d, J = 7.9 Hz, 1H, ArH), 7.93 (s, 1H, ArH), 7.65-7.68 (m, 2H, ArH), 7.56 (s, 1H, ArH), 7.46- 7.51 (m, 2H, ArH), 7.43 (d, J = 8.5 Hz, 1H, ArH), 7.35 (t, J = 6.3 Hz, 1H, ArH), 7.29-7.32 (m, 2H, ArH), 7.09 (brs, 1H, H-1’), 4.98-5.01 (m, 3H, H-7, H- 3’), 4.49 (s, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.85-2.90 (m, 1H, H-2’a), 2.71 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.38-2.43 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.9, 167.8, 138.7, 136.3, 135.2, 134.5, 132.7, 129.2, 126.6, 125.7, 125.4, 125.1, 125.0, 124.5, 124.4, 123.8, 122.7, 121.5, 121.2, 120.3, 119.5, 119.4 (2×C), 115.2, 114.2, 114.0, 113.5, 112.3, 109.0, 106.6, 94.8, 82.5, 82.4, 60.2, 53.2, 45.4, 34.5, 29.2, 27.1; HRESI-MS m/z 743.1432 [M + H]+ (calcd for C39H32N6O3BrS, 743.1434)。
The preparation of 4 compound 4 of embodiment
Under argon gas protection, in 100 mL, two mouthfuls of reaction flasks, 5- methoxytryptamine (1.0 g, 5.26 mmol) are added with 15 mL Tetrahydrofuran dissolution is added 1.5 mL triethylamines, adds di-tert-butyl dicarbonate (1.37 g, 6.32 mmol) at 10 DEG C, and 10 DEG C 1h is reacted, water is added to terminate reaction, ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: Ethyl acetate (v/v 5:1) elutes to obtain white powder productN[2- (3- (5- methoxy-Indole)) ethyl] t-butyl carbamate (1.51 g, yield 99%).1H NMR (600 MHz, CDCl3) δ 8.18 (s, 1H, NH), 7.27 (d, J = 8.8 Hz, 1H, ArH), 7.06 (s, 1H, ArH), 7.01 (s, 1H, ArH), 6.89 (dd, J = 8.8, 1.5 Hz, 1H, ArH), 4.61 (brs, 1H, NH), 3.89 (s, 3H, OMe), 3.46-3.50 (m, 2H, CH2), 2.94 (t, J = 6.4 Hz, 2H, CH2), 1.46 (s, 9H, 3×CH3); 13C NMR (150 MHz, CDCl3) δ 156.0, 154.0, 131.5, 127.7, 122.8, 112.8, 112.3, 111.9, 100.6, 79.1, 55.9, 40.7, 28.4(3×C), 25.8; ESI-MS m/z 313.1 [M + Na]+.In 100 mL, two mouthfuls of reaction flasks, it is addedN[2- (3- (5- methoxy-Indole)) ethyl] 55 mL THF/H of t-butyl carbamate (1.3 g, 4.48 mmol)2O (10:1) dissolves, and DDQ(2.0 g, 8.96 mmol are added at 0 DEG C), it reacts 2 hours at this temperature, reaction solution pours into 100 In mL ethyl acetate, be washed till with saturated sodium bicarbonate solution it is colourless, ethyl acetate layer with anhydrous sodium sulfate it is dry after be concentrated, silicon Plastic column chromatography separation, petroleum ether: ethyl acetate (v/v 1:1) elutesN[2- oxygen subunit -2- (3- (5- methoxy-Indole)) Ethyl] t-butyl carbamate (1.1 g, yield 81%).1H NMR (600 MHz, DMSO-d 6) δ 11.86 (brs, 1H, NH), 8.33 (d, J =3.1 Hz, 1H, ArH), 7.67 (d, J = 2.5 Hz, 1H, ArH), 7.37 (d, J = 8.8 Hz, 1H), 6.97 (t, J = 5.9 Hz, 1H, NH), 6.85 (dd, J = 8.8, 2.5 Hz, 1H), 4.26 (d, J = 5.9 Hz, 2H, CH2), 3.78 (s, 3H, OMe), 1.41 (s, 9H, 3×CH3);13C NMR (150 MHz, DMSO-d 6) δ 190.7, 156.0, 155.4, 133.4, 131.2, 126.2, 113.8, 112.9, 112.7, 102.9, 77.8, 55.2, 46.7, 28.3(3×C); ESI-MS m/z 327.1 [M + Na ]+.It willN[2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl] t-butyl carbamate (1.1 g, 3.62 mmol) is used 10 mL trifluoroacetic acids dissolve, and react one hour at 10 DEG C, and benzene (5 mL × 3 time) are added and are azeotroped off trifluoroacetic acid to obtain the final product It arrivesN0.9 g of [2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl] trifluoroacetic acid ammonium, yield 83%.3'-N(1- miaow The thio formyl of azoles) the iodomethane salt (200 mg, 0.28 mmol) of staurosporine imidazole fragment is dissolved in 5 mL DMF, is added 0.5 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl] trifluoroacetic acid ammonium (169 mg, 0.56 Mmol), it reacts at room temperature 24 hours.Reaction solution is diluted with 10 mL ethyl acetate, with the salt pickling of 1N, anhydrous sodium sulfate It is concentrated after drying.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3 '-N-[N(2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl) aminothio formyl] 96 mg of staurosporine, yield 48%.1H NMR (600 MHz, DMSO-d 6) δ 11.93 (d, J = 3.0 Hz, 1H, NH), 9.30 (d, J = 8.0 Hz, 1H, ArH), 8.63 (s, 1H, NH), 8.45 (d, J = 3.0 Hz, 1H, ArH), 8.06 (d, J = 7.8 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.90 (brs, 1H, NH), 7.74 (d, J = 8.3 Hz, 1H, ArH), 7.70 (d, J = 2.5 Hz, 1H, ArH), 7.46-7.51 (m, 2H, ArH), 7.41 (d, J = 8.8 Hz, 1H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.31 (t, J = 7.5 Hz, 1H, ArH), 7.10 (t, J = 7.6 Hz, 1H, H-1’), 6.87 (dd, J = 8.8, 2.5 Hz, 1H, ArH), 5.94 (brs, 1H, H-3’), 4.94-5.05 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H-4’), 3.79 (s, 3H, 5’’’-OMe), 2.96 (s, 3H, 3'-NCH3), 2.85 (s, 3H, 4'-OCH3), 2.71-2.76 (m, 1H, H-2’a), 2.37 (s, 3H, 6’-CH3), 2.27-2.30 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.0, 182.4, 172.0, 155.5, 139.0, 136.4, 133.5, 132.8, 131.3, 129.2, 126.3, 125.7, 125.4, 125.0, 125.0, 123.8, 122.7, 121.5, 120.4, 119.5, 119.4, 115.3, 114.2, 114.0, 113.9, 113.0, 112.7, 109.2, 102.9, 95.0, 83.0, 82.4, 60.4, 55.3, 54.3, 51.9, 45.5, 32.8, 29.5, 27.7; ESI-MS m/z 735.2[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, it is added 3 '-N-[N(2- oxygen subunit -2- (3- (5- methoxyl group Yin Diindyl)) ethyl) aminothio formyl] staurosporine (38 mg, 0.053 mmol), 6 mL methylene chloride and 200 are addedµL Ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, and methylene chloride extraction is anhydrous It is concentrated after sodium sulphate is dry, half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords 5 ' '-methoxyl group Fu Ruide click 30 mg of azoles alkali first (compound 4), yield 79%.1H NMR (600 MHz, DMSO-d 6) δ 11.23 (s, 1H, NH), 9.31 (d, J = 8.0 Hz, 1H, ArH), 8.65 (s, 1H, NH), 8.06 (d, J = 7.7 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.67 (d, J = 8.2 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.53 (d, J = 2.0 Hz, 1H, ArH), 7.45-7.51 (m, 2H, ArH), 7.30-7.36 (m, 3H, ArH), 7.26 (brs, 1H, ArH), 7.07-7.10 (m, 1H, H-1’), 6.84 (dd, J = 8.8, 2.0 Hz, 1H, ArH), 5.02 (s, 2H, H-7), 4.97 (d, J = 12.2 Hz, 1H, H-3’), 4.50 (brs, 1H, H-4’), 3.84 (s, 3H, 5’’’-OMe), 2.91 (s, 3H, 3'-NCH3,), 2.84- 2.89 (m, 1H, H-2’a), 2.70 (s, 3H, 4’-OMe), 2.44 (s, 3H, 6’-CH3), 2.38-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 172.0, 167.3, 154.0, 138.8, 136.3, 133.7, 132.7, 131.6, 129.3, 125.9,125.8, 125.4, 125.2, 125.0, 123.8, 123.6, 122.7, 121.5, 120.7, 120.4, 119.6, 119.5, 115.2, 114.2, 113.6, 112.8, 112.1, 109.1, 106.7, 100.8, 94.8, 82.5, 82.4, 60.2, 55.4, 53.3, 45.5, 34.5, 29.3, 27.1; HRESI-MS m/z 695.2433 [M + H]+ (calcd for C40H35N6O4S, 695.2435)。
The preparation of 5 compound 5 of embodiment
Under argon gas protection, in 100 mL, two mouthfuls of reaction flasks, tryptamines (200 mg, 1.25 mmol) are added with 15 mL tetrahydro furans It mutters dissolution, is added 0.5 mL triethylamine, at 10 DEG C plus di-tert-butyl dicarbonate (301 mg, 1.38 mmol), 10 DEG C of reaction 1h, Water is added to terminate reaction, ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, petroleum ether: acetic acid second Ester (v/v 3:1) elutes to obtain white powder productN[2- (3- indoles) ethyl] t-butyl carbamate (250 mg, yield 77%), ESI-MSm/z 261.3 [M + H]+.In 100 mL, two mouthfuls of reaction flasks, it is addedN[2- (3- indoles) ethyl] ammonia 11 mL THF/H of base t-butyl formate (250 mg, 0.96 mmol)2O (10:1) dissolves, and DDQ(436 is added at 0 DEG C Mg, 1.92 mmol), it reacts 2 hours at this temperature, reaction solution pours into 100 mL ethyl acetate, with unsaturated carbonate hydrogen Sodium solution be washed till it is colourless, ethyl acetate layer with anhydrous sodium sulfate it is dry after be concentrated, silica gel column chromatography separation, petroleum ether: acetic acid second Ester (v/v 1:1) elutesN[2- oxygen subunit -2- (3- indoles) ethyl] t-butyl carbamate (170 mg, yield 64%), ESI-MS m/z 297.0 [M + Na]+.It willN[2- oxygen subunit -2- (3- bromo indole) ethyl] t-butyl carbamate (170 Mg, 0.62 mmol) it is dissolved with 5 mL trifluoroacetic acids, it is reacted one hour at 10 DEG C, benzene (5 mL × 3 time) azeotropic is added Trifluoroacetic acid is removed to obtainN158 mg of [2- oxygen subunit -2- (3- indoles) ethyl] trifluoroacetic acid ammonium, yield 93%.Argon gas Under protection, in 100 mL, two mouthfuls of reaction flask, 2.33 g staurosporines (5.0 mmol) is added and is dissolved with 50 mL tetrahydrofurans, 2 mL triethylamines are added, are added at 0 DEG C 1.3 g di-tert-butyl dicarbonates (6.0 mmol), 0 DEG C of 30 min of reaction adds water to terminate Reaction, methylene chloride extraction are concentrated after anhydrous sodium sulfate is dry, silica gel column chromatography separation, methylene chloride: methanol (v/v 30: 1) 3'- is affordedNTertbutyloxycarbonyl staurosporine 2.18g, yield 76%.1H NMR (600 MHz, DMSO-d 6) δ 9.32 (d, J = 7.9 Hz, 1H, ArH), 8.62 (s, 1H, NH), 7.99-8.08 (m, 2H, ArH), 7.64 (d, J = 8.2 Hz, 1H, ArH), 7.46-7.51 (m, 2H, ArH), 7.29-7.37 (m, 2H, ArH), 7.00 (t, J = 7.6 Hz, 1H, H-1’), 5.01 (s, 2H, H-7), 4.48-4.65 (m, 1H, H-3’), 4.28 (s, 1H, H-4’), 2.72-2.83 (m, 4H, 3'-NCH3, H-2’a), 2.64 (s, 3H, 4'-OCH3), 2.34 (s, 3H, 6'-CH3), 2.14-2.21 (m, 1H, H-2’b), 1.57/1.46 (s, 9H, 3×4’’-CH3) ;13C NMR (125 MHz, DMSO-d 6) δ 171.9, 154.9/154.2, 139.0/138.8, 136.2, 132.7, 129.1, 125.7, 125.3, 124.9(2×C), 123.7, 122.6, 121.4, 120.3, 119.5, 119.4, 115.2, 114.1, 113.7, 108.9, 94.6, 84.0/83.3, 82.2, 79.6/79.3, 60.5, 50.5/ 49.7, 45.4, 30.1, 29.5, 28.1(3×C), 27.0; ESI-MS m/z 589.2[M + Na]+.Argon gas protection Under, in 100 mL, two mouthfuls of reaction flasks, 3'-NTertbutyloxycarbonyl staurosporine (2.0 g, 3.54 mmol), with 30 mL bis- Chloromethanes/methanol (1:1) dissolution, is added chlorosuccinimide (745 mg, 5.6 mmol) at room temperature, anti-at a temperature of this It answers 6 hours, adds water to terminate reaction, methylene chloride extraction, and use anhydrous Na2SO4It is dry, evaporated in vacuo, silica gel column chromatography point From methylene chloride: methanol (v/v 30:1) obtains 3- chloro- 3 '-NTertbutyloxycarbonyl staurosporine (1.03 g, yield 48%)。1H NMR (400 MHz, DMSO-d 6) δ 9.32 (d, J = 2.0 Hz, 1H, ArH), 8.70 (s, 1H, NH), 8.01-8.10 (m, 2H, ArH), 7.70 (d, J = 8.0 Hz, 1H, ArH), 7.47-7.53 (m, 2H, ArH), 7.35 (t, J = 8.0 Hz, 1H, ArH), 7.01 (t, J = 7.6 Hz, 1H, H-1’), 5.01 (s, 2H, H-7), 4.44-4.62 (m, 1H, H-3’), 4.27 (brs, 1H, H-4’), 2.76 (s, 3H, 3'- NCH3), 2.60-2.68 (m, 4H, 4'-OCH3, H-2’a), 2.33 (s, 3H, 6'-CH3), 2.11-2.20 (m, 1H, H-2’b), 1.56/1.45 (m, 9H, 3×4’’-CH3); 13C NMR (100 MHz, DMSO-d 6) δ 171.8, 154.9/154.2, 138.8, 134.6, 133.2, 128.9, 125.7, 125.2, 125.1, 124.6, 123.8, 123.7, 123.6, 121.6, 120.5, 119.4, 114.6, 114.2, 113.9/113.8, 110.7, 94.7, 83.9/83.2, 82.3, 79.7/79.4, 60.5, 50.4/49.6, 45.6, 30.2, 29.5, 28.1(3×C), 27.0; ESI-MS m/z 623.3[M + Na]+.In 100 mL, two mouthfuls of reaction flasks, 3- chloro- 3 '-is addedNTertbutyloxycarbonyl Staurosporine (1.03 g, 1.72 mmol) is dissolved with 10 mL methylene chloride.0 DEG C of 8 mL trifluoroacetic acid of addition, at a temperature of this Reaction 1 hour, be added after concentration 50 mL saturated sodium bicarbonate aqueous solutions stir 0.5 hour, after be extracted with dichloromethane, it is anhydrous It is concentrated after sodium sulphate is dry, silica gel column chromatography separation, methylene chloride: ethyl acetate (v/v 5:1) affords 3- chlorine cross spore Alkali (800 mg, yield 93%).1H NMR (600 MHz, DMSO-d 6) δ 9.32 (d, J = 2.1 Hz, 1H, ArH), 8.61 (s, 1H, NH), 7.96-7.99 (m, 2H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH), 7.46 (dd, J = 8.0, 2.0 Hz, 1H, ArH), 7.42 (t, J = 8.0 Hz, 1H, ArH), 7.28 (t, J = 8.0 Hz, 1H, ArH), 6.69-6.71 (m, 1H, H-1’), 4.96 (s, 2H, H-7), 4.05 (d, J = 3.5 Hz, 1H, H-3’), 3.85-3.87 (m, 1H, H-4’), 3.34 (s, 3H, 4'-OCH3), 3.23-3.26 (m, 1H, H-3’), 2.47-2.52 (m, 1H, H-2’a), 2.28-2.32 (m, 4H, H-2’b, 3'-NCH3), 1.42 (s, 3H, 6’-CH3); 13C NMR (150 MHz, DMSO-d 6) δ 172.1, 139.5, 134.7, 132.5, 129.9, 127.6, 124.5(2×C), 124.4, 123.7, 123.5, 123.3, 120.9, 119.8, 118.7, 115.4, 113.9, 113.0, 110.0, 91.1, 82.7, 80.0, 57.2, 49.8, 45.5, 33.2, 29.7, 29.3; ESI-MS m/z 523.2[M + Na]+.By 20 mL dichloros of 3- chlorine staurosporine (470 mg, 0.94 mmol) Methane dissolution, is added 2 mL triethylamines and N, N '-thiocarbonyldiimidazole (502 mg, 2.82 mmol), ambient temperature overnight at room temperature Reaction.Reaction solution pours into 20mL ice water, methylene chloride extraction, is concentrated after the dry organic phase of anhydrous sodium sulfate, silica gel column chromatography Separation, methylene chloride: methanol=30:1 (v/v) affords 3- chloro- 3 '-N410 mg of (the thio formyl of 1- imidazoles) staurosporine, Yield 71%.1H NMR (600 MHz, DMSO-d 6) δ 9.34 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.11 (s, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.03 (d, J = 8.3 Hz, 1H, ArH), 7.51-7.68 (m, 4H, ArH), 7.38 (t, J = 7.4 Hz, 1H, ArH), 7.14 (brs, 1H, ArH), 7.05 (brs, 1H, H-1’), 5.46 (brs, 1H, H-3’), 5.01 (s, 2H, H-7), 4.78 (brs, 1H, H-4’), 3.03-3.07 (m, 4H, 3’-NCH3, H-2’a), 2.70 (s, 3H, 4’-OMe), 2.39-2.46 (m, 4H, 6’-CH3, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 179.4, 171.8, 138.8, 137.7, 134.6, 133.1, 129.1, 129.0, 126.0, 125.5, 125.2, 124.7, 123.9, 123.8, 123.7, 121.7, 120.7, 119.9, 119.6, 114.8, 114.3, 113.5, 110.6, 94.9, 82.0, 81.7, 60.4, 58.2, 45.6, 38.2, 29.4, 27.0; ESI-MS m/z 633.0[M +Na]+.By 3- chloro- 3 '-N-(1- The thio formyl of imidazoles) staurosporine (360 mg, 0.59 mmol) is dissolved in 10 mL acetonitriles, 0.5 mL of iodomethane, room is added Temperature reaction 24 hours.Reaction solution is directly concentrated, with 50mL petroleum ether: methylene chloride=4:1(v/v) mixed solution wash it is pure i.e. Obtain 3- chloro- 3 '-N300 mg of iodomethane salt of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment, yield 68%.1H NMR (600 MHz, DMSO-d 6) δ 9.69 (s, 1H, ArH), 9.35 (d, J = 1.8 Hz, 1H, ArH), 8.73 (s, 1H, NH), 8.14 (brs, 1H, ArH), 8.10 (d, J = 7.7 Hz, 1H, ArH), 8.07 (d, J = 8.3 Hz, 1H, ArH), 7.87 (brs, 1H, ArH), 7.69 (d, J = 8.0 Hz, 1H, ArH), 7.52- 7.55 (m, 2H, ArH), 7.39 (t, J = 7.5 Hz, 1H, ArH), 7.19 (brs, 1H, H-1’), 5.45 (d, J = 11.3 Hz, 1H, H-3’), 5.02 (s, 2H, H-7), 4.75 (s, 1H, H-4’), 3.90 (s, 3H, 5’’-NCH3), 3.05-3.11 (m, 4H, 3’-NCH3, H-2’a), 2.69 (s, 3H, 4’-OMe), 2.43- 2.48 (m, 4H, 6’-CH3, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 174.3, 171.7, 138.7, 138.0, 134.6, 133.1, 129.1, 126.0, 125.5, 125.2, 124.7, 123.9, 123.8, 123.7(2 ×C), 121.8, 121.2, 120.7, 119.6, 114.8, 114.3, 113.5, 110.6, 94.7, 81.9, 81.2, 60.5, 59.1, 45.6, 38.5, 36.5, 29.2, 26.7; ESI-MS m/z 625.3[M-I]+.3- is chloro- 3’-NThe iodomethane salt (280 mg, 0.37 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is dissolved in 10 mL In DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- indoles) ethyl] trifluoroacetic acid ammonium (200 mg, 0.74 Mmol), it reacts at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the salt pickling of 1N, anhydrous sodium sulfate It is concentrated after drying.Silica gel column chromatography separation, petroleum ether: ethyl acetate=1:1 (v/v) affords 3- chloro- 3 '-N-[N(2- oxygen Subunit -2- (3- indoles) ethyl) aminothio formyl] 130 mg of staurosporine, yield 49%.1H NMR (600 MHz, DMSO-d 6) δ 12.03 (s, 1H, NH), 9.33 (d, J = 2.0 Hz, 1H, ArH), 8.70 (s, 1H, NH), 8.50 (d, J = 1.7 Hz, 1H, ArH), 8.18 (d, J = 7.3 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.92 (brs, 1H, NH), 7.79 (d, J = 8.7 Hz, 1H, ArH), 7.49-7.53 (m, 3H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.20-7.25 (m, 2H, ArH), 7.10 (t, J = 7.7 Hz, 1H, H-1’), 5.92 (brs, 1H, H-3’), 4.97-5.08 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H-4’), 2.96 (s, 3H, 3'- NCH3), 2.85 (s, 3H, 4'-OCH3), 2.71-2.76 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26-2.32 (m, 1H, H-2’b); 13C NMR (150MHz, DMSO-d 6) δ 190.0, 182.4, 171.8, 139.1, 136.4, 134.7, 133.3, 133.2, 128.9, 125.8, 125.4, 125.3, 125.1, 124.5, 123.8, 123.7(2×C), 122.9, 121.8, 121.5, 121.2, 120.5, 119.4, 114.7, 114.2, 114.1, 113.9, 112.2, 110.9, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.8, 29.5, 27.6; ESI-MS m/z 739.2[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- is added Chloro- 3 '-N-[N(2- oxygen subunit -2- (3- indoles) ethyl) aminothio formyl] staurosporine (61 mg, 0.085 mmol), 6 mL methylene chloride and 200 are addedµL ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride adds water after reaction 1 hour Reaction is terminated, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1(v/v) Afford 3- chlorine Fu Ruide carbazole alkali first (compound 5) 43 mg, yield 73%.1H NMR (600 MHz, DMSO-d 6) δ 11.36 (s, 1H, NH), 9.35 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 8.6 Hz, 1H, ArH), 7.82 (d, J = 7.8 Hz, 1H, ArH), 7.2 (d, J = 7.8 Hz, 1H, ArH), 7.58 (brs, 1H, ArH), 7.55 (brs, 1H, ArH), 7.52 (dd,J = 8.7, 2.1 Hz, 1H, ArH), 7.49 (t, J = 7.8 Hz, 1H, ArH), 7.45 (d, J = 8.1 Hz, 1H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.18 (t, J = 7.5 Hz, 1H, ArH), 7.08-7.13 (m, 2H , ArH, H-1’), 5.02 (s, 2H, H-7), 4.97 (d, J = 12.0 Hz, 1H, H-3’), 4.49 (brs, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.84-2.90 (m, 1H, H-2’a), 2.70 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.37-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.4, 138.8, 136.5, 134.7, 133.9, 133.1, 129.1, 125.9, 125.3, 125.1, 124.8, 124.6, 123.8, 123.7(2×C), 122.8, 121.8, 121.6, 120.6, 120.5, 119.7, 119.4, 119.2, 114.7, 114.2, 113.6, 112.0, 110.8, 106.9, 94.9, 82.5(2×C), 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 699.1938 [M + H]+ (calcd for C39H32N6O3ClS, 699.1940) 。
The preparation of 6 compound 6 of embodiment
3- chloro- 3 '-NThe iodomethane salt (300 mg, 0.40 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl] trifluoroacetic acid ammonium (116 mg, 0.40 mmol) is reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- chloro- 3 '-N- [N(2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl) aminothio formyl] 150 mg of staurosporine, yield 50%.1H NMR (600 MHz, DMSO-d 6) δ 12.16 (s, 1H, NH), 9.33 (d, J = 2.1 Hz, 1H, ArH), 8.71 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.07 (d, J = 7.7 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.95 (brs, 1H, NH), 7.85 (dd, J = 9.8, 2.1 Hz, 1H, ArH), 7.80 (d, J = 8.7 Hz, 1H, ArH), 7.50-7.54 (m, 3H, ArH), 7.38 (t, J = 7.4 Hz, 1H, ArH), 7.09-7.12 (m, 2H, ArH, H-1’), 5.92 (brs, 1H, H-3’), 4.95-5.05 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.86 (s, 3H, 4'-OCH3), 2.72-2.76 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26-2.32 (m, 1H, H- 2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.1, 182.5, 171.8, 158.6 (d, 1 J C-F = 234.1 Hz), 139.1, 134.8 (2×C), 133.2, 133.0, 128.9, 126.0 (d, 3 J C-F = 10.0 Hz), 125.8, 125.3, 125.1, 124.5, 123.8, 123.7(2×C), 121.6, 120.5, 119.4, 114.7, 114.3 (d, 4 J C-F = 4.0 Hz), 114.3, 114.0, 113.5 (d, 3 J C-F = 10.0 Hz), 111.1 (d,2 J C-F = 23.8 Hz), 110.9, 106.0 (d, 2 J C-F = 23.8 Hz), 95.1, 82.8, 82.5, 60.4, 54.3, 51.9, 45.6, 32.8, 29.5, 27.6; ESI-MS m/z 757.2 [M + Na]+.Under argon gas protection, In 25 two mouthfuls of mL reaction flasks, 3- chloro- 3 '-is addedN-[N(2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl) aminothio first Acyl] staurosporine (50 mg, 0.068 mmol), 6 mL methylene chloride and 200 are addedµL ethyl alcohol dissolves, and is added at 0 DEG C 400 µL trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, and methylene chloride extraction is concentrated, half after anhydrous sodium sulfate is dry Prepare HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- chloro- 5 ' ' '-fluorine Fu Ruide carbazole alkali first (compound 6) 30 Mg, yield 62%.1H NMR (600 MHz, DMSO-d 6) δ 11.47 (s, 1H, NH), 9.34 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.02-8.08 (m, 2H, ArH), 7.72 (t, J = 7.9 Hz, 1H, ArH), 7.65 (brs, 1H, ArH), 7.43-7.56 (m, 5H, ArH), 7.35-7.38 (m, 1H, ArH), 7.07-7.10 (m, 1H, ArH), 7.03 (t, J = 9.0 Hz, 1H, H-1’), 5.02 (s, 2H, H-7), 4.96 (d, J = 12.7 Hz, 1H, H-3’), 4.49 (brs, 1H, H-4’), 2.90 (s, 3H, 3'-NCH3), 2.85-2.89 (m, 1H, H-2’a), 2.70 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.37-2.41 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.6, 157.4 (d, 1 J C-F = 232.8 Hz), 138.8, 134.7, 134.1, 133.2, 133.1, 129.1, 126.0, 125.3, 125.2, 124.9, 124.9 (d, 3 J C-F = 9.7 Hz), 124.6, 123.8 (2×C), 123.7, 121.6, 120.6, 120.0, 119.4, 114.7, 114.2, 113.7, 113.1 (d, 3 J C-F = 9.7 Hz), 110.8, 110.1(d, 2 J C-F = 26.2 Hz), 107.2 (d, 4 J C-F = 4.4 Hz), 104.0 (d, 2 J C-F = 26.2 Hz), 94.9, 82.5, 82.5, 60.2, 53.2, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 717.1843[M + H]+ (calcd for C39H31N6O3ClFS, 717.1845)。
The preparation of 7 compound 7 of embodiment
3- chloro- 3 '-NThe iodomethane salt (110 mg, 0.15 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] trifluoroacetic acid ammonium (46 mg, 0.15 mmol) are reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- chloro- 3 '-N- [N(2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl) aminothio formyl] 50 mg of staurosporine, yield 45%.1H NMR (600 MHz, DMSO-d 6) δ 9.32 (d, J = 2.0 Hz, 1H, ArH), 8.71 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.16 (d, J = 2.0 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.96 (brs, 1H, NH), 7.79 (d, J = 8.7 Hz, 1H, ArH), 7.49-7.55 (m, 3H, ArH),7.37 (t, J = 7.4 Hz, 1H, ArH), 7.26 (dd, J = 8.6, 2.1 Hz, 1H, ArH), 7.10 (t, J = 7.7 Hz, 1H,H-1’), 5.91 (brs, 1H, H-3’), 4.94-5.07 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.85 (s, 3H, 4'-OCH3), 2.72-2.76 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26- 2.32 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.8, 139.1, 135.0, 134.7, 133.2, 128.9, 126.6, 126.5, 125.7, 125.3, 125.1, 124.5, 123.8, 123.7(2×C), 122.9, 121.7, 121.5, 120.5, 120.3, 119.4, 114.7, 114.2, 114.0, 113.9, 113.8, 110.9, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.8, 29.5, 27.6; ESI-MS m/z 773.0[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- chloro- 3 '-is addedN- [N(2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl) aminothio formyl] staurosporine (27 mg, 0.036 mmol), add Enter 6 mL methylene chloride and 200µL ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride, after reaction 1 hour plus water is whole It only reacts, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1 (v/v) is washed It is de- to obtain 3,5 ' ' '-dichloro Fu Ruide carbazole alkali first (compound 7) 14 mg, yield 53%.1H NMR (600 MHz, DMSO-d 6) δ 11.70 (s, 1H, NH), 9.35 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.08 (d, J = 7.7 Hz, 1H, ArH), 8.05 (d, J = 8.4 Hz, 1H, ArH), 7.78 (brs, 1H, ArH), 7.73 (d, J = 8.6 Hz, 1H, ArH), 7.66 (brs, 1H, ArH), 7.45-7.56 (m, 4H, ArH), 7.37 (t, J = 7.0 Hz, 1H, ArH), 7.18 (d, J = 8.6 Hz, 1H, ArH), 7.10 (t, J = 7.0 Hz, 1H, H-1’), 5.03 (s, 2H, H-7), 4.98 (d, J = 13.0 Hz, 1H, H-3’), 4.49 (brs, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.86-2.90 (m, 1H, H-2’a), 2.70 (s, 3H, 4'-OCH3), 2.42 (s, 3H, 6'-CH3), 2.38-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.7, 138.8, 135.0, 134.7, 134.4, 133.1, 129.1, 128.5, 125.9 (2×C), 125.3, 125.1, 124.7, 124.6, 124.3, 123.8, 123.7, 123.6, 121.8, 121.6, 120.5, 119.6, 119.4, 118.2, 114.7, 114.2, 113.6 (2×C), 106.7, 94.9, 82.5, 82.4, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0；HRESI-MS m/z 755.1368 [M + H]+ (calcd for C39H30N6O3Cl2NaS, 755.1369)。
The preparation of 8 compound 8 of embodiment
3- chloro- 3 '-NThe iodomethane salt (110 mg, 0.15 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- bromo indole)) ethyl] trifluoroacetic acid ammonium (52 mg, 0.15 mmol) are reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- chloro- 3 '-N- [N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio formyl] 45 mg of staurosporine, yield 38%.1H NMR (600 MHz, DMSO-d 6) δ 12.22 (s, 1H, NH), 9.33 (s, 1H, ArH), 8.70 (s, 1H, NH), 8.57 (s, 1H, ArH), 8.31 (s, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 8.02 (d,J = 8.6 Hz, 1H, ArH), 7.95 (brs, 1H, NH), 7.79 (d, J = 8.6 Hz, 1H, ArH), 7.36-7.52 (m, 5H, ArH), 7.10 (t, J = 7.5 Hz, 1H, H-1’), 5.90 (brs, 1H, H-3’), 4.92-5.05 (m, 4H, H-7, H-3’’), 4.52 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.86 (s, 3H, 4'-OCH3), 2.71-2.74 (m, 1H, H-2’a), 2.35 (s, 3H, 6'-CH3), 2.26- 2.31 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.8, 139.1, 135.1, 134.7, 134.5, 133.2, 128.9, 127.2, 125.7, 125.5, 125.3, 125.1, 124.5, 123.8, 123.7(2×C), 123.3, 121.5, 120.5, 119.4, 114.7, 114.6, 114.3, 114.2, 114.0, 113.6, 110.9, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.8, 29.5, 27.6; ESI-MS m/z 817.0[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- chloro- 3 '-is addedN-[N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio formyl] staurosporine (30 mg, 0.038 mmol), 6 mL methylene chloride and 200 are addedµL ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride adds water after reaction 1 hour Reaction is terminated, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1(v/v) Afford chloro- 5 ' ' '-bromine of 3- Fu Ruide carbazole alkali first (compound 8) 14 mg, yield 47%.1H NMR (600 MHz, DMSO-d 6) δ 11.58 (s, 1H, NH), 9.35 (d, J = 1.8 Hz, 1H, ArH), 8.71 (s, 1H, NH), 8.08 (d, J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 8.5 Hz, 1H, ArH), 7.92 (brs, 1H, ArH), 7.73 (d, J = 8.7 Hz, 1H, ArH), 7.65 (d, J = 2.4 Hz, 1H, ArH), 7.56 (brs, 1H, ArH), 7.48-7.54 (m, 2H, ArH), 7.42 (d, J = 8.6 Hz, 1H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.29 (dd, J = 8.6, 1.8 Hz, 1H, ArH), 7.09-7.11 (m, 1H, H-1’), 5.03 (s, 2H, H-7), 4.96-4.99 (m, 1H, H-3’), 4.49 (s, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.86-2.90 (m, 1H, H-2’a), 2.70 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.38-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.8, 138.8, 135.2, 134.7, 134.5, 133.1, 129.1, 126.6, 125.9, 125.3, 125.1, 124.5(2×C), 124.4, 123.8, 123.7, 123.6, 121.6, 121.2, 120.5, 119.5, 119.4, 114.7, 114.2, 114.0, 113.6, 112.2, 110.8, 106.6, 94.9, 82.5, 82.4, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 777.1042 [M + H]+ (calcd for C39H31N6O3BrClS, 777.1045)。
The preparation of 9 compound 9 of embodiment
3- chloro- 3 '-NThe iodomethane salt (280 mg, 0.37 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl] trifluoro second Sour ammonium (111 mg, 0.37 mmol) reacts at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with 1N's Salt pickling is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2It is chloro- that O=9:1 (v/v) affords 3- 3’-N-[N(2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl) aminothio formyl] 119 mg of staurosporine, yield 43%。1H NMR (600 MHz, DMSO-d 6) δ 11.92 (s, 1H, NH), 9.33 (s, 1H, ArH), 8.70 (s, 1H, NH), 8.43 (s, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.90 (brs, 1H, NH), 7.79 (d, J = 8.7 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 7.48-7.52 (m, 2H, ArH), 7.36-7.40 (m, 2H, ArH), 7.10 (t, J = 7.6 Hz, 1H, H-1’), 6.87 (dd, J = 8.7, 2.4 Hz, 1H, ArH), 5.93 (brs, 1H, H-3’), 4.95- 5.03 (m, 4H, H-7, H-3’’), 4.50 (s, 1H, H-4’), 3.78 (s, 3H, 5'''-OCH3), 2.95 (s, 3H, 3'-NCH3), 2.83 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26-2.32 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 189.9, 182.4, 171.8, 155.5, 139.1, 134.8, 133.5, 133.2, 131.3, 129.0, 126.3, 125.8, 125.3, 125.1, 124.5, 123.8, 123.7(2×C), 121.6, 120.5, 119.4, 114.7, 114.3, 114.0(2×C), 113.0, 112.7, 110.9, 102.9, 95.1, 82.9, 82.5, 60.4, 55.3, 54.2, 51.8, 45.6, 32.7, 29.4, 27.6; ESI-MS m/z 769.2[M + Na]+.Under argon gas protection, in 25 mL two In mouth reaction flask, 3- chloro- 3 '-is addedN-[N(2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl) aminothio formyl] Staurosporine (35 mg, 0.047 mmol) is added 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol, 400 μ is added at 0 DEG C L trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- chloro- 5 ' ' '-methoxyl group Fu Ruide carbazole alkali first (compound 9) 16 Mg, yield 47%.1H NMR (600 MHz, DMSO-d 6) δ 11.20 (s, 1H, NH), 9.34 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.08 (d, J = 7.8 Hz, 1H, ArH), 8.05 (d, J = 8.6 Hz, 1H, ArH), 7.72 (dd, J = 8.7, 2.0 Hz, 1H, ArH), 7.55 (s, 1H, ArH), 7.48-7.53(m, 3H, ArH), 7.3-7.38 (m, 2H, ArH), 7.24 (brs, 1H, ArH), 7.08-7.11 (m, 1H, H- 1’), 6.83 (dd, J = 8.8, 2.0 Hz, 1H, ArH), 5.02 (s, 2H, H-7), 4.97 (d, J = 12.0 Hz, 1H, H-3 '), 4.50 (s, 1H, H-4 '), 3.83 (s, 3H, 5'''-OCH3), 2.90 (s, 3H, 3'-NCH3), 2.86-2.89 (m, 1H, H-2’a), 2.67 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'- CH3), 2.38-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.3, 153.9, 138.8, 134.7, 133.7, 133.1, 131.6, 129.1, 125.9, 125.3, 125.1(2×C), 124.6, 123.8, 123.7, 123.6, 123.5, 121.6, 120.7, 120.5, 119.4, 114.6, 114.2, 113.6, 112.7, 112.0, 110.8, 106.7, 100.8, 94.9, 82.5(2×C), 60.2, 55.4, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 729.2040 [M + H]+ (calcd for C40H34N6O4ClS, 729.2045)。
The preparation of 10 compound 10 of embodiment
Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3'- is addedNTertbutyloxycarbonyl staurosporine (1.0 g, 1.77 Mmol), dissolved with 30 mL methylene chloride/methanols (1:1), be added at 0 DEG C bromo-succinimide (347 mg, 1.95 Mmol), reacted 0.5 hour at a temperature of this, add water to terminate reaction, methylene chloride extraction, and use anhydrous Na2SO4It is dry, vacuum It is evaporated, silica gel column chromatography separation, petroleum ether: ethyl acetate (v/v 1:1) obtains 3- bromo- 3 '-NTertbutyloxycarbonyl cross spore 1.07 g of alkali, yield 94%.1H NMR (400 MHz, DMSO-d 6) δ 9.48 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.00-8.10 (m, 2H, ArH), 7.60-7.66 (m, 2H, ArH), 7.50 (brs, 1H), 7.36 (t,J = 7.4 Hz, 1H, ArH), 7.01 (t, J = 7.5 Hz, 1H, H-1’), 5.01 (s, 2H, H-7), 4.44-4.63 (m, 1H, H-3’), 4.28 (brs, 1H, H-4’), 2.76 (s, 3H, 3'-NCH3), 2.60- 2.67 (m, 4H, 4'-OCH3, H-2’a), 2.33 (s, 3H, 6'-CH3), 2.11-2.20 (m, 1H, H-2’b), 1.56/1.46 (m, 9H, 3×4’’-CH3); 13C NMR (100 MHz, DMSO-d 6) δ 171.8, 154.8/ 154.2, 138.8, 134.9, 133.2, 128.8, 127.6, 127.5, 125.5, 125.2, 124.3, 123.6, 121.6, 120.4, 119.4, 114.6, 114.0, 113.8/113.7, 111.6, 111.1, 94.7, 83.9/ 83.2, 82.3, 79.7/79.3, 60.5, 50.4/49.6, 45.6, 30.1, 29.5, 28.1(3×C), 26.9; ESI-MS m/z 667.2[M + Na]+.In 100 mL, two mouthfuls of reaction flasks, 3- bromo- 3 '-is addedNTertbutyloxycarbonyl cross spore Alkali (1.07 g, 1.66 mmol) is dissolved with 10 mL methylene chloride.0 DEG C of 8 mL trifluoroacetic acid of addition, reaction 1 is small at a temperature of this When, 50 mL saturated sodium bicarbonate aqueous solutions are added after concentration and stir 0.5 hour, after be extracted with dichloromethane, anhydrous sodium sulfate is dry Concentration after dry, silica gel column chromatography separation, methylene chloride: ethyl acetate (v/v 5:1) affords 3- bromine staurosporine (450 Mg, yield 50%).1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 2.0 Hz, 1H, ArH), 7.92 (d,J = 8.0 Hz, 1H, ArH), 7.89 (d, J = 8.0 Hz, 1H, ArH), 7.54 (d, J = 8.0, 2.0 Hz, 1H, ArH), 7.41-7.44 (m, 1H, ArH), 7.31-7.34 (m, 1H, ArH), 7.16 (d, J = 8.0 Hz, 1H, ArH), 6.49-6.51 (m, 1H, H-1’), 6.45 (s, 1H, NH), 5.01 (s, 2H, H- 7), 3.85-3.87 (m, 1H, H-4’), 3.42 (s, 3H, 4'-OCH3), 3.33-3.35 (m, 1H, H-3’), 2.69-2.72 (m, 1H, H-2’a), 2.34-2.39 (m, 4H, H-2’b, 3'-NCH3 ), 1.50 (s, 3H, 6’-CH3); 13C NMR (100 MHz, CDCl3) δ 173.3, 139.8, 135.1, 132.5, 130.6, 128.9, 127.7, 127.7, 124.0, 124.4, 124.3, 120.6, 120.1, 118.4, 115.3, 114.4, 114.3, 112.6, 108.3, 91.0, 84.1, 80.1, 57.2, 50.1, 45.9, 33.3, 30.1, 29.7; ESI-MS m/ z 567.1[M + Na]+.30 mL methylene chloride of 3- bromine staurosporine (600 mg, 1.1 mmol) are dissolved, at room temperature 3 mL triethylamines and N, N '-thiocarbonyldiimidazole (587 mg, 3.3 mmol), ambient temperature overnight reaction is added.Reaction solution pours into In 30 mL ice water, methylene chloride is extracted, and is concentrated after the dry organic phase of anhydrous sodium sulfate, silica gel column chromatography separation, methylene chloride: Methanol=30:1 (v/v) affords 3- bromo- 3 '-N631 mg of (the thio formyl of 1- imidazoles) staurosporine, yield 88%.1H NMR (600 MHz, DMSO-d 6) δ 9.45 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.12 (brs, 1H, ArH), 8.08 (d, J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 7.8 Hz, 1H, ArH) , 7.64 (brs, 1H, ArH), 7.62-7.66 (m, 2H, ArH), 7.53 (t, J = 7.8 Hz, 1H, ArH), 7.38 (t, J = 7.8 Hz, 1H, ArH), 7.15 (brs, 1H, ArH), 7.05 (brs, 1H, H-1’), 5.46 (brs, 1H, H-3’), 5.03 (s, 2H, H-7), 4.78 (brs, 1H, H-4’), 3.00-3.08 (m, 4H, 3’-NCH3, H-2’a), 2.76 (s, 3H, 4’-OMe), 2.38-2.46 (m, 4H, 6’-CH3, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 179.4, 171.7, 138.9, 137.7, 134.9, 133.2, 129.1, 129.0, 127.7, 127.6, 125.8, 125.5, 124.4, 123.7, 121.7, 120.7, 119.9, 119.6, 114.8, 114.2, 113.6, 111.8, 111.1, 94.9, 82.0, 81.7, 60.4, 58.1, 45.6, 38.2, 29.4, 26.9; ESI-MS m/z 677.2[M + Na]+.By 3- bromo- 3 '-N(the thio formyl of 1- imidazoles) staurosporine (583 mg, 0.89 mmol) is dissolved in 45 mL acetonitriles, and 1 mL of iodomethane is added, and is reacted at room temperature 24 hours.Reaction solution is direct Concentration, with 50 mL petroleum ethers: methylene chloride=4:1(v/v) mixed solution wash it is pure up to 3- bromo- 3 '-N(1- imidazoles is thio Formyl) staurosporine imidazole fragment 521 mg of iodomethane salt, yield 74%.1H NMR (600 MHz, DMSO-d 6) δ 9.69 (s, 1H, ArH), 9.50 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.14 (brs, 1H, ArH), 8.09 (d, J = 7.7 Hz, 1H, ArH), 8.06 (d, J = 8.4 Hz, 1H, ArH), 7.86 (brs, 1H, ArH), 7.63-7.67 (m, 2H, ArH), 7.54 (t, J = 7.6 Hz, 1H, ArH), 7.39 (t, J = 7.6 Hz, 1H, ArH), 7.17-7.20 (m, 1H), 5.39 (d, J = 12.4 Hz, 1H, H-3’), 5.02 (s, 2H, H- 7), 4.75 (s, 1H, H-4’), 3.92 (s, 3H, 5’’-NCH3), 3.06-3.11 (m, 4H, 3’-NCH3, H- 2’a), 2.71 (s, 3H, 4’-OMe), 2.43-2.47 (m, 4H, 6’-CH3, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 174.3, 171.7, 138.7, 138.0, 134.9, 133.1, 129.1, 127.7, 127.6, 125.8, 125.5, 124.4, 123.7, 123.1, 121.8, 121.2, 120.8, 119.6, 114.9, 114.2, 113.5, 111.8, 111.1, 94.7, 81.9, 81.2, 60.5, 59.1, 45.6, 38.5, 36.5, 29.2, 26.7; ESI-MS m/z 669.2[M-I]+.3- bromo- 3 '-N(the thio formyl of 1- imidazoles) staurosporine imidazole fragment Iodomethane salt (110 mg, 0.14 mmol) be dissolved in 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit- 2- (3- indoles) ethyl] trifluoroacetic acid ammonium (38 mg, 0.14 mmol), it reacts at room temperature 24 hours.20 mL of reaction solution Ethyl acetate dilution is concentrated after anhydrous sodium sulfate is dry with the salt pickling of 1N.Half preparation HPLC separation, MeOH:H2O=9: 1 (v/v) affords 3- bromo- 3 '-N-[N(2- oxygen subunit -2- (3- indoles) ethyl) aminothio formyl] staurosporine 52 Mg, yield 49%.1H NMR (600 MHz, DMSO-d 6) δ 12.03 (d, J = 2.4 Hz, 1H, NH), 9.48 (d, J = 2.0 Hz, 1H, ArH), 8.70 (s, 1H, NH), 8.50 (d, J = 3.0 Hz, 1H, ArH), 8.18 (d, J = 7.5 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.92 (brs, 1H, NH), 7.75 (d, J = 8.7 Hz, 1H, ArH), 7.63 (dd, J = 8.6, 2.0 Hz, 1H, ArH), 7.49-7.52 (m, 2H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.19-7.25 (m, 2H, ArH), 7.09 (t, J = 8.0 Hz, 1H, H-1’), 5.92 (brs, 1H, H-3’), 4.97-5.07 (m, 4H, H-7, H-3’), 4.52 (s, 1H, H-4’), 2.95 (s, 3H, 3'- NCH3), 2.85 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26-2.31 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d6) δ 190.0, 182.4, 171.8, 139.1, 136.4, 135.0, 133.3, 133.2, 128.9, 127.7, 127.5, 125.6, 125.4, 125.2, 124.3, 123.6, 122.9, 121.8, 121.6, 121.2, 120.5, 119.4, 114.7, 114.1(2×C), 114.0, 112.2, 111.6, 111.3, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.6, 29.5, 27.5; ESI-MS m/z 783.2[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- is added Bromo- 3 '-N-[N(2- oxygen subunit -2- (3- indoles) ethyl) aminothio formyl] staurosporine (36 mg, 0.047 mmol), 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol are added, 400 μ L trifluoroacetic anhydride are added at 0 DEG C, add water after reaction 1 hour Reaction is terminated, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1(v/v) Afford 3- bromine Fu Ruide carbazole alkali first (compound 10) 19 mg, yield 55%.1H NMR (600 MHz, DMSO-d 6) δ 11.38 (s, 1H, NH), 9.50 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.07 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H, ArH), 7.62-7.69 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.55 (s, 1H, ArH), 7.49 (t, J = 7.7 Hz, 1H, ArH), 7.45 (d, J = 8.0 Hz, 1H, ArH), 7.37 (t, J = 7.2 Hz, 1H, ArH), 7.18 (t,J = 7.4 Hz, 1H, ArH), 7.08-7.13 (m, 2H, ArH, H-1’), 5.03 (s, 2H, H-7), 4.97 (d, J = 12.8 Hz, 1H), 4.49 (s, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.85-2.89 (m, 1H, H-2’a), 2.70 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.37-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.4, 138.8, 136.5, 135.0, 133.9, 133.1, 129.0, 127.7, 127.6, 125.8, 125.3, 124.8, 124.3, 123.6, 122.8, 121.8, 121.6, 120.6, 120.5, 119.6, 119.4, 119.1, 114.7, 114.0, 113.6, 112.0, 111.6, 111.2, 106.9, 94.9, 82.5, 82.5, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MSm/z 743.1431 [M + H]+ (calcd for C39H32N6O3BrS, 743.1434)。
The preparation of 11 compound 11 of embodiment
3- bromo- 3 '-NThe iodomethane salt (228 mg, 0.29 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl] trifluoroacetic acid ammonium (84 mg, 0.29 mmol) are reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- bromo- 3 '-N- [N(2- oxygen subunit -2- (3- (5- fluoro indole)) ethyl) aminothio formyl] 101 mg of staurosporine, yield 45%.1H NMR (600 MHz, DMSO-d 6) δ 12.16 (s, 1H, NH), 9.48 (s, 1H, ArH), 8.70 (s, 1H, NH), 8.57 (s, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.94 (s, 1H, NH), 7.85 (d, J = 9.8 Hz, 1H, ArH), 7.74 (d, J = 8.7 Hz, 1H, ArH), 7.62 (dd, J = 8.6, 2.0 Hz, 1H, ArH), 7.48-7.54 (m, 2H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.07-7.11 (m, 2H, ArH, H-1’), 5.91 (brs, 1H, H-3’), 4.95-5.05 (m, 4H, H-7, H-3’’), 4.51 (brs, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.84 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26- 2.33 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.8, 158.6 (d, 1 J C-F = 234.8 Hz), 139.1, 135.0, 134.9, 133.3, 133.1, 128.9, 127.7, 127.6, 126.1 (d, 3 J C-F = 10.8 Hz), 125.6, 125.3, 124.4, 123.7, 121.6, 120.5, 119.4, 114.8, 114.3 (d, 4 J C-F = 4.2 Hz), 114.2, 114.0, 113.5 (d, 3 J C-F = 10.8 Hz), 111.7, 111.4, 111.1 (d, 2 J C-F = 24.0 Hz), 106.0 (d, 2 J C-F = 24.0 Hz), 95.1, 82.9, 82.5, 60.4, 54.3, 51.9, 45.7, 32.8, 29.5, 27.6; ESI-MS m/z 801.2 [M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- bromo- 3 '-is addedN-[N(2- oxygen subunit -2- (3- (5- fluorine Yin Diindyl)) ethyl) aminothio formyl] staurosporine (50 mg, 0.064 mmol), 6 mL methylene chloride and 200 are added µL Ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, and methylene chloride extraction is anhydrous It is concentrated after sodium sulphate is dry, half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords bromo- 5 ' ' '-fluorine of 3- Fu Ruide 24 mg of carbazole alkali first (compound 11), yield 50%.1H NMR (600 MHz, DMSO-d 6) δ 11.49 (s, 1H, NH), 9.49 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.03 (d,J = 8.5 Hz, 1H, ArH), 7.62-7.68 (m, 3H, ArH), 7.53-7.56 (m, 2H, ArH), 7.48 (t, J = 7.8 Hz, 1H, ArH), 7.44-7.46 (m, 1H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.01-7.10 (m, 2H, ArH, H-1’), 5.02 (s, 2H, H-7), 4.96 (d, J = 12.0 Hz, 1H, H-3’), 4.48 (brs, 1H, H-4’), 2.88 (s, 3H, 3'-NCH3), 2.84-2.88 (m, 1H, H- 2’a), 2.69 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.37-2.41 (m, 1H, H-2’b);13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.5, 157.4 (d, 1 J C-F = 231.8 Hz), 138.8, 135.0, 134.1, 133.2, 133.1, 129.0, 127.7, 127.6, 125.8, 125.3, 124.9 (d, 3 J C-F = 9.8 Hz), 124.9, 124.3, 123.6, 121.6, 120.5, 120.0, 119.4, 114.7, 114.1, 113.6, 113.1 (d, 3 J C-F = 9.8 Hz), 111.7, 111.2, 110.1(d, 2 J C-F = 25.4 Hz), 107.2 (d, 4 J C-F = 4.5 Hz), 103.9 (d, 2 J C-F = 25.4 Hz), 94.9, 82.5, 82.4, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 761.1337 [M + H]+ (calcd for C39H31N6O3BrFS, 761.1340)。
The preparation of 12 compound 12 of embodiment
3- bromo- 3 '-NThe iodomethane salt (200 mg, 0.25 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] trifluoroacetic acid ammonium (76 mg, 0.25 mmol) are reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- bromo- 3 '-N- [N(2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl) aminothio formyl] 90 mg of staurosporine, yield 44%.1H NMR (600 MHz, DMSO-d 6) δ 12.21 (s, 1H, NH), 9.47 (d, J = 2.0 Hz, 1H, ArH), 8.70 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.16 (d, J = 2.0 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.95 (brs, 1H, NH), 7.75 (d,J = 8.7 Hz, 1H, ArH), 7.63 (dd, J = 8.6, 2.0 Hz, 1H, ArH), 7.54 (d, J = 8.6 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.26 (dd, J = 8.6, 2.1 Hz, 1H, ArH), 7.09 (t, J = 7.7 Hz, 1H, H-1’), 5.90 (brs, 1H, H- 3’), 4.93-5.05 (m, 4H, H-7, H-3’), 4.52 (s, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.86 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.35 (s, 3H, 6'-CH3), 2.26- 2.32 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.8, 139.1, 135.0, 134.9, 134.7, 133.2, 128.9, 127.7, 127.5, 126.6, 126.5, 125.6, 125.3, 124.3, 123.7, 122.9, 121.6, 120.5, 120.3, 119.4, 114.7, 114.1, 114.0, 113.9, 113.8, 111.6, 111.3, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.8, 29.5, 27.5; ESI-MS m/z 817.0[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- bromo- 3 '-is addedN- [N(2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl) aminothio formyl] staurosporine (38 mg, 0.048 mmol), add Enter 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol, 400 μ L trifluoroacetic anhydride are added at 0 DEG C, after reaction 1 hour plus water is whole It only reacts, methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1 (v/v) is washed It is de- to obtain bromo- 5 ' ' '-chlorine of 3- Fu Ruide carbazole alkali first (compound 12) 18 mg, yield 48%.1H NMR (600 MHz, DMSO-d 6) δ 11.58 (s, 1H, NH), 9.50 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.06 (t, J = 7.5 Hz, 1H, ArH), 8.03 (d, J = 8.4 Hz, 1H, ArH), 7.79 (brs, 1H, ArH), 7.62- 7.68 (m, 3H, ArH), 7.56 (s, 1H, ArH), 7.46-7.50 (m, 2H, ArH), 7.36 (t, J = 7.5 Hz, 1H, ArH), 7.18 (dd, J = 8.4, 1.9 Hz, 1H, ArH), 7.09 (brs, 1H, H-1’), 5.02 (s, 2H, H-7), 4.95-4.99 (m, 1H, H-3’), 4.48 (s, 1H, H-4’), 2.90 (s, 3H, 3'-NCH3), 2.85-2.89 (m, 1H, H-2’a), 2.69 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'- CH3), 2.37-2.42 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.7, 138.8, 134.9 (2×C), 134.5, 133.1, 129.0, 127.7, 127.6, 125.9, 125.8, 125.3, 124.7, 124.3 (2×C), 123.6, 121.9, 121.6, 120.5, 119.6, 119.4, 118.2, 114.7, 114.0, 113.6 (2×C), 111.7, 111.2, 106.8, 94.9, 82.5, 82.4, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 777.1044[M + H]+ (calcd for C39H31N6O3BrClS, 777.1045)。
The preparation of 13 compound 13 of embodiment
3- bromo- 3 '-NThe iodomethane salt (100 mg, 0.13 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- chloro-indole)) ethyl] trifluoroacetic acid ammonium (45 mg, 0.13 mmol) is reacted at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the hydrochloric acid of 1N It washes, is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- bromo- 3 '-N- [N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio formyl] 45 mg of staurosporine, yield 42%.1H NMR (600 MHz, DMSO-d 6) δ 9.48 (d, J = 1.8 Hz, 1H, ArH), 8.71 (s, 1H, NH), 8.56 (s, 1H, ArH), 8.31 (d, J = 1.6 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.02 (d, J = 8.5 Hz, 1H, ArH), 7.97 (brs, 1H, NH), 7.75 (d, J = 8.7 Hz, 1H, ArH), 7.63 (dd, J = 8.6, 1.8 Hz, 1H, ArH), 7.49-7.52 (m, 2H, ArH), 7.36-7.38 (m, 2H, ArH), 7.09 (t, J = 7.7 Hz, 1H, H-1’), 5.90 (s, 1H, H-3’), 4.92-5.07 (m, 4H, H-7, H-3’), 4.52 (s, 1H, H-4’), 2.95 (s, 3H, 3'-NCH3), 2.86 (s, 3H, 4'-OCH3), 2.71-2.74 (m, 1H, H-2’a), 2.35 (s, 3H, 6'-CH3), 2.26-2.31 (m, 1H, H- 2’b); 13C NMR (150 MHz, DMSO-d 6) δ 190.2, 182.5, 171.8, 139.1, 135.3, 135.0, 134.6, 133.2, 128.9, 127.7, 127.5, 127.3, 125.6, 125.4, 125.3, 124.3, 123.7, 123.3, 121.6, 120.5, 119.4, 114.7, 114.5, 114.4, 114.1, 114.0, 113.6, 111.6, 111.3, 95.1, 82.8, 82.5, 60.4, 54.2, 51.9, 45.6, 32.8, 29.5, 27.5; ESI-MS m/z 861.2[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- bromo- 3 '-is addedN-[N(2- oxygen subunit -2- (3- (5- bromo indole)) ethyl) aminothio formyl] staurosporine (50 mg, 0.060 mmol), 6 mL methylene chloride are added With 200µL ethyl alcohol dissolves, and is added 400 at 0 DEG CµL trifluoroacetic anhydride, after reaction 1 hour plus water terminates reaction, methylene chloride Extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9:1 (v/v) affords 3,5 ' ' '-two Bromine Fu Ruide carbazole alkali first (compound 13) 26 mg, yield 53%.1H NMR (600 MHz, DMSO-d 6) δ 11.66 (s, 1H, NH), 9.49 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.07 (d, J = 7.7 Hz, 1H, ArH), 8.04 (d, J = 8.5 Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.62-7.69 (m, 3H, ArH), 7.55 (s, 1H, ArH), 7.49 (d, J = 8.0 Hz, 1H, ArH), 7.43 (d, J = 8.5 Hz, 1H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.28-7.30 (m, 1H, ArH), 7.08-7.11 (m, 1H, H-1’), 5.04 (s, 2H, H-7), 4.97 (d, J = 12.7 Hz, 1H, H-3’), 4.49 (s, 1H, H-4’), 2.91 (s, 3H, 3'-NCH3), 2.85-2.89 (m, 1H, H-2’a), 2.69 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.36-2.41 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 171.8, 167.8, 138.8, 135.2, 135.0, 134.5, 133.1, 129.1, 127.7, 127.6, 126.6, 125.8, 125.3, 124.5, 124.4, 124.3, 123.6, 121.6, 121.2, 120.5, 119.5, 119.4, 114.7, 114.1(2×C), 113.6, 112.2, 111.7, 111.2, 106.6, 94.9, 82.5, 82.4, 60.2, 53.1, 45.6, 34.5, 29.2, 27.0; HRESI-MS m/z 821.0539 [M + H]+ (calcd for C39H31N6O3Br2S, 821.0539)。
The preparation of 14 compound 14 of embodiment
3- bromo- 3 '-NThe iodomethane salt (200 mg, 0.25 mmol) of (the thio formyl of 1- imidazoles) staurosporine imidazole fragment is molten In 10 mL DMF, be added 1.0 mL of triethylamine andN[2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl] trifluoro second Sour ammonium (75 mg, 0.25 mmol) reacts at room temperature 24 hours.Reaction solution is diluted with 20 mL ethyl acetate, with the salt of 1N Pickling is concentrated after anhydrous sodium sulfate is dry.Half preparation HPLC separation, MeOH:H2O=9:1 (v/v) affords 3- bromo- 3 '-N-[N(2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl) aminothio formyl] 109 mg of staurosporine, yield 56% 。1H NMR (600 MHz, DMSO-d 6) δ 11.92 (s, 1H, NH), 9.47 (s, 1H, ArH), 8.70 (s, 1H, NH), 8.43 (d, J = 2.0 Hz, 1H, ArH), 8.07 (d, J = 7.6 Hz, 1H, ArH), 8.02 (d, J = 8.4 Hz, 1H, ArH), 7.89 (brs, 1H, NH), 7.74 (d, J = 8.6 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 7.63 (d, J = 8.6 Hz, 1H, ArH), 7.50 (t, J = 7.6 Hz, 1H, ArH), 7.36-7.41 (m, 2H, ArH), 7.09 (t, J = 7.6 Hz, 1H, H-1’), 6.87 (dd, J = 8.6, 2.1 Hz, 1H, ArH), 5.93 (brs, 1H, H-3’), 4.93-5.03 (m, 4H, H-7, H-3’’), 4.50 (s, 1H, H-4 '), 3.78 (s, 3H, 5'''-OCH3), 2.95 (s, 3H, 3'-NCH3), 2.82 (s, 3H, 4'-OCH3), 2.71-2.75 (m, 1H, H-2’a), 2.36 (s, 3H, 6'-CH3), 2.26-2.32 (m, 1H, H-2’b); 13C NMR (150 MHz, DMSO-d 6) δ 189.9, 182.4, 171.8, 155.5, 139.1, 135.0, 133.4, 133.2, 131.3, 129.0, 127.7, 127.5, 126.3, 125.6, 125.3, 124.3, 123.7, 121.6, 120.5, 119.4, 114.7, 114.1, 113.9 (2×C), 113.0, 112.7, 111.6, 111.4, 102.9, 95.1, 82.9, 82.5, 60.4, 55.3, 54.2, 51.8, 45.6, 32.7, 29.4, 27.6; ESI-MS m/z 813.2[M + Na]+.Under argon gas protection, in 25 mL, two mouthfuls of reaction flasks, 3- bromo- 3 '-is addedN- [N(2- oxygen subunit -2- (3- (5- methoxy-Indole)) ethyl) aminothio formyl] and staurosporine (56 mg, 0.071 Mmol), 6 mL methylene chloride and the dissolution of 200 μ L ethyl alcohol are added, 400 μ L trifluoroacetic anhydride are added at 0 DEG C, react 1 hour Afterwards plus water terminates reaction, and methylene chloride extraction is concentrated after anhydrous sodium sulfate is dry, and half prepares HPLC separation, MeOH:H2O=9: 1 (v/v) affords bromo- 5 ' ' '-methoxyl group of 3- Fu Ruide carbazole alkali first (compound 14) 32 mg, yield 59%.1H NMR (600 MHz, DMSO-d 6) δ 11.21 (s, 1H, NH), 9.50 (s, 1H, ArH), 8.71 (s, 1H, NH), 8.07 (d,J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 8.5 Hz, 1H, ArH), 7.62-7.68 (m, 2H, ArH), 7.55 (s, 1H, ArH), 7.51 (s, 1H, ArH), 7.49 (t, J = 7.8 Hz, 1H, ArH), 7.34-7.37 (m, 2H, ArH), 7.24 (s, 1H, ArH), 7.09 (t, J = 7.6 Hz, 1H, H- 1’), 6.83 (dd, J = 8.5, 1.6 Hz, 1H), 5.04 (s, 2H, H-7), 4.96 (d, J = 12.0 Hz, 1H, H-3 '), 4.49 (s, 1H, H-4 '), 3.83 (s, 3H, 5'''-OCH3), 2.90 (s, 3H, 3'-NCH3), 2.85-2.89 (m, 1H, H-2’a), 2.68 (s, 3H, 4'-OCH3), 2.43 (s, 3H, 6'-CH3), 2.37- 2.43 (m, 1H, H-2’b); 13C NMR (150MHz, DMSO-d 6) δ 171.8, 167.3, 153.9, 138.8, 134.9, 133.7, 133.1, 131.6, 129.1, 127.7, 127.6, 125.8, 125.3, 125.1, 124.4, 123.6, 123.5, 121.6, 120.7, 120.5, 119.4, 114.7, 114.1, 113.6, 112.7, 112.0, 111.7, 111.2, 106.7, 100.8, 94.9, 82.5, 82.5, 60.2, 55.4, 53.1, 45.6, 34.5, 29.1, 27.0; HRESI-MS m/z 773.1536[M + H]+ (calcd for C40H34N6O4BrS, 773.1540)。
In order to further verify the beneficial effect of compound that the present invention synthesizes, by being synthesized in embodiment 1-14 scheme Compound carry out anti-tumor activity test, specific experiment is as follows:
1, experimental method
The preparation of sample solution: test sample is the compound 1 ~ 14 synthesized in above-described embodiment 1 ~ 14.It accurately weighs suitable Sample is measured, the solution of required concentration is configured to DMSO, for active testing.
The squamous subculture of cell line and cell: active testing uses K562, MV-4-11, HL-60 and PBMC cell.It is various Cell is with the RPMI-1640 culture medium for containing 10% FBS, the squamous subculture in the incubator that 37 DEG C are passed through 5% carbon dioxide.
This experiment is using Cell Titer Glo(CTG) method detection different pharmaceutical to K562, MV-4-11, HL-60 and PBMC The growth inhibition effect of cell.
CTG method: adenosine triphyosphate (abbreviation atriphos, ATP) participates in a variety of enzymatic reactions in organism, is One index of living cells metabolism, content have directly reacted the quantity and cell state of cell.To thin in experimentation Isometric CTG reagent is added in born of the same parents' culture medium, measures luminous value, and in optical signal and system, luminous value is directly proportional to ATP amount, and ATP is positively correlated with viable count again, therefore can be contained by detection ATP and be measured cell viability.
When active testing, K562, MV-4-11, HL-60 and PBMC cell of logarithmic growth phase are trained with fresh IMDM It is every milliliter 2 × 10 that density, which is made, in feeding basigamy4The cell suspension of a cell, cell are inoculated in 96 well culture plates after counting, 2000 cell/100μThe hole L/, every hole are added 90μL culture solution (containing serum) overnight incubation, adds 10μL drug solution, after Continuous culture 48 hours.Then 100 are addedμL CTG is stored at room temperature 10 min, measures luminous value, 0.5 ms.It calculates according to the following formula Cell proliferation rate (%) under each concentration: IR%=(control group values of chemiluminescence-experimental group values of chemiluminescence)/control group chemistry Luminous value × 100%.Using Graph Pad software, IC is calculated50。
PKC-412 is positive controls.
2, experimental result
Experimental result is as shown in table 1.
1. 1 ~ 14 couple of human leukemia cell's proliferation inhibition activity (IC of Fu Ruide carbazole alkali first derivative of table50)
Compound MV4-11 (μM) K562 (μM) HL-60 (μM) PBMC (μM)
1 0.513 >10 >10 >10
2 0.422 >10 >10 >10
3 0.413 >10 >10 >10
4 0.364 >10 >10 >10
5 0.564 >10 >10 >10
6 0.321 >10 >10 >10
7 0.589 >10 >10 >10
8 0.426 >10 >10 >10
9 0.441 >10 >10 >10
10 0.355 >10 >10 >10
11 0.964 >10 >10 >10
12 0.698 >10 >10 >10
13 0.394 >10 >10 >10
14 0.512 >10 >10 >10
PKC-412 0.037 >10 >10 >10
As shown in Table 1,
(1) 1 ~ 14 pair of human leukemia cell's MV4-11 cell strain of compound all has very strong inhibitory activity, IC50Lower than 1μM。
(2) 1 ~ 14 pair of human peripheral blood mononuclear cell's PBMC inhibiting effect of compound is weaker, IC50It is all larger than 10μM。
Show that all compounds of the present invention have highly selective inhibiting effect to human leukemia cell's MV4-11 cell strain (to weaker, the IC of activity of other leukemia cell line HL-60s and K56250It is all larger than 10μM).
3, experiment conclusion
By above-mentioned experiment it is found that the Fu Ruide carbazole alkali Class A compound that synthesizes of the present invention is selectively to human leukemia cell MV4-11 cell strain has very strong inhibitory activity, and weaker to human peripheral blood mononuclear cell's PBMC cell strain inhibiting effect, this Show that it can be developed as the drug of the prevention and treatment leukaemia of high-efficiency low-toxicity.
The above embodiments are merely examples for clarifying the description, and does not limit the embodiments.For institute For the those of ordinary skill in category field, other various forms of variations or change can also be made on the basis of the above description It is dynamic.There is no necessity and possibility to exhaust all the enbodiments.And obvious variation extended from this or change It moves still within the protection scope of the invention.

Claims (4)

1. a kind of Fu Ruide carbazole alkali Class A compound, it is characterised in that: the compound is with staurosporine or halogenated cross spore Alkali is that basic skeleton is made, structural formula be (I) formula:
(I)；
Wherein, R1Are as follows:-H or halogen, R2Are as follows:-H, halogen or methoxyl group；
The compound producing step include: sulphur acylation reaction, with iodomethane salt-forming reaction, substitution reaction and dehydration cyclization react, Specifically:
(1) R1When selected from-H, the preparation method comprises the following steps: staurosporine (Ia) is dissolved in methylene chloride, triethylamine is then added, with N, N '- Thiocarbonyldiimidazole carries out sulphur acylation reaction；Then in acetonitrile solvent, compound (Ib) is obtained at salt with iodomethane；In N, N- Substitution reaction, which is carried out, with indolecthanamine in solvent dimethylformamide obtains compound (Ic)；In dichloromethane solvent, with three Dehydration cyclization, which is carried out, under fluoroacetic acid acid anhydride and ethyl alcohol effect obtains Fu Ruide carbazole alkali Class A compound (I)；
(2) R1When selected from halogen, the preparation method comprises the following steps: by staurosporine in methanol or dichloromethane solvent with halogenated succinimide acyl Imines carries out halogenating reaction, obtains halogenated staurosporine；Halogenated staurosporine (Ia) is dissolved in methylene chloride again, three second are then added Amine, with N, N '-thiocarbonyldiimidazole carries out sulphur acylation reaction；Then in acetonitrile solvent, compound is obtained at salt with iodomethane (Ib)；Substitution reaction, which is carried out, with indolecthanamine in N,N-dimethylformamide solvent obtains compound (Ic)；In methylene chloride In solvent, Fu Ruide carbazole alkali Class A compound (I) is obtained with dehydration cyclization is carried out under trifluoroacetic anhydride and ethyl alcohol effect.
2. a kind of Fu Ruide carbazole alkali Class A compound according to claim 1, it is characterised in that: the R1Selected from-H, Cl, Br, R2Selected from-H, F, Cl, Br ,-OMe.
3. a kind of Fu Ruide carbazole alkali Class A compound described in -2 any one according to claim 1, it is characterised in that: described Fu Ruide carbazole alkali Class A compound preparation prevention or treatment leukaemia drug in application.
4. a kind of Fu Ruide carbazole alkali Class A compound according to claim 3, it is characterised in that: the compound When as drug, it can directly use or be used in the form of pharmaceutical composition, which contains 0.1-99% The compound, remaining is pharmaceutical carrier.
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CN114853784A (en) * 2022-06-16 2022-08-05 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Staurosporine compound and preparation method and application thereof

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CN114437109A (en) * 2022-03-08 2022-05-06 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Halogenated derivative of staurosporine, preparation method and application thereof
CN114437109B (en) * 2022-03-08 2023-09-29 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Philippine halogenated derivative and preparation method and application thereof
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CN114853784B (en) * 2022-06-16 2023-09-05 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Staurosporine compound and preparation method and application thereof

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