CN108822017A - New indole ketone compound and its preparation method and medicinal usage - Google Patents
New indole ketone compound and its preparation method and medicinal usage Download PDFInfo
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- 0 CC1(C(CC(S)=O)C(*2(C)C)=[O+])C2=CC=C(*)C1 Chemical compound CC1(C(CC(S)=O)C(*2(C)C)=[O+])C2=CC=C(*)C1 0.000 description 8
- IADICDAQVWLEFR-JWGURIENSA-N CC(C)CC(Nc(cc1/C2=C/NC(C=CC3C)=CC3N3CCN(C)CC3)ccc1NC2=O)=O Chemical compound CC(C)CC(Nc(cc1/C2=C/NC(C=CC3C)=CC3N3CCN(C)CC3)ccc1NC2=O)=O IADICDAQVWLEFR-JWGURIENSA-N 0.000 description 1
- JYQHWTIOFCQGQJ-UHFFFAOYSA-N CC(N(c(c(C1=[F])c2)ccc2[N+]([O-])=O)C1=O)=O Chemical compound CC(N(c(c(C1=[F])c2)ccc2[N+]([O-])=O)C1=O)=O JYQHWTIOFCQGQJ-UHFFFAOYSA-N 0.000 description 1
- QSKPIPLYKIWPNZ-XFFZJAGNSA-N CCO/C=C(/c1cc([N+]([O-])=O)ccc1N1C(C)=O)\C1=O Chemical compound CCO/C=C(/c1cc([N+]([O-])=O)ccc1N1C(C)=O)\C1=O QSKPIPLYKIWPNZ-XFFZJAGNSA-N 0.000 description 1
- XFEDBFOVMZUQDO-PLRJNAJWSA-N CN(CC1)CCC1C(NCc(cc1/C2=C/Nc3cccc(N4CCN(C)CC4)c3)ccc1NC2=O)=O Chemical compound CN(CC1)CCC1C(NCc(cc1/C2=C/Nc3cccc(N4CCN(C)CC4)c3)ccc1NC2=O)=O XFEDBFOVMZUQDO-PLRJNAJWSA-N 0.000 description 1
- BZOGQPUOVKLXII-UHFFFAOYSA-N OC(CC(c(cc([s]1)Cl)c1Cl)=O)(C(C1)C(N2)=CC=C1F)C2=O Chemical compound OC(CC(c(cc([s]1)Cl)c1Cl)=O)(C(C1)C(N2)=CC=C1F)C2=O BZOGQPUOVKLXII-UHFFFAOYSA-N 0.000 description 1
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses new indole ketone compounds shown in compound of formula I and its physiologically acceptable salt, solvate and crystal form, the antitumor actions of the pharmaceutical preparation containing the compound and the compound.
Description
Technical field
The present invention relates to the new indole ketone compounds of general formula I and physiologically acceptable salt, these compounds exist
Purposes in oncotherapy, and the pharmaceutical composition containing the compound.
Background technique
Indolone structure is one of the advantage skeleton in anti-tumor drug research, in recent years by the close of Pharmaceutical Chemist
Concern.
Compound with single indolone advantage skeleton is widely present in anti-tumor drug and synthesized micromolecule, currently,
Existing more than ten single indole ketone compound is in preclinical study, clinical research as anti-tumor drug and has listed the stage.
Wherein, Sunitinib was listed in 2006, was mainly used for clinical treatment malignant stromal tumors or metastatic renal cell cancer.
Toceranib phosphate got the Green Light in 2009 and successfully lists, the treatment for tumour.
Indigo red (Indirubin) and its derivative are the representative compounds with double indolone advantage skeletons, naturally
Product indigo red, isoindigo are red etc. all to have good anti-tumor activity.Wherein, indigo red is resisted in traditional Chinese medicine danggui longhui pills, danggui longhui wan
The effective component of tumour is clinically used for the treatment of anti-chronic myelocytic leukemia；Its derivative indigo red -3'- oxime
(Indirubin-3'-oxime, IM) has compared with the higher anti-tumor activity of indigo red, be proved to be a variety of kinases (CDKs,
Protein kinase C, Casein kinase 1, GSK-3 etc.) effective inhibitor, also have AntiHIV1 RT activity, anti-angiogenesis
Isoreactivity.However, such compound is since comprising big conjugation group, dissolubility difference and bioavilability are low.
The present invention, which dexterously cuts open a five-ring heterocycles in double indolone structures, to be split, and destroys big conjugated system, while again
The advantage skeleton of single indolone is remained, it is simple and novel novel with antitumor action that design has synthesized a series of structures
Indole ketone compound.
Summary of the invention
The purpose of the present invention is to provide new indole ketone compounds shown in a kind of Formulas I.
Another object of the present invention is to provide new indole ketone compounds, reactive intermediate and its classes shown in Formulas I
Like the preparation method of object.
Another object of the present invention is to provide purposes of the Formulas I compound represented in oncotherapy.
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
The present invention is the new compound for being related to having general formula I and physiologically acceptable salt：
Wherein, R1Selected from hydrogen, nitro, halogen, amino or-NHCOR3；
R2Selected from-COR4Or-NHR4,
R3Selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyrroles, N- methyl piperidine or C1-C4Alkyl；
R4Selected from substituted or unsubstituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, take
Generation or unsubstituted indyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrole
Piperazine base, substituted or unsubstituted pyrimidine radicals, substituted or unsubstituted Imidazopyridazine base；
The substituent group is selected from one or more hydroxyls, methoxyl group, halogen, imidazole radicals, cyclohexyl, N methyl piperazine, contains
1~3 heteroatomic five-membered ring alkyl, containing 1~3 heteroatomic hexa-atomic naphthenic base or contain 1~3 heteroatomic seven yuan
Naphthenic base.
Preferred R1For nitro, hydrogen, halogen ,-NHCOR3,
Preferred R3Phenyl, one or more the methoxy-substituted phenyl, pyrrole replaced for phenyl, one or more halogens
It coughs up, N- methyl piperidine, C1-C4Alkyl；
Preferred R4For substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, indoles, pyrroles, Imidazopyridazine,
Preferred substituent group dioxane between one or more hydroxyls or halogen, cyclohexyl, N methyl piperazine, 1,3-.
Preferred compound of formula I, including but not limited to, general formula IA compound represented and its stereoisomer and physiology
Upper acceptable salt：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4It does not take selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substitution or
The indyl in generation, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substitution do not take
The pyrimidine radicals in generation, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Between dioxane；R4When for the other groups, the substituent group is selected from one or more halogens.
Preferred compound of formula I, including but not limited to, general formula IB compound represented and its stereoisomer and physiology
Upper acceptable salt：
Wherein, R3Phenyl, one or more the methoxy-substituted phenyl, pyrrole replaced selected from phenyl, one or more halogens
It coughs up, N- methyl piperidine, C1-C4Alkyl；
R4Phenyl, the pyrimidine radicals replaced selected from N methyl piperazine.
The invention also discloses the important activity intermediates of preparation of compounds of formula I, including but not limited to, shown in general formula II
Compound and its stereoisomer and physiologically acceptable salt：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4It does not take selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substitution or
The indyl in generation, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substitution do not take
The pyrimidine radicals in generation, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Between dioxane；R4When for the other groups, the substituent group is selected from one or more halogens.
Most preferred compound is selected from following group：
The invention also discloses the methods for preparing the compounds of this invention, include the following steps：
Formula III compound reacts production II important intermediate, the Formulas I Aization that the latter generates in dehydration with formula IV compound
Close object：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4It does not take selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substitution or
The indyl in generation, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substitution do not take
The pyrimidine radicals in generation, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Between dioxane；R4When for the other groups, the substituent group is selected from one or more halogens.
N- acetyl group alkene ether intermediate V is generated by raw material of 5- nitroindoline -2- ketone, then obtains enamine with arylamine reaction
Object VI is closed, obtains compound VII, compound VIII through hydrolysis, reduction reaction respectively, then obtain through condensation reaction with different carboxylic acids
Formulas I B compound：
Wherein, R3Phenyl, one or more the methoxy-substituted phenyl, pyrrole replaced selected from phenyl, one or more halogens
It coughs up, N- methyl piperidine, C1-C4Alkyl；
R4Phenyl, the pyrimidine radicals replaced selected from N methyl piperazine.
According to the present invention, the compounds of this invention can exist in the form of isomers, and the usually described " chemical combination of the present invention
Object " includes the isomers of the compound.
The compounds of this invention may be present the cis-trans-isomer of double bond, the present invention include all possible stereoisomer and
The mixture of two or more isomers.If there is cis/trans isomers, the present invention relates to cis form and trans forms and
The mixture of these forms can separate according to conventional methods if necessary to individual isomer.
Further aspect of the present invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition
Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid
Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine
Content in compositions is usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle
Or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin,
Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection
And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made,
Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute
Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream
Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second
Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum
Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card
Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second
Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin
Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet
Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen
Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization
The daily Suitable dosage ranges for closing object are 0.01-150mg/Kg weight, preferably 0.1-100mg/Kg weight, more preferably 1-
60mg/Kg weight, most preferably 2-30mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage units
Administration, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
Pharmaceutical research shows that compound of Formula I of the invention is inhibited to kinds of tumor cells, therefore, can
For treating malignant tumour.
Specific embodiment
Invention is further described with reference to embodiments, but these embodiments are not limit the scope of the invention.
Nuclear Magnetic Resonance is Varian Mercury-300 type, and Mercuryplus-400 type is inside designated as TMS, chemical shift
(δ) is provided with hundred a ten thousandths (ppm).Mass spectrograph is Exactive PlusTM LC/MSD Orbitrap tandem mass spectrometer
(Thermo Fisher Scientific).Fusing point is measured with Fisher Scientific micro-meldometer, the non-school of thermometer
Just.Column chromatography for separation silica gel H or thick silica gel (200-300 mesh), thin-layer chromatography silica G F 254 are Qingdao Haiyang chemical industry
Factory's product.Testing agents useful for same is that chemistry is pure or analysis is pure, after purchase not after further treatment, is directly used.Solvent for use is equal
Pure to analyze, wherein tetrahydrofuran, pyridine are anhydrous solvent；Dimethyl sulfoxide and N,N-dimethylformamide are dry through molecular sieve
It is dry, directly use.Other solvents are unspecified then unprocessed.
The preparation of general formula compound II：
5- fluoro indigo red (165mg, 1mmol), 3- acetylindole (160mg, 1mmol) are added sequentially to the anhydrous second of 8mL
In alcohol, after mixing evenly, it is added diethylamine (1mmol), is stirred overnight at room temperature.After complete reaction, stop reaction, remove under reduced pressure
Solvent obtains bronzing oily liquids, and 100mL anhydrous ether is added into oily liquids, is stirred at room temperature, there is faint yellow solid analysis
Out, solid is filtered out, is washed 2 times with a small amount of dehydrated alcohol, dries, obtains embodiment 1, white solid, 246mg, yield 76%.
Embodiment 2 is prepared according to similar synthetic method.
Embodiment 1：
White solid, yield 76%, m.p.206-208 DEG C.
1H NMR(300MHz,DMSO-d6) δ 11.97 (s, 1H), 10.23 (s, 1H), 8.39 (s, 1H), 7.98 (d, J=
7.8Hz, 1H), 7.44 (d, J=8.1Hz, 1H), 7.25-7.07 (m, 3H), 6.97 (td, J=9.6,2.7Hz, 1H), 6.77
(dd, J=8.4,4.2Hz, 1H), 6.15 (s, 1H), 3.90 (d, J=16.2Hz, 1H), 3.44 (d, J=16.2Hz, 1H) .HR-
ESI-MS:M/z=325.0979 [M+H]+,calculated for C18H14FN2O3:325.0983.
Embodiment 2：
White solid, yield 75%, m.p.195-179 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.30 (s, 1H), 7.56 (s, 1H), 7.20 (dd, J=8.4,2.7Hz,
1H), 7.00 (m, 1H), 6.78 (dd, J=8.4,4.5Hz, 1H), 6.21 (s, 1H), 3.91 (d, J=17.7Hz, 1H), 3.50
(d, J=17.7Hz, 1H) .HR-ESI-MS:M/z=359.9647 [M+H]+,calculated for C14H9Cl2FNO3S:
359.9659.
The preparation of general formula compound IA：
1 compound of embodiment (200mg, 0.62mmol) is added in 5mL dehydrated alcohol, is stirred evenly, dense salt is added
Sour 2mL is stirred 2 hours at 60 DEG C.Reaction solution gradually becomes orange red by faint yellow, after TLC monitors fully reacting, stops anti-
It answers.After reaction solution is cooled to room temperature, with saturation Na2CO3Solution is neutralized to pH as neutrality, has a large amount of solids to be precipitated, by solid mistake
Filter is washed 2-3 times, dry embodiment 3, orange-yellow powdery product 160mg, yield 84%.According to similar synthetic method
Prepare embodiment 4~15.
The physicochemical data of general formula compound IAa
Embodiment 3：
Orange-yellow powder, yield 84%, m.p.275-277 DEG C.
1H NMR(400MHz,DMSO-d6) δ 12.30 (s, 1H), 10.75 (s, 1H), 8.62 (d, J=3.2Hz, 1H),
8.35 (dd, J=15.6,5.6Hz, 2H), 7.75 (s, 1H), 7.51 (dd, J=5.6,2.8Hz, 1H), 7.31-7.24 (m,
2H), 7.20 (td, J=8.8,2.8Hz, 1H), 6.86 (dd, J=8.4,4.8Hz, 1H) .HR-ESI-MS:M/z=307.0863
[M+H]+,calculated for C18H12FN2O2:307.0877.
Embodiment 4：
Red powder, yield 80%, m.p.237-239 DEG C.
1H NMR(300MHz,DMSO-d6) δ 12.26 (s, 1H), 10.78 (s, 1H), 8.38 (dd, J=9.9,2.7Hz,
1H), 7.60 (s, 1H), 7.30 (m, 1H), 7.26-7.17 (m, 2H), 6.86 (dd, J=8.7,4.5Hz, 1H), 6.32 (m,
1H).HR-ESI-MS:M/z=257.0712 [M+H]+,calculated for C14H10FN2O2:257.0721.
Embodiment 5：
Red powder, yield 64%, m.p.213-215 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.83 (s, 1H), 8.31 (dd, J=9.6,2.7Hz, 1H), 8.16 (s,
1H), 7.76 (d, J=3.6Hz, 1H), 7.63 (s, 1H), 7.25 (td, J=9.0,2.7Hz, 1H), 6.85 (m, 2H) .HR-
ESI-MS:M/z=258.0554 [M+H]+,calculated for C14H9FNO3:258.0561.
Embodiment 6：
Orange-yellow powder, yield 71%, m.p.217-219 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.88 (s, 1H), 8.34 (dd, J=6.9,2.7Hz, 2H), 8.25 (d, J=
3.0Hz, 1H), 8.12 (s, 1H), 7.28 (td, J=9.0,2.7Hz, 1H), 6.89 (dd, J=8.7,4.5Hz, 1H) .HR-
ESI-MS:M/z=275.0276 [M+H]+,calculated for C13H8FN2O2S:275.0285.
Embodiment 7：
Orange-yellow powder, yield 85%, m.p.253-254 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.86 (s, 1H), 9.31 (d, J=1.5Hz, 1H), 8.96 (d, J=
2.4Hz, 1H), 8.88 (dd, J=2.4,1.5Hz, 1H), 8.33 (dd, J=9.6,2.7Hz, 1H), 8.29 (s, 1H), 7.28
(td, J=8.7,2.7Hz, 1H), 6.89 (dd, J=8.7,4.5Hz, 1H) .HR-ESI-MS:M/z=270.0667 [M+H]+,
calculated for C14H9FN3O2:270.0673.
Embodiment 8：
Orange-yellow powder, yield 80%, m.p.238-240 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.86 (s, 1H), 8.20 (d, J=5.1Hz, 1H), 7.97 (dd, J=9.6,
2.7Hz, 1H), 7.78 (s, 1H), 7.35 (d, J=5.1Hz, 1H), 7.24 (td, J=9.0,2.7Hz, 1H), 6.87 (dd, J=
8.7,4.5Hz,1H).HR-ESI-MS:M/z=307.9932 [M+H]+,calculated for C14H8ClFNO2S:
307.9943.
Embodiment 9：
Orange-yellow powder, yield 66%, m.p.244-245 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.86 (s, 1H), 8.01 (dd, J=9.6,2.7Hz, 1H), 7.66 (s,
1H), 7.58 (s, 1H), 7.27 (td, J=9.0,2.7Hz, 1H), 6.89 (dd, J=8.7,4.5Hz, 1H) .HR-ESI-MS:m/
Z=341.9541 [M+H]+,calculated for C14H7Cl2FNO2S:341.9553.
Embodiment 10：
Orange-yellow powder, yield 77%, m.p.250-251 DEG C.
1H NMR(400MHz,DMSO-d6) δ 14.27 (s, 1H), 13.40 (s, 1H), 8.72 (s, 1H), 8.45 (d, J=
10.4Hz, 1H), 8.27 (dd, J=9.2,3.6Hz, 1H), 8.16 (d, J=8.0Hz, 1H), 7.82 (s, 1H), 7.40 (t, J=
7.6Hz, 1H), 7.01 (t, J=9.2Hz, 2H) .HR-ESI-MS:M/z=284.0715 [M+H]+, calculated for
C16H11FNO3:284.0718.
Embodiment 11：
Orange red powder, yield 94%, m.p.203-205 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.80 (s, 1H), 7.81 (dd, J=9.6,2.7Hz, 1H), 7.73 (m,
2H), 7.53 (d, J=1.8Hz, 1H), 7.20 (td, J=9.0,2.7Hz, 1H), 7.09 (d, J=8.1Hz, 1H), 6.86 (dd,
J=8.7,4.5Hz, 1H), 6.18 (s, 2H) .HR-ESI-MS:M/z=312.0656 [M+H]+,calculated for
C17H11FNO4:312.0667.
Embodiment 12：
Red powder, yield 73%, m.p.250-252 DEG C.
1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),9.41(s,1H),8.37–8.20(m,3H),8.09–
7.92 (m, 3H), 7.83 (s, 1H), 7.69 (s, 1H), 7.25 (td, J=9.0,2.7Hz, 1H), 6.90 (dd, J=8.7,
4.5Hz,1H).HR-ESI-MS:M/z=334.0976 [M+H]+,calculated for C19H13FN3O2:334.0986.
Embodiment 13：
Orange-yellow powder, yield 63%, m.p.255-257 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.80 (s, 1H), 8.80 (s, 1H), 8.42 (d, J=9.6Hz, 1H), 8.27
(dd, J=9.6,2.4Hz, 1H), 7.89 (s, 1H), 7.71 (d, J=9.6Hz, 1H), 7.22 (td, J=8.8,2.8Hz, 1H),
6.85 (dd, J=8.4,4.4Hz, 1H) .HR-ESI-MS:M/z=343.0391 [M+H]+,calculated for
C16H9ClFN4O2:343.0393.
Embodiment 14：
Pink powder, yield 92%, m.p.210-212 DEG C.
1H NMR(300MHz,DMSO-d6) δ 10.83 (s, 1H), 8.01 (d, J=8.4Hz, 2H), 7.87 (dd, J=9.3,
2.7Hz, 1H), 7.79 (s, 1H), 7.46 (d, J=8.1Hz, 2H), 7.23 (td, J=9.0,2.7Hz, 1H), 6.88 (dd, J=
8.7,4.5Hz,1H),2.62(m,1H),1.80(m,4H),1.71(m,1H),1.52-1.33(m,4H),1.33-1.20(m,
1H).HR-ESI-MS:M/z=350.1553 [M+H]+,calculated for C22H21FNO2:350.1551.
Embodiment 15：
Orange-yellow powder, yield 66%, m.p.218-220 DEG C.
1H NMR(400MHz,DMSO-d6) δ 11.51 (s, 1H), 8.99 (s, 1H), 8.28 (d, J=8.8Hz, 1H), 8.04
(d, J=8.0Hz, 2H), 7.90 (s, 1H), 7.46 (d, J=8.0Hz, 2H), 7.07 (d, J=8.8Hz, 1H), 2.62 (m,
1H),1.79(m,4H),1.71(m,1H),1.52–1.35(m,4H),1.33–1.20(m,1H).HR-ESI-MS:M/z=
377.1489[M+H]+,calculated for C22H21N2O4:377.1496.
The preparation of general formula compound IB：
(a)CH(OEt)3,acetic anhydride,150℃,1h；(b)dry DMF,110℃,10h；(c)1M NaOH
(aq),methanol,r.t.,3-4h；(d)Pd/C,H2,CH3OH/CH2Cl2,r.t.；(e)HATU,triethylamine,
DMSO,r.t.
5- nitroindoline -2- ketone (2.18g, 12.3mmol) is added in acetic anhydride (20mL), after mixing evenly, is added
Triethyl orthoformate (6mL, 12.3 × 3mmol), is heated to 150 DEG C, stops reaction, liquid cooling to be reacted after being stirred at reflux 1 hour
But to room temperature, there are a large amount of solid Off-white solids to be precipitated, filter to obtain white solid, mother liquor continues that solid, filtering is precipitated after standing
White solid is obtained, filtering to mother liquor is stood repeatedly and solid is no longer precipitated.Merge gained white solid, distill water washing with a small amount of,
It is dry, obtain N- acetyl group alkene ether intermediate V 2.3g, yield 68%.HR-ESI-MS:M/z=277.0814 [M+H]+,
calculated for C13H13N2O5:277.0819.
Above-mentioned intermediate (450mg, 1.9mmol), 2- aminopyrimidine (190mg, 2.0mmol) are added to anhydrous DMF
In (8mL), after mixing evenly, 110 DEG C are heated to, stirred lower reaction 10 hours.After TLC monitors fully reacting, stop reaction, it will
Reaction solution is cooled to room temperature, and is had a large amount of faint yellow solids to be precipitated, is added with stirring mixed solvent (H2O:IPrOH=10:1)
11mL, filtering, a small amount of distillation water washing of solid is dry, obtains yellow solid.The yellow solid is added to anhydrous methanol
In (50mL), sodium hydroxide (5mL, 1mol/L) is added after being stirred at room temperature uniformly, is stirred at room temperature 3-4 hours, stops reaction, use is dilute
Hydrochloric acid (1mol/L) neutralization reaction liquid has a large amount of faint yellow solids to be precipitated to neutrality, filters, washing, dry product VI
338mg, yield 63%.1H NMR(400MHz,DMSO-d6) δ 11.32 (s, 1H), 11.11 (d, J=11.8Hz, 1H), 9.18-
9.04 (m, 1H), 8.72-8.64 (m, 3H), 8.03 (t, J=10.6Hz, 1H), 7.21 (s, 1H), 7.02 (d, J=8.4Hz,
1H).
Product VI (283mg, 1.0mmol) is added to mixed solvent (30mL, the CH of anhydrous methanol and methylene chloride3OH:
CH2Cl2=1:1) in, it is stirring evenly and then adding into the Pd/C (120mg) of water content 10%, after hydrogen displacement three times, room temperature normal pressure hydrogen
Compression ring is stirred overnight under border.After TLC monitors fully reacting, stop reaction, reaction solution is filtered to remove Pd/C with diatomite, and filtrate subtracts
Pressure is evaporated, and obtains yellow solid, and column chromatography for separation obtains embodiment 16, faint yellow solid product 100mg, yield 40%.
By COMPOUNDS EXAMPLE 16 (100mg, 0.4mmol), HATU (200mg, 0.53mmol) is added in 4mL DMSO,
It stirs evenly, triethylamine 10 is added and drips, stirring after five minutes, is added 2,6- dichlorobenzoic acid (80mg, 0.42mmol), room temperature is stirred
It mixes overnight.After fully reacting, stop reaction, 20mL distilled water is added into reaction solution, there is yellow solid precipitation, filters, washing,
Drying, column chromatography for separation obtain embodiment 17, faint yellow solid product 58mg, yield 34%.It is prepared according to similar synthetic method
TM-45。
Embodiment 18~25 is prepared according to similar synthetic method.
The physicochemical data of general formula compound IAb
Embodiment 16：
Yellow solid, yield 40%, m.p.230-242 DEG C.
1H NMR(400MHz,DMSO-d6) δ 11.00 (d, J=11.4Hz, 1H), 10.22 (s, 1H), 8.62 (d, J=
4.8Hz, 2H), 8.41 (d, J=11.4Hz, 1H), 7.11 (t, J=4.8Hz, 1H), 6.79 (d, J=1.8Hz, 1H), 6.57
(d, J=8.2Hz, 1H), 6.37 (dd, J=8.2,2.0Hz, 1H), 4.62 (s, 2H) .HR-ESI-MS:M/z=254.1031 [M
+H]+,calculated for C13H12N5O2:254.1036.
Embodiment 17：
Faint yellow solid, yield 34%, m.p.263-265 DEG C.
1H NMR(400MHz,DMSO-d6) δ 11.01 (d, J=11.3Hz, 1H), 10.68 (s, 1H), 10.57 (s, 1H),
8.66 (m, 2H), 8.61 (d, J=11.8Hz, 1H), 7.98 (s, 1H), 7.56 (m, 2H), 7.50 (d, J=7.4Hz, 1H),
7.24 (d, J=7.2Hz, 1H), 7.16 (s, 1H), 6.87 (d, J=7.8Hz, 1H) .HR-ESI-MS:M/z=426.0506 [M+
H]+,calculated for C20H14Cl2N5O2:426.0519.
Embodiment 18：
Faint yellow solid, yield 95%, m.p.268-270 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.94 (d, J=11.6Hz, 1H), 10.61 (s, 1H), 9.91 (s, 1H),
8.63 (d, J=4.8Hz, 2H), 8.55 (d, J=11.6Hz, 1H), 7.97 (d, J=1.8Hz, 1H), 7.93 (d, J=8.8Hz,
2H), 7.34 (dd, J=8.4,1.8Hz, 1H), 7.13 (t, J=4.8Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 6.82 (d, J
=8.4Hz, 1H), 3.80 (s, 3H) .HR-ESI-MS:M/z=388.1390 [M+H]+,calculated for C21H18N5O3:
388.1404.
Embodiment 19：
Faint yellow solid, yield 33%, m.p.278-280 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.76 (d, J=12.6Hz, 1H), 10.45 (s, 1H), 9.92 (s, 1H),
8.56 (d, J=12.6Hz, 1H), 8.05-7.90 (m, 3H), 7.17 (t, J=8.0Hz, 2H), 7.05 (d, J=8.4Hz, 2H),
6.95 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 6.63 (d, J=8.0Hz, 1H), 3.83
(s,3H),3.23(s,4H),2.53(s,4H),2.27(s,3H).HR-ESI-MS:M/z=484.2332 [M+H]+,
calculated for C28H30N5O3:484.2343.
Embodiment 20：
Faint yellow solid, yield 45%, m.p.254-255 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.81 (d, J=12.4Hz, 1H), 10.51 (d, J=16.4Hz, 2H),
8.62 (d, J=12.6Hz, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 7.26-7.10 (m, 4H), 6.96 (s, 1H), 6.82 (d,
J=8.4Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 6.63 (d, J=7.8Hz, 1H), 3.20 (s, 4H), 2.45 (s, 4H),
2.22(s,3H).HR-ESI-MS:M/z=490.20378 [M+H]+,calculated for C27H26F2N5O2:490.2049.
Embodiment 21：
Faint yellow solid, yield 43%, m.p.260-262 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.84 (d, J=12.4Hz, 1H), 10.48 (s, 2H), 8.62 (d, J=
12.4Hz, 1H), 7.96 (d, J=3.2Hz, 1H), 7.55 (dd, J=5.6,3.2Hz, 2H), 7.48 (dt, J=16.0,
5.6Hz, 1H), 7.22-7.12 (m, 2H), 6.96 (s, 1H), 6.82 (dd, J=8.4,4.4Hz, 2H), 6.63 (d, J=
8.4Hz,1H),3.21(s,4H),2.45(s,4H),2.22(s,3H).HR-ESI-MS:M/z=522.1456 [M+H]+,
calculated for C27H26Cl2N5O2:522.1458.
Embodiment 22：
Faint yellow solid, yield 57%, m.p.262-263 DEG C.
1H NMR(400MHz,DMSO-d6) δ 11.52 (s, 1H), 10.74 (d, J=12.4Hz, 1H), 10.43 (s, 1H),
9.59 (s, 1H), 8.55 (d, J=12.4Hz, 1H), 7.83 (s, 1H), 7.18 (m, 2H), 7.01 (s, 1H), 6.93 (d, J=
7.8Hz, 2H), 6.80 (d, J=8.4Hz, 1H), 6.74 (d, J=7.8Hz, 1H), 6.63 (d, J=8.4Hz, 1H), 6.14 (s,
1H),3.21(s,4H),2.45(s,4H),2.22(s,3H).HR-ESI-MS:M/z=443.2184 [M+H]+,calculated
for C25H27N6O2:443.2190.
Embodiment 23：
Faint yellow solid, yield 45%, m.p.268-270 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.77 (d, J=12.4Hz, 1H), 10.39 (s, 1H), 9.60 (s, 1H),
8.53 (d, J=12.4Hz, 1H), 7.87 (s, 1H), 7.16 (t, J=8.2Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 6.94
(s, 1H), 6.74 (d, J=8.2Hz, 2H), 6.62 (d, J=8.4Hz, 1H), 3.20 (s, 4H), 2.81 (d, J=10.8Hz,
2H), 2.45 (s, 4H), 2.22 (s, 4H), 2.15 (s, 3H), 1.86 (t, J=10.8Hz, 2H), 1.66 (m, 4H) .HR-ESI-
MS:M/z=475.2812 [M+H]+,calculated for C27H35N6O2:475.2816.
Embodiment 24：
Faint yellow solid, yield 82%, m.p.256-258 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.77 (d, J=12.4Hz, 1H), 10.39 (s, 1H), 9.59 (s, 1H),
8.53 (d, J=12.4Hz, 1H), 7.81 (s, 1H), 7.16 (t, J=8.0Hz, 1H), 7.04 (d, J=7.8Hz, 1H), 6.93
(s, 1H), 6.75 (d, J=8.0Hz, 2H), 6.62 (d, J=7.8Hz, 1H), 3.20 (s, 4H), 2.45 (s, 4H), 2.22 (s,
3H), 2.15 (d, J=6.8Hz, 2H), 2.10-2.02 (m, 1H), 0.94 (s, 6H) .HR-ESI-MS:M/z=434.2539 [M+
H]+,calculated for C25H32N5O2:434.2551.
Embodiment 25：
Faint yellow solid, yield 68%, m.p.281-283 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.76 (d, J=12.4Hz, 1H), 10.48 (s, 1H), 10.16 (s, 1H),
8.58 (d, J=12.4Hz, 1H), 7.95 (s, 1H), 7.83 (d, J=7.8Hz, 1H), 7.78 (d, J=10.0Hz, 1H), 7.58
(dd, J=14.0,7.8Hz, 1H), 7.43 (t, J=8.4Hz, 1H), 7.17 (m, 2H), 6.95 (s, 1H), 6.83 (d, J=
8.2Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.63 (d, J=8.0Hz, 1H), 3.21 (s, 4H), 2.46 (s, 4H), 2.22
(s,3H).HR-ESI-MS:M/z=472.2130 [M+H]+,calculated for C27H27FN5O2:472.2143.
Pharmacological evaluation
Inhibiting effect of the compound of the present invention to kinds of tumor cells
Method one：
The screening of object anti-tumor activity is with taxol (Taxol) for reference substance.All mesh are determined by MTT method
Object is marked to HCT-116 (human colon cancer cell), HepG2 (human liver tumor cell), BGC-823 (gastric carcinoma cells), NCI-H1650
The cell of (Non-small cell lung carcinoma cell), A2780 (Proliferation of Human Ovarian Cell) grow half-inhibitory concentration IC50.
As a result：
The IC of several the compounds of this invention is measured and calculated respectively50(μM) value.The results are shown in Table 1.
Inhibiting effect of 1. test-compound of table to kinds of tumor cells
Method two：
The screening of object anti-tumor activity is with indigo red -3'- oxime (IM) for reference substance.Pass through SRB
(Sulforhodamine B) method determines structure representativeness object to KB (KB cell), KBvin (KB drug resistance
Strain), A549 (human lung carcinoma cell), MCF-7 (human breast cancer cell), the cell of MDA-MB-231 (triple negative breast cancer cell) it is raw
Long half-inhibitory concentration IC50.
As a result：
The IC of several the compounds of this invention is measured and calculated respectively50(μM) value.The results are shown in Table 2.
Inhibiting effect of 2. test-compound of table to kinds of tumor cells
Claims (11)
1. a kind of new indole ketone compounds and its physiologically acceptable salt indicated by the following general formula I：
Wherein, R1Selected from hydrogen, nitro, halogen, amino or-NHCOR3；
R2Selected from-COR4Or-NHR4,
R3Selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyrroles, N- methyl piperidine or C1-C4Alkyl；
R4Selected from substituted or unsubstituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substitution or
Unsubstituted indyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted thienyl, substituted or unsubstituted pyrazine
Base, substituted or unsubstituted pyrimidine radicals, substituted or unsubstituted Imidazopyridazine base；
The substituent group is selected from one or more hydroxyls, methoxyl group, halogen, imidazole radicals, cyclohexyl, N methyl piperazine, contains 1~3
A heteroatomic five-membered ring alkyl contains 1~3 heteroatomic hexa-atomic naphthenic base or contains 1~3 heteroatomic heptatomic ring alkane
Base.
2. compound according to claim 1, which is characterized in that the compound be general formula IA compound represented and
Physiologically acceptable salt：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4Selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted
It is indyl, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted
Pyrimidine radicals, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from dioxy between one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Heterocycle；R4When for the other groups, the substituent group is selected from one or more halogens.
3. compound according to claim 1, which is characterized in that the compound be general formula IB compound represented and
Physiologically acceptable salt：
Wherein, R3Phenyl, one or more methoxy-substituted phenyl, pyrroles, the N- replaced selected from phenyl, one or more halogens
Methyl piperidine, C1-C4Alkyl；
R4Phenyl, the pyrimidine radicals replaced selected from N methyl piperazine.
4. the reactive intermediate of compound described in claim 1, which is characterized in that the reactive intermediate is shown in general formula II
Compound and physiologically acceptable salt：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4Selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted
It is indyl, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted
Pyrimidine radicals, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from dioxy between one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Heterocycle；R4When for the other groups, the substituent group is selected from one or more halogens.
5. compound according to claims 1 to 4, which is characterized in that the compound is selected from：
6. the preparation method of compound described in Claims 1 to 5, which is characterized in that include the following steps：
Formula III compound reacts production II important intermediate, the Formulas I A compound that the latter generates in dehydration with formula IV compound：
Wherein, R1Selected from hydrogen, nitro, halogen；
R4Selected from substituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted
It is indyl, substituted or unsubstituted pyrrole radicals, substituted thienyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted
Pyrimidine radicals, substituted or unsubstituted Imidazopyridazine base；
Wherein, R4When for substituted phenyl, the substituent group is selected from dioxy between one or more hydroxyls, imidazole radicals, cyclohexyl, 1,3-
Heterocycle；R4When for the other groups, the substituent group is selected from one or more halogens.
N- acetyl group alkene ether intermediate V is generated by raw material of 5- nitroindoline -2- ketone, then obtains enamine compound with arylamine reaction
VI obtains compound VII, compound VIII through hydrolysis, reduction reaction respectively, then obtains Formulas I B through condensation reaction with different carboxylic acids
Compound：
Wherein, R3Phenyl, one or more methoxy-substituted phenyl, pyrroles, the N- replaced selected from phenyl, one or more halogens
Methyl piperidine, C1-C4Alkyl；
R4Phenyl, the pyrimidine radicals replaced selected from N methyl piperazine.
7. a kind of compound as described in Claims 1 to 5 any one claim containing effective dose and pharmaceutically
The pharmaceutical composition of acceptable carriers.
8. pharmaceutical composition according to claim 7, which is characterized in that the pharmaceutical composition be selected from tablet, capsule,
Pill, injection, sustained release preparation, controlled release preparation or various particulate delivery systems.
9. purposes of the compound as claimed in any one of claims 1 to 5 as anti-tumor drug.
10. purposes according to claim 9, which is characterized in that the tumour is colon cancer, liver cancer, gastric cancer, non-small cell
Lung cancer, oophoroma, nasopharyngeal carcinoma, breast cancer.
11. purposes according to claim 10, which is characterized in that the breast cancer is triple negative breast cancer.
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| CN110818611B (en) * | 2018-08-13 | 2023-01-24 | 中国科学院上海药物研究所 | Indolone compounds, preparation method, pharmaceutical composition and application thereof |
| CN114213396A (en) * | 2022-01-27 | 2022-03-22 | 深圳市乐土生物医药有限公司 | Indole-2-ketone compound and preparation method and application thereof |
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