CN104876928B - 7-azaindole quinoline-2-ketone compounds and preparation method thereof - Google Patents

7-azaindole quinoline-2-ketone compounds and preparation method thereof Download PDF

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CN104876928B
CN104876928B CN201510229131.1A CN201510229131A CN104876928B CN 104876928 B CN104876928 B CN 104876928B CN 201510229131 A CN201510229131 A CN 201510229131A CN 104876928 B CN104876928 B CN 104876928B
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acid
ethyl
compound
pyrrole
dimethyl
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CN104876928A (en
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刘明亮
郭慧元
王明华
夏桂民
李林虎
王春兰
沈伟艺
陈仕洪
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Institute of Medicinal Biotechnology of CAMS
Zhejiang Starry Pharmaceutical Co Ltd
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Zhejiang Starry Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to 7 azaindole quinoline 2 ketone compounds, its preparation method and medical usage and the antineoplastic pharmaceutical compositions with it as effective ingredient shown in formula (I).More particularly; 7 azaindole quinoline 2 ketone compounds that the present invention relates to; it is halogen at 5 bit substituents of parent nucleus; 3 bit substituents are 2 containing various amido formacyls; 4 dimethyl pyrrole 5 methylene; it, with compared with series antineoplastic medicament Sutent, has more superior anti-tumor activity.

Description

7-azaindole quinoline-2-ketone compounds and preparation method thereof
Technical field
The invention belongs to medicinal chemistry arts, relate to the 7-azaindole quinoline-2-ketone compounds with anti-tumor activity And preparation method thereof, and the antineoplastic pharmaceutical compositions containing them.Specifically, relate to 5-(5-halo-2-oxo-1, 2-dihydro-3H-pyrroles [2,3-b] pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide compounds and system thereof Preparation Method.
Background technology
Multiple receptor tyrosine kinases inhibitor is the study hotspot in antitumor field in recent years, the most existing several outstanding product Kind be approved listing, multiple material standed fors be in clinic or preclinical study stage (J Shenyang Pharm Univ.2011,28, 1005；Chinese J Org Chem.2011,31,1595).
As first multiple receptor tyrosine kinases inhibitor being approved by the FDA in the United States listing, Sutent (Sunitinib) multiple solid tumor is shown clear and definite antitumor activity (Chin J New Drugs Clin Rem.2007,26, 474), its clinical indication is the gastrointestinal stromal tumors and metastatic renal cell not responding to standard treatment or not being resistant to Cancer.This product is currently in II and/or the III clinical trial phase stage to the research of other solid tumors.Regrettably, Sutent is There is the report of drug resistance.
In recent years, this area scientist has carried out more comprehensive structural modification to Sutent, and if screen obtain dry values Obtain the compound having the symptom of a trend or material standed for (Bioorg.Med.Chem.Lett.2007,17,3814 evaluated further； Bioorg.Med.Chem.Lett.2007,17,3819；J.Med.Chem.2010,53,8140； Bioorg.Med.Chem.Lett.2011,21,3062；Med.Chem.Res.2013,22,1723).But, all these repair Decorations are all on the basis of retaining Sutent mother nucleus structure (indole-2-ketone), on its 1-position, 3-position and/or 5-position Substituent group is transformed and optimizes, and has no the report modified itself Sutent mother nucleus structure.
In order to overcome the defect existing for above-mentioned prior art, present inventor has performed and study widely, by Sutent CH on parent nucleus (indole-2-ketone) 7-position substitutes by its isostere atom N, and design has synthesized a series of 7-azaindole Quinoline-2-ketone compounds, and determine their anti-tumor activity.Finally found that, 5-(the 5-halogen of document different from the past report Generation-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide class Compound has beyond thought powerful antitumor activity, with compared with series antineoplastic medicament-Sutent, has more superior Anti-tumor activity.
Summary of the invention
It is an object of the invention to provide a class by leading to 7-azaindole quinoline-2-ketone compounds and the medicine thereof that formula (I) represents With salt,
Wherein:
X represents fluorine, chlorine, bromine；
R represents and contains two C simultaneously1～C3The secondary amine of-alkyl, wherein two alkyl can be identical, it is also possible to It is different, or R represents cyclammonium base.
The most acceptable atoxic pharmaceutical salts of formula (I) compound of the present invention, including with mineral acid, such as salt The salt that acid, sulphuric acid are formed, and organic acid, such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, wine The salt that stone acid, fumaric acid, mandelic acid, ascorbic acid or malic acid are formed, and aminoacid, such as alanine, aspartic acid, rely ammonia The salt of acid formation or and sulfonic acid, the salt formed such as methanesulfonic acid, p-methyl benzenesulfonic acid.
The present invention specifically includes following compound, and their pharmaceutical salts:
(Z)-N-[2-(dimethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-{2-[methyl (ethyl) amido] ethyl }-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] Pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(diethylin) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(dimethylamino) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(diethylin) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyrrole Pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyrrole Pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyrrole Pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(piperidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(piperazine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(4-methylpiperazine-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide,
(Z)-N-[2-(4-ethyl piperazidine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide.
Offer formula (I) compound and the preparation method of pharmaceutical salts thereof are provided.Such as reaction scheme 1 Shown in.
Reaction scheme 1:
In reaction scheme 1, X and R defines as the aforementioned.
In proton solvent, add alkali, make formula (II) compound and formula (III) compound carry out formula by condensation reaction (I) compound.For this proton solvent reacted selected from water, alcohol or alcohol-water mixed solvent；Described alkali is selected from triethylamine, pyrrole Cough up alkane, piperidines, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Formula (II) compound being used as starting material in the present invention is known compound, and domestic all have supply of commodities.(III) Compound is also known compound, and method can easily prepare with reference to known in existing publication, such as Lv K etc., Bioorg.Med.Chem.Lett.2011,21,3062；Med.Chem.Res.2013,22,1723.
Compound and the medicinal usage of pharmaceutical salts thereof shown in offer formula (I) are provided.
Compound shown in formula (I) of the present invention and pharmaceutical salts answering in the medicine of preparation treatment solid tumor and non-physical tumor thereof With.
Solid tumor of the present invention includes pulmonary carcinoma, breast carcinoma, gastric cancer, bladder cancer, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, head and neck Cancer, esophageal carcinoma, colon cancer, cancer of pancreas, renal carcinoma, carcinoma of prostate, osteocarcinoma and the brain cancer；Described non-physical tumor refers to leukemia.
Further object is that offer one is containing compound and the drug regimen of pharmaceutical salts thereof shown in formula (I) Thing.
Pharmaceutical composition of the present invention, possibly together with pharmaceutically acceptable carrier.
Pharmaceutical composition of the present invention, using compound shown in formula (I) and pharmaceutical salts thereof as the work of antitumor drug Property composition.
Compound and pharmaceutical salts weight ratio in the composition thereof shown in the formula (I) that pharmaceutical composition contains be 0.1～ 99.9%, pharmaceutically acceptable carrier weight ratio in the composition is 0.1～99.9%.
Pharmaceutical composition exists to be suitable for medicinal dosage form.
Medicinal preparation is tablet, capsule, granule, pill, powder, unguentum, suspensoid, injection, injectable powder, bolt Agent, cream, drop or patch.Wherein, described tablet is sugar coated tablet, film coated tablet, enteric coated tablet or slow releasing tablet；Institute Stating capsule is hard capsule, soft capsule, slow releasing capsule；Described injectable powder is lyophilized injectable powder.
The pharmaceutical composition of the present invention, as dosage form, the effective dose of the invention compound contained in every dose be 0.1～ 1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, it is possible to refer to each take agent Amount, as each taken 100mg.
The pharmaceutical composition of the present invention is being prepared as powder, tablet, is dispersibling powder, capsule, cachet, suppository and ointment When the solid of form or semisolid pharmaceutical formulation, solid carrier can be used.Spendable solid carrier be preferably selected from diluent, One or more materials in flavoring agent, solubilizing agent, lubricant, suspending agent, binding agent, extender etc., can be maybe encapsulating substance. In powderous preparations, contain the micronised active composition of 5～70% in the carrier.Suitable solid carrier includes magnesium carbonate, hard Fatty acid magnesium, Pulvis Talci, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethyl cellulose, low boiling Wax, cocoa butter etc..Owing to they are prone to be administered, tablet, powder, cachet and capsule etc. represent best oral administration solid system Agent.
The liquid preparation of the present invention includes solution, suspension and emulsion.Such as, the ejection preparation of parenteral administration can be water Or water-propylene glycol solution form, regulating its isotonic degree, pH etc. makes to be suitable to the physiological condition of live body.Liquid preparation may also be fabricated which Solution form in Polyethylene Glycol, aqueous solution.Appropriate coloring agent, tune can be added by being dissolved in water by active component Taste agent, stabilizer and thickening agent, prepare oral aqueous solution.Micronized active component can be dispersed in stickum the most natural The aqueous suspensions being administered orally is suitable to preparation in rubber polymer, methylcellulose, sodium carboxymethyl cellulose and other known suspending agent.
Homogeneous for ease of administration and dosage, said medicine preparation is configured to dosage unit form is particularly advantageous. The dosage unit form of preparation refers to be adapted as the physical separation unit of single dose, and each unit contains generation desired to be controlled The active component of the scheduled volume calculated of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule or dress Powder in tubule or bottle, or it is contained in ointment, gel or the cream in pipe or bottle.
Although in dosage unit form, the amount of contained active component can change, but is typically based on selected active component Effect, regulation is in the range of 1～800mg.
Those skilled in the art can determine the preferred dose being suitable to certain situation according to a conventional method.Typically, treatment is started Amount, less than the optimal dose of active component, is then gradually increased dosage, until reaching optimum therapeuticing effect.Need for treatment , total daily dose can single administration or mark time administration.
-2-the ketone compounds of 7-azaindole quinoline shown in formula (I) of the present invention, with existing same series antineoplastic medicament-Shu Ni Compare for Buddhist nun, there is more superior anti-tumor activity.And, the drug safety of the present invention is higher, effectively reduces medicine Toxic and side effects.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
Embodiment 1 (Z)-N-[2-(dimethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acid (167mg, 1mmol), 1-(3-dimethylamino-propyl)-3-second Base carbodiimide hydrochloride (230mg, 1.2mmol), I-hydroxybenzotriazole (162mg, 1.2mmol) and N, N-dimethyl formyl The mixture of amine (15mL), after 0-4 DEG C of stirring reaction 20min, adds N, N-dimethyl-ethylenediamine (0.26mL, 2mmol), with 12h is stirred at room temperature after temperature reaction 30min.Add distilled water diluting, adjust pH=9 with saturated sodium carbonate solution, containing the two of 10% methanol Chloromethanes extracts 15mLx3 time, washes 1 time, and saturated common salt is washed 1 time, and anhydrous sodium sulfate is dried.Sucking filtration, filtrate reduced in volume obtains Red oil (yield 59%).
Above-mentioned oily liquids and 5-fluorine-7-azaindole-2-ketone (80mg, 0.53mmol) are dissolved in dehydrated alcohol (8mL), Add 6 piperidines and reaction 2h is stirred at room temperature.Filter, filter cake washing with alcohol, be dried, obtain crocus solid 102mg (yield: 49%), mp:272-274 DEG C.
1H NMR (400MHz, DMSO-d6) δ 13.50 (s, 1H), 11.52 (s, 1H), 8.19 (dd, J=9.2,2.7Hz, 1H), 7.98 (dd, J=2.7,1.7Hz, 1H), 7.80 (s, 1H), 7.53-7.56 (t, J=5.6Hz, 1H), 3.30-3.34 (m, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.39 (t, J=6.8Hz, 2H), 2.20 (s, 6H).
MS-ESI(m/z):372.23(M+H)+.
HRMS-ESI(m/z):Calcd.for C19H23O2N5F(M+H)+:372.18303；Found:372.18296.
Under stirring, in the methanol suspension of above-mentioned crocus solid (100mg, 0.27mmol), it is passed through dry salt acid gas 30min, rear return stirring 30min.It is down to room temperature, sucking filtration, is dried, obtains off-white color solid 52mg (yield 40%).
C19H23N5O2F·3HCl C H N F Cl
Value of calculation 47.60 5.43 14.61 3.97 21.92
Measured value 47.59 5.45 14.62 4.00 21.94
Following salt can also be prepared similarly, such as:
(Z)-N-[2-(dimethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide malate.
Embodiment 2 (Z)-N-{2-[methyl (ethyl) amido] ethyl }-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles-3-carboxylic acid elder generation and N, N-first Base ethylethylenediamine generation condensation reaction, the most again with 5-fluorine-7-azaindole-2-ketone be condensed, obtain crocus solid (yield: 50%).
1H NMR (400MHz, DMSO-d6) δ: 13.50 (s, 1H), 11.52 (s, 1H), 8.19 (dd, J=9.2,2.7Hz, 1H), 7.98 (dd, J=2.7,1.7Hz, 1H), 7.81 (s, 1H), 7.48 (t, J=5.6Hz, 1H), 3.28 (q, J=6.4Hz, 2H), 2.57-2.51 (m, 4H), 2.46 (s, 3H), 2.43 (s, 3H), 2.20 (s, 3H), 0.97 (t, J=7.1Hz, 3H).
MS-ESI(m/z):386.63(M+H)+.
HRMS-ESI(m/z):Calcd.for C20H24O2N5F(M+H)+:386.20126；Found:386.20113.
Embodiment 3 (Z)-N-[2-(diethylin) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles-3-carboxylic acid elder generation and N, N-bis- Ethylethylenediamine generation condensation reaction, the most again 7-azaindole-2-ketone chloro-with 5-condensation, obtain yellow solid (yield: 52%), mp:225-226 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.45 (s, 1H), 11.61 (s, 1H), 8.35 (d, J=2.2Hz, 1H), 8.02 (d, J=2.2Hz, 1H), 7.84 (s, 1H), 7.48 (t, J=5.2Hz, 1H), 3.28 (q, J=6.2Hz, 2H), 2.55 2.50 (m, 6H), 2.46 (s, 3H), 2.43 (s, 3H), 0.98 (t, J=7.1Hz, 6H).
MS-ESI(m/z):416.31(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H27O2N5Cl(M+H)+:416.18478；Found:416.18492.
Embodiment 4 (Z)-N-[2-(dimethylamino) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles-3-carboxylic acid elder generation and N, N-bis- Methyl ethylenediamine generation condensation reaction, the most again with 5-bromo-7-azaindole-2-ketone be condensed, obtain orange/yellow solid (yield: 48%), mp:272-273 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.60 (s, 1H), 8.46 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.55 (t, J=5.6Hz, 1H), 3.31 (q, J=5.6Hz, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.39 (t, J=6.8Hz, 2H), 2.19 (s, 6H).
MS-ESI(m/z):432.15(M+H)+.
HRMS-ESI(m/z):Calcd.for C19H23O2N5Br(M+H)+:432.10296；Found:432.10328.
Embodiment 5 (Z)-N-[2-(diethylin) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles-3-carboxylic acid elder generation and N, N-bis- Ethylethylenediamine generation condensation reaction, the most again with 5-bromo-7-azaindole-2-ketone be condensed, obtain crocus solid (yield: 52%), mp:242-244 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.61 (s, 1H), 8.47 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.49 (t, J=5.5Hz, 1H), 3.28 (q, J=6.4Hz, 2H), 2.53 (q, J=7.6Hz, 6H), 2.46 (s, 3H), 2.43 (s, 3H), 0.98 (t, J=7.6Hz, 6H).
MS-ESI(m/z):460.20(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H27O2N5Br(M+H)+:460.13426；Found:460.13460.
Embodiment 6 (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2, 3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-(2-ammonia Ethyl) pyrrolidine generation condensation reaction, the most again with 5-fluorine-7-azaindole-2-ketone be condensed, obtain yellow solid (yield: 51%), mp:249-250 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.49 (s, 1H), 11.52 (s, 1H), 8.19 (dd, J=9.2,2.7Hz, 1H), 7.98 (dd, J=2.7,1.7Hz, 1H), 7.80 (s, 1H), 7.58 (t, J=5.6Hz, 1H), 3.34 (q, J=6.4Hz, 2H), 2.57 (t, J=6.9Hz, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 1.71-1.67 (m, 4H) .13C NMR (126MHz, DMSO-d6) δ: 169.61,164.59,155.52,148.89,137.47,131.59,130.88 (d, J=27.3Hz), (126.62,125.89,121.66,121.37 d, J=6.4Hz), 113.72 (d, J=23.7Hz), 111.87 (d, J= 2.4Hz),56.06,55.16(2C),35.41,18.60(2C),13.41,10.57.
MS-ESI(m/z):398.63(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H25O2N5F(M+H)+:398.19868；Found:398.19890.
Embodiment 7 (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2, 3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-(2-ammonia Ethyl) pyrrolidine generation condensation reaction, the most again 7-azaindole-2-ketone chloro-with 5-condensation, obtain yellow solid (yield: 52%), mp:265-267 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.55 (s, 1H), 8.35 (d, J=2.2Hz, 1H), 8.02 (d, J=2.2Hz, 1H), 7.85 (s, 1H), 7.58 (t, J=5.6Hz, 1H), 3.30-3.34 (m, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.39 (t, J=6.8Hz, 2H), 3.33 (q, J=6.8Hz, 2H), 2.56 (t, J=6.9Hz, 3H), 2.49-2.46(m,4H),2.45(s,3H),2.42(s,3H),1.72-1.65(m,4H).13C NMR(126MHz,DMSO-d6) δ:169.30,164.34,150.95,142.10,137.89,131.87,126.79,126.04,125.28,124.36, 121.72,121.47,111.17,54.78(2C),53.54,38.06,23.22(2C),13.31,10.50.
MS-ESI(m/z):414.84(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H25O2N5Cl(M+H)+:414.16913；Found:414.16917.
Embodiment 8 (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2, 3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-(2-ammonia Ethyl) pyrrolidine generation condensation reaction, the most again with 5-bromo-7-azaindole-2-ketone be condensed, obtain yellow solid (yield: 54%), mp:282-283 DEG C.
1H NMR (400MHz, DMSO-d6) δ: 13.43 (s, 1H), 11.59 (s, 1H), 8.46 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.58 (t, J=5.6Hz, 1H), 3.33 (q, J=5.2Hz, 2H), 2.56 (t, J=6.9Hz, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 1.68 (m, 4H) .13C NMR (126MHz, DMSO-d6) δ: 169.15,164.34,151.17,144.22,137.91,131.92,127.83,126.83,126.06,122.29,121.51, 112.59,111.06,54.78(2C),53.55,38.04,23.21(2C),13.32,10.50.
MS-ESI(m/z):458.26(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H25O2N5Br(M+H)+:458.11861；Found:458.11868.
Embodiment 9 (Z)-N-[2-(piperidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3- B] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-ammonia second Phenylpiperidines generation condensation reaction, is condensed with 5-bromo-7-azaindole-2-ketone, obtains yellow solid (yield: 49%).
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.59 (s, 1H), 8.46 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.58 (t, J=5.6Hz, 1H), 3.33 (q, J=5.2Hz, 2H), 2.56 (t, J=6.9Hz, 6H), 2.45 (s, 3H), 2.42 (s, 3H), 1.45 (m, 4H), 1.34 (m, 2H).
MS-ESI(m/z):472.49(M+H)+.
HRMS-ESI(m/z):Calcd.for C22H26O2N5Br(M+H)+:472.28701；Found:472.28712.
Embodiment 10 (Z)-N-[2-(piperazine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2, 3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-ammonia second Base piperazine generation condensation reaction, is condensed with 5-bromo-7-azaindole-2-ketone, obtains yellow solid (yield: 51%).
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.59 (s, 1H), 8.47 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.56 (t, J=5.6Hz, 1H), 3.32 (q, J=5.2Hz, 2H), 2.70 (t, J=6.9Hz, 4H), 2.55 (t, J=6.9Hz, 6H), 2.46 (s, 3H), 2.43 (s, 3H).
MS-ESI(m/z):473.28(M+H)+.
HRMS-ESI(m/z):Calcd.for C21H25O2N6Br(M+H)+:473.11358；Found:473.211364.
Embodiment 11 (Z)-N-[2-(4-methylpiperazine-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrrole Cough up [2,3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-4-first Base-1-aminoethyl piperazine generation condensation reaction, the most again with 5-bromo-7-azaindole-2-ketone be condensed, obtain yellow solid (yield: 48%).
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.59 (s, 1H), 8.47 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.56 (t, J=5.6Hz, 1H), 3.32 (q, J=5.2Hz, 2H), 2.53 (t, J=6.9Hz, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 2.36 (s, 8H), 2.24 (s, 3H).
MS-ESI(m/z):487.32(M+H)+.
HRMS-ESI(m/z):Calcd.for C22H27O2N6Br(M+H)+:487.14568；Found:487.14506.
Embodiment 12 (Z)-N-[2-(4-ethyl piperazidine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrrole Cough up [2,3-b] pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide
With the preparation method of embodiment 1 compound, 2,4-dimethyl-5-aldehyde radical-1H-pyrroles's-3-carboxylic acids elder generations and N-4-second Base-1-aminoethyl piperazine generation condensation reaction, the most again with 5-bromo-7-azaindole-2-ketone be condensed, obtain yellow solid (yield: 49%).
1H NMR (400MHz, DMSO-d6) δ: 13.44 (s, 1H), 11.59 (s, 1H), 8.47 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.56 (t, J=5.6Hz, 1H), 3.33 (q, J=5.2Hz, 2H), 2.53 (m, 4H), 2.46 (s, 3H), 2.43 (s, 3H), 2.36 (s, 8H), 2.24 (s, 3H), 0.98 (t, J=7.6Hz, 3H).
MS-ESI(m/z):501.31(M+H)+.
HRMS-ESI(m/z):Calcd.for C23H29O2N6Br(M+H)+:501.13248；Found:501.13239.
The test example 1 anti-tumor activity (IC to solid tumor cell50: μM)
This experimental example is to study the compounds of this invention anti-tumor activity to solid tumor cell, and test method uses SRB (Sulforhodamine) method.
According to tumor cell growth rates, the adherent solid tumor cell being in exponential phase is inoculated in 170 μ L/ holes 96 well culture plates, dosing after adherent growth 24h (30 μ L/ hole), each concentration sets 3 multiple holes.And set the normal saline of respective concentration Vehicle controls and acellular zeroing hole.Tumor cell is at 37 DEG C, 5%CO2Under the conditions of cultivate 48h.After cultivation, take out culture plate, Every hole adds the trichloroacetic acid (TCA) 50uL4 DEG C of 50% (m/v) and places lh, fixing cell.Abandon fixative, with distilled water wash 5 Secondary, the most after drying, every hole adds SRB solution 100uL, and ambient temperatare is put 10-30min, dyeed.Remove supernatant, use 1% acetic acid washs 5 times, in air after natural drying, adds the Tris solution in 150 μ L/ holes, vibrates on oscillator plate 10min.Measure the OD value at 570nm with enzyme-linked immunosorbent assay instrument, return to zero with blank.Calculate tumor cell as follows The suppression ratio of growth: suppression ratio=[(OD570 control wells-OD570 dosing holes)/OD570 control wells] × 100%.According to each control of the concentration rate, adopt With Logit method calculation of half inhibitory concentration IC50.Each of the above experiment repeats 2～3 times, obtains the average IC of 2～3 experiments50 Value is as final index.
Table 1 lists the some representation compounds in the formula I compound of the application to multiple solid tumor cell (HT-29/ Colon cancer, MCF-7/ breast carcinoma, A549/ pulmonary carcinoma, PANC-1/ cancer of pancreas, HeLa/ cervical cancer) anti-tumor activity, and with similar Antitumor drug-Sutent compares.
Table 1 embodiment 1,3,4,8, the 11 compound anti-tumor activity (IC to solid tumor cell50: μM)
From table 1, embodiment 1,3,4,8,11 compound in the formula I compound of the application is thin to multiple solid tumor The anti-tumor activity of born of the same parents' (HT-29/ colon cancer, MCF-7/ breast carcinoma, A549/ pulmonary carcinoma, PANC-1/ cancer of pancreas, HeLa/ cervical cancer) (IC50: 2.10-18.21 μM) it is control compound Sutent (IC50: 6.70-> 30 μM) 1.2-> 5.8 times.
Although in above-mentioned experiment, the present invention selected part embodiment carries out experiment test, but it practice, the present invention Other drug also can obtain the therapeutic effect same or like with said medicine.
Although, the present invention is described in detail the most with a general description of the specific embodiments, but On the basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Cause This, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.

Claims (13)

1. compound and pharmaceutical salts thereof shown in formula (I),
Wherein:
X represents fluorine, chlorine, bromine；
R represents and contains two C simultaneously1～C3The secondary amine of-alkyl, wherein two alkyl is identical, or different, or Person R represents pyrrolidin-1-yl, piperidin-1-yl, piperazine-1-base, 4-methylpiperazine-1-yl or 4-ethyl piperazidine-1-base.
Compound and pharmaceutical salts thereof shown in formula the most according to claim 1 (I), it is characterised in that its compound is:
A, (Z)-N-[2-(dimethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
B, (Z)-N-{2-[methyl (ethyl) amido] ethyl }-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyrrole Pyridine-3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
C, (Z)-N-[2-(diethylin) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
D, (Z)-N-[2-(dimethylamino) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
E, (Z)-N-[2-(diethylin) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
F, (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
G, (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
H, (Z)-N-[2-(pyrrolidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine- 3-methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
I, (Z)-N-[2-(piperidin-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
J, (Z)-N-[2-(piperazine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] pyridine-3- Methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
K, (Z)-N-[2-(4-methylpiperazine-1-yl) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] Pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide；
L, (Z)-N-[2-(4-ethyl piperazidine-1-base) ethyl]-5-(5-bromo-2-oxo-1,2-dihydro-3H-pyrroles [2,3-b] Pyridin-3-yl methylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide.
Compound and pharmaceutical salts thereof shown in formula the most according to claim 1 and 2 (I), it is characterised in that described pharmaceutical salts, Refer to the salt formed with mineral acid, organic acid.
Compound and pharmaceutical salts thereof shown in formula the most according to claim 1 and 2 (I), it is characterised in that described pharmaceutical salts, Refer to the salt formed with aminoacid, sulfonic acid.
Compound and pharmaceutical salts thereof shown in formula the most according to claim 3 (I), it is characterised in that described mineral acid is: salt Acid, sulphuric acid；Described organic acid is: acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, richness Horse acid, mandelic acid, ascorbic acid or malic acid.
Compound and pharmaceutical salts thereof shown in formula the most according to claim 4 (I), it is characterised in that described aminoacid is: third Propylhomoserin, aspartic acid, lysine, described sulfonic acid is: methanesulfonic acid, p-methyl benzenesulfonic acid.
7. prepare (I) compound of formula described in claim 1 or 2 and the method for pharmaceutical salts thereof for one kind, it is characterised in that it include as Lower step:
In proton solvent, add alkali, carry out condensation reaction in room temperature to 100 DEG C, formula II compound and formula (III) compound 0.5～10 hour, obtain formula (I) compound,
Wherein:
The definition of X, R is with claim 1.
Formula (I) compound and the preparation method of pharmaceutical salts thereof the most according to claim 7, it is characterised in that described proton Solvent is selected from water, alcohol or alcohol-water mixed solvent；Described alkali selected from triethylamine, pyrrolidine, piperidines, sodium carbonate, sodium bicarbonate, Potassium carbonate, sodium hydroxide or potassium hydroxide.
9. compound shown in formula described in claim 1 or 2 (I) and pharmaceutical salts thereof are at preparation treatment solid tumor and the medicine of non-physical tumor Application in thing.
Application the most according to claim 9, it is characterised in that described solid tumor refers to: pulmonary carcinoma, breast carcinoma, gastric cancer, bladder cancer, ovum Nest cancer, uterus carcinoma, nasopharyngeal carcinoma, head and neck cancer, esophageal carcinoma, colon cancer, cancer of pancreas, renal carcinoma, carcinoma of prostate, osteocarcinoma and the brain cancer；Described Non-physical tumor refers to leukemia.
11. containing compound and the pharmaceutical composition of pharmaceutical salts thereof shown in formula (I) described in claim 1 or 2.
12. pharmaceutical compositions according to claim 11, it is characterised in that containing pharmaceutically acceptable carrier.
13. pharmaceutical compositions according to claim 11, it is characterised in that be prepared as any pharmaceutically useful dosage form.
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