CN106810549B - 7- azaindoles and its application containing dihydrogen dazin structure - Google Patents
7- azaindoles and its application containing dihydrogen dazin structure Download PDFInfo
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- CN106810549B CN106810549B CN201611231832.XA CN201611231832A CN106810549B CN 106810549 B CN106810549 B CN 106810549B CN 201611231832 A CN201611231832 A CN 201611231832A CN 106810549 B CN106810549 B CN 106810549B
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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 invention discloses a kind of 7- azaindoles containing dihydrogen dazin structure, its geometric isomer and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, and preparation method thereof.The present invention contains the 7- azaindoles of dihydrogen dazin structure, and its pharmaceutically acceptable salt, hydrate or solvate are as active ingredient, it is prepared by mixing into composition with pharmaceutically acceptable carrier or excipients, and is prepared into clinically acceptable dosage form.The application in proliferative disease drug is treated and/or prevented to the compounds of this invention in preparation, and the application in the drug of preparation treatment and/or pre- anti-cancer is treated and/or prevented in the drug of lung cancer, liver cancer, gastric cancer, colon cancer, breast cancer in preparation and applied.
Description
Technical field
The present invention relates to new Benzazole compounds, in particular to a kind of 7- Azaindoles containing dihydrogen dazin structure
Compound and its application.
Background technique
Malignant tumour is a kind of disease for seriously endangering human health and life.The death rate caused by human malignancies is only
Inferior to angiocarpy, it is arranged in second.The whole world is about diagnosed to be 10,000,000 tumor patients every year at present, and 7,000,000 people die of by swelling
Related disease caused by tumor, there are about 1,800,000 people to die of cancer, Zhan Quanqiu 1/4 every year for China.
C-Met kinases is hepatocyte growth factor receptor, is one of tyrosine kinase receptor family member, the c-Met of people
Gene is located at No. 7 chromosome long arm (7q31), and about 110kb contains 21 exons.Mature c-Met is by 5.0 × 104α it is sub-
Base and 1.4 × 105β subunit form heterodimer, extracellular region be α chain, intracellular region be β chain, two chains by disulfide bond be connected.
The phosphorylation of the Tyr1234 and Tyr1235 of region of activation can activate c-Met kinases.
C-Met kinases is widely present in epithelial tissue, is played an important role in embryonic development and wound healing.
Recent research indicate that c-Met kinases lung cancer, colon cancer, liver cancer, the carcinoma of the rectum, gastric cancer, kidney, oophoroma, glioma,
Abnormal high expression, mutation or activity change are presented in the tumor tissues such as melanoma, breast cancer, prostate cancer.C-Met kinases
The proliferation that can promote tumour cell adjusts the migration of tumour cell, enhances the invasive ability of tumour cell and induced tumor is new
The generation of angiogenic.
Currently, c-Met kinases has become an important target spot of anti-tumor drug research.Discovery oforally
active pyrrolopyridine-and aminopyridine-based Met kinase inhibitors.Bioorg.
Med.Chem.Lett.,2008,18,3224–3229；Discovery of Pyrrolopyridine-Pyridone Based
Inhibitors of Met Kinase:Synthesis,X-ray Crystallographic Analysis,and
The document reports such as Biological Activities.J.Med.Chem.2008,51,5330-5341 are one as shown in formula 1
The synthesis of serial 7- azaindoles and its pharmacology activity research show the c-Met kinases of the azaindole structure containing 7-
Inhibitor significantly inhibits malignant tumour.
In order to develop new and effective anti-tumor drug, the present inventor has carried out extensively 7- azaindoles
Multiple structural points are modified and are transformed, synthesized a series of 7- containing dihydrogen dazin structure of structure novels by research
Azaindole analog derivative.
Summary of the invention
It is an object of the invention to provide a kind of the 7- azaindoles containing dihydrogen dazin structure and its application.
7- azaindoles, its geometry that the present invention is provided as shown in general formula I containing dihydrogen dazin structure are different
Structure body and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, general formula I are as follows:
Wherein:
R1For hydrogen, methyl, ethyl or cyano；
R2The hydrogen or fluorine identical or different selected from 1~4；
X is O or S；
R3、R4Hydrogen, halogen, (C are selected from for 1~21~C6) alkyl, (C1~C6) alkoxy, by halogenated (C1~C4) alkane
Base or (C1~C4) alkoxy, (C1~C6) alkyl sulfenyl, by single or double (C1~C6Alkyl) replace amino, (C1~C6) alkyl
Acylamino-, (C1~C6) alkyl sulphinyl, (C1~C6) alkyl acyl, by single or double (C1~C6Alkyl) replace carbamyl
Base, (C1~C3) alkylenedioxy group.
Present invention is preferably related to such as above-mentioned compounds of formula I, its geometric isomer or its pharmaceutically acceptable salt,
Hydrate, solvate or prodrug, in which:
R1For hydrogen or methyl；
R2For F, replace position by the ortho position on phenyl ring with X even carbon atom；
X is O；
R3For CH3Or CF3,
R4Fluorine, chlorine, methyl, methoxyl group, trifluoromethyl or trifluoromethoxy are selected from for 1~2.
In the present invention, the 7- azaindoles containing dihydrogen dazin structure of the general formula I are particularly preferably following
One of compound, but these compounds are not meant to any limitation of the invention:
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- phenyl -1,6-
Dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (adjacent toluene
Base) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (3- fluorophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (4- fluorophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2,4 dichloro benzene base) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (the bromo- 2- fluorophenyl of 4-) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoro
Methyl) phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoro
Methoxyl group) phenyl) -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(o-tolyl) -1,6- dihydrogen dazin -3- formamide,
1- (2,5- 3,5-dimethylphenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygen
Base) phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (4- fluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (3,4- difluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup)
Phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (the bromo- 2- fluorophenyl of 4-) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygen
Base) phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (3- bromophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(2- (trifluoromethoxy) phenyl) -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(4- methoxyl group) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2,5- 3,5-dimethylphenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2- fluorophenyl) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3,4- difluorophenyl) -4-
Methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (the chloro- 4- fluorophenyl of 3-) -4-
Methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3- bromophenyl) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (2-
(trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (4-
(methoxyl group) -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- phenyl -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2- fluorophenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (3- fluorophenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (the chloro- 4- fluorophenyl of 3-)-N- (fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup)
Phenyl) -4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (2,4 dichloro benzene base)-N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- (2- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- (3- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide.
Moreover, according to some usual methods of the art, general formula I of the present invention containing dihydrogen dazin structure
7- azaindoles can generate its pharmaceutically acceptable salt with acid.Acid may include inorganic acid or organic acid,
The salt formed with following acid is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzene
Sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, Tartaric acid, benzene sulfonic acid, benzene first
Acid or p-methyl benzenesulfonic acid etc..
In addition, the invention also includes the prodrugs of the compounds of this invention.According to the present invention, prodrug is spreading out for compound of Formula I
Biology, their own may have weaker activity or even without activity, but upon administration, in physiological conditions (such as
Pass through metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
Unless otherwise noted, term used herein " halogenated " refers to fluoro, chloro, bromo or iodo；" alkyl " is
Refer to the alkyl of linear chain or branched chain；" naphthenic base " refers to substituted or unsubstituted naphthenic base；" alkenyl " refers to the alkene of linear chain or branched chain
Base；" alkynyl " refers to the alkynyl of linear chain or branched chain；" aryl " refers to organic group obtained by the hydrogen atom removed in aromatic hydrocarbons,
Such as phenyl, naphthalene；5-10 unit's heteroaryl includes the hetero atoms that N, O and S are selected from containing one or more, wherein each heteroaryl
Cyclic annular system can be monocycle or polycyclic, and cyclic annular system is armaticity, contain 5-10 atom altogether, it can be cited for example that
Imidazole radicals, pyridyl group, pyrimidine radicals, pyrazolyl, (1,2,3) and (1,2,4)-triazolyl, pyrazinyl, tetrazole radical, furyl, thiophene
Base, isoxazolyl, oxazolyl, pyrazolyl, pyrrole radicals, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzo
Thiazolyl, indyl, quinolyl etc.；5-10 circle heterocyclic ring base includes the hetero atoms that N, O and S are selected from containing one or more, wherein
The cyclic annular system of each heteroaryl can be monocycle or polycyclic, but be it is nonaromatic, cyclic annular system contains 5-10 altogether
A atom can include optionally 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, it can be cited for example that pyrrolidinyl, morpholinyl, piperazine
Base, piperidyl, thiazolinyl etc..
Synthetic route 1~3 describes the preparation of compound of Formula I of the invention below, and all raw materials are all to pass through this
Method described in a little chemical formulas, by organic chemistry filed method preparation well-known to the ordinarily skilled artisan or commercially available.
Whole final compounds of the invention are prepared by method described in these chemical formulas or by similar method
, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these chemical formulas are such as
Definition hereafter or such as the definition in foregoing teachings.
Compound of Formula I according to the invention, X, R1、R2、R3And R4If foregoing teachings part defines, the road Jun Kean
The method of line 1 is made by intermediate A and intermediate B by substitution reaction.
Compound of formula I according to the invention, X O, other substituent groups such as foregoing teachings are defined, the preparation side of intermediate A
Method is as shown in Scheme 2:
When X is S, the preparation of compound A can be by the intermediate a and R of route 22Substituted 4- nitro thiophenol is substituted,
Two-step reaction is restored to be made.
Type I compound according to the invention, the preparation method of intermediate B such as route 3, other substituent groups such as foregoing teachings institute
Definition.
The substituent R of all intermediates in above three routes1、R2、R3、R4As defined in foregoing teachings.
The present invention can contain the 7- azaindoles and its pharmacy of dihydrogen dazin structure containing above-mentioned general formula I
Upper acceptable salt, hydrate or solvate mix system with pharmaceutically acceptable carrier or excipients as active ingredient
Standby and to be prepared into clinically acceptable dosage form at composition, above-mentioned pharmaceutically acceptable excipients refer to any can be used for
Diluent, adjuvant and/or the carrier of pharmaceutical field.Derivative of the invention can be applied in combination with other active ingredients, only
Them are wanted not generate other unfavorable effects, such as allergic reaction.
The 7- azaindoles that the above-mentioned general formula I of the present invention contains dihydrogen dazin structure are used for the clinical dosage of patient
It can basis: the year of active constituent therapeutic efficiency in vivo and bioavilability, their metabolism and discharge rate and patient
Age, gender, disease phase carry out appropriate adjustment, but adult daily dosage generally should be 10~500mg, preferably 50~
300mg.Therefore, when pharmaceutical composition of the invention is made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation
It should contain the 7- azaindoles of dihydrogen dazin structure containing the above-mentioned general formula I of 10~500mg, preferably 50~
300mg.According to the guidance of doctor or pharmacist, these preparations can divide at certain intervals is administered (preferably one to six several times
It is secondary).
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common figurations in drug field
Agent.Several dosage form as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer
With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive, profit
Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix etc..
Pharmaceutical preparation can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs
It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
Have the function of strong inhibition c-Met kinases the invention further relates to compounds of formula I, and further relates to such change
Object and its pharmaceutically acceptable salt, hydrate, solvate or prodrug are closed in preparation treatment due to the extremely high table of c-Met kinases
Purposes up in the drug of diseases caused, the especially purposes in the drug of preparation treatment and/or pre- anti-cancer.
Reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-proliferate drug list
Solely use, or can with the anti-proliferate Drug combination that has listed, for treating and/or preventing proliferative disease,
Such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
It has also been found that the above-mentioned 7- azaindoles containing dihydrogen dazin structure are in preparation treatment and/or in advance
Application in the drug of anti-cancer.The compounds of this invention has inhibition tumor cell growth activity in vitro, and therefore, it may be used as
The drug of preparation treatment and/or pre- anti-cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, son
Palace, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma
Deng.
It being found by testing c-Met kinase activity, the compounds of this invention has significant inhibition c-Met kinase activity,
There is stronger inhibiting effect to the highly expressed lung cancer of c-Met, liver cancer, gastric cancer, colon cancer, breast cancer etc., it is especially useful in preparation is controlled
Treat and/or prevent the drug of lung cancer.
It is independent that reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-tumor drug
It uses, or can be with the anti-tumor drug (such as the platinum medicine cis-platinum, camptothecine Irinotecan, Changchun that have listed
Flower bases drug Noviburn, deoxidation born of the same parents' former times class drug gemcitabine, etoposide, taxol etc.) it is used in combination.Combination therapy is logical
Cross each therapeutic component simultaneously, sequence or separate administration to realize.
Specific embodiment
In order to better explain the present invention, below in conjunction with specific embodiment, the present invention is described in further detail, but
Limiting the invention for they.
Embodiment is intended to illustrate and be not intended to limit the scope of the invention.The nuclear magnetic resonance spectroscopy BrukerARX- of compound
300 measurements, mass spectrum are measured with Agilent1100LC/MSD；Agents useful for same is that analysis is pure or chemical pure.
General formula I contains the 7- azaindoles of dihydrogen dazin structure:
0 compound of Examples 1 to 3, structural formula such as the following table 1 institute is made according to the method for preparing general formula I in the present invention respectively
Show.
The structural formula of 1 Examples 1 to 30 of table
Embodiment 1
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- phenyl -1,6-
Dihydrogen dazin -3- formamide
Step 1: 4- (4-nitrophenoxy) -1H- pyrrolo- [2,3-b] pyridine (b)
In the three-necked bottle of 250mL, diphenyl ether (51.843g, 0.3mol) is preheated to whole dissolutions, is then sequentially added
The chloro- 7- azaindole (9.996g, 0.066mol) of 4- and 4- nitrophenol (16.862g, 0.107mol) are warming up to 190 DEG C instead
Should about 1h, during which having a large amount of solids can not stir, when temperature rises to 130 DEG C or so solid dissolve, solution present it is faint yellow, with
Temperature increases, and solution colour is deepened, and appearance is dark brown, is still faint yellow when sampling contact plate.After reaction solution is cooling, it is slowly added dropwise
2h is stirred into 400mL ethyl acetate, the solid of precipitation filters, and filtration cakes torrefaction obtains khaki powder 8.285g, i.e. 4- (4- nitre
Phenoxyl) -1H- pyrrolo- [2,3-b] pyridine (b), yield 46.3%.
Step 2: 4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl oxygroup) aniline (A)
By 4- made from step 1 (4-nitrophenoxy) -1H- pyrrolo- [2,3-b] pyridine (b) (5.102g,
It 0.0187mol) adds to ethyl alcohol (100mL), ferric trichloride (2.687g, 0.00994mol) and activity is sequentially added under stirring condition
Hydrazine hydrate (9.445g, 0.1887mol) is added dropwise in charcoal (8.440g, 0.703mol) when being warming up to 50 DEG C or so.It is added dropwise to complete
After be warming up to 80 DEG C of reflux about 10min.Reaction solution is cooling, filters, filtrate revolving, and after being evaporated plus 75mL water is ultrasonic, is precipitated a large amount of
Yellow solid filters, and yellow powder 2.432g, i.e. 4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl oxygroup) are obtained after filtration cakes torrefaction
Aniline (A), yield 53.6%.
Step 3: along ethyl -3- oxo -2- (Phenylhydrazono) ethyl butyrate (e)
In the there-necked flask of 500mL be added 50mL water and 200mL alcohol mixed solution, be added anhydrous sodium acetate stir to
Ethyl acetoacetate is added after dissolution, 2h is stirred at room temperature, it is spare.Aniline and 50mL water, room are added in another 250mL there-necked flask
Temperature is lower to be added dropwise concentrated hydrochloric acid, and the aqueous solution of sodium nitrite is added dropwise in drop when being cooled to -5 DEG C after finishing, keep solution temperature to be lower than 0 DEG C, drop
30min is reacted at 0 DEG C after finishing, a small amount of water is added if having solid in solution, so that diazonium salt solution keeps clarification.By second
The mixed solution of ethyl acetoacetic acid ethyl ester is cooled to solution temperature at 0 DEG C hereinafter, loading onto mechanical stirring, and above-mentioned resulting diazonium salt is molten
Liquid is slowly dropped into, keep solution temperature at 0 DEG C hereinafter, with diazonium salt solution instillation, have a large amount of yellow in reaction solution
Solid generate, drop finish after add 100mL water, after in 0 DEG C or less reaction 2h.Yellow solid obtained in above-mentioned reaction solution is taken out
Filter, filter cake are washed with water, dry, obtain 17g product, i.e., along ethyl -3- oxo -2- (Phenylhydrazono) ethyl butyrate (e), receive
Rate about 95% or more.
Step 4: ethyl -4- methyl -6- oxo -1- phenyl -1,6- dihydrogen dazin -3- carboxylic acid, ethyl ester (f)
By intermediate e (5g, 0.033mol) made from step 3, carbethoxymethylene triphenyl phosphorus (9.39g,
0.027mol) and Et2NH (0.28mL, 0.0027mol) is added in DMSO at room temperature, is warming up to 85 DEG C of reaction 4h.It is intermediate
Body e reaction is endless.Reaction solution is cooled to during room temperature falls back, is extracted with DCM, organic layer uses saturated common salt water washing again
Three times, anhydrous sodium sulfate is dry.It filters, is evaporated DCM and obtains brown oil, obtain ethyl -4- methyl -6- oxo -1- phenyl -
1,6- dihydrogen dazin -3- carboxylic acid, ethyl ester (f), yield 85%.
Step 5: ethyl -4- methyl -6- oxo -1- phenyl -1,6- dihydrogen dazin -3- carboxylic acid (g)
Intermediate f is dissolved in 50mL ethyl alcohol, 10%NaOH is added dropwise at room temperature and makes the pH value of solution to after 12, is warming up to
60 DEG C of reaction 4h.The most of a large amount of water of addition, aqueous solution later is evaporated off in reaction solution to be extracted with ethyl acetate, separates water layer,
The water layer dilute hydrochloric acid of 6M adjusts pH value to after 2~3, and with DCM aqueous layer extracted, DCM solution is dried, filtered with anhydrous sodium sulfate,
Yellow solid, i.e. ethyl -4- methyl -6- oxo -1- phenyl -1,6- dihydrogen dazin -3- carboxylic acid (g), yield are obtained after concentration
70%.
Step 6: ethyl -4- methyl -6- oxo -1- phenyl -1,6- dihydrogen dazin -3- formyl chloride (B)
Intermediate g (0.01mol) is added in the toluene of 30mL, SOCl is added2(6mL) and pyridine (5d) are warming up to 85
DEG C reaction 6h.After reaction solution is cooled to room temperature, toluene and SOCl are removed under reduced pressure2, obtain oily liquids acyl chlorides, i.e. ethyl-
4- methyl -6- oxo -1- phenyl -1,6- dihydrogen dazin -3- formyl chloride (B), yield 50%
Step 7: N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- benzene
Base -1,6- dihydrogen dazin -3- formamide
Intermediate A (0.05g, 0.00021mol) and n,N-diisopropylethylamine (0.5mL, 0.003mol) are added into 10mL
In methylene chloride, intermediate B (0.2g, 0.00073mol) is dissolved in 5mL methylene chloride, above-mentioned dichloromethane is added dropwise at 0 DEG C
It in alkane solution, is added dropwise, is slowly increased to room temperature, react 1~2 hour.After completion of the reaction, the sodium hydroxide water of 5mL5% is added
Aqueous solution stirs half an hour, is transferred in 250mL separatory funnel, adds 25mL methylene chloride, use saturated aqueous sodium carbonate
It washes (50mL*3) three times, saturated common salt washing is primary, depressurizes steaming vibrating dichloromethane, obtains faint yellow solid powder 0.05g, yield
46.14%.
ESI-MS m/z:532.1；1H NMR(300MHz,DMSO-d6)δ12.22(s,1H),11.56(s,1H),9.04
(s, 1H), 8.26 (s, 1H), 7.79 (d, J=6.8Hz, 2H), 7.63 (d, J=7.8Hz, 1H), 7.56 (d, J=7.0Hz,
2H), 7.40 (s, 2H), 7.20 (d, J=8.8Hz, 2H), 6.94 (s, 1H), 6.66 (s, 1H), 6.61 (s, 1H), 2.68 (s,
3H).
According to the method for embodiment 1, first with R1The chloro- 7- azaindole of substituted 4- and R2Substituted 4- nitrophenol, warp
Step 1 replaces, step 2 reduction reaction obtains intermediate A；R4Substituted aniline elder generation diazotising again with R3Substituted acetoacetate
Ethyl ester obtains intermediate B through step 3 even summation, step 4 cycloaddition, step 5 hydrolysis, step 6 acyl chloride reaction；Later in
2~30 compound of embodiment is made by step 7 substitution reaction in mesosome A and intermediate B respectively.
Embodiment 2
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (adjacent toluene
Base) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:451.2；1H NMR(300MHz,DMSO-d6)δ12.20(s,1H),11.64(s,1H),8.23
(d, J=6.3Hz, 1H), 7.71 (d, J=6.7Hz, 2H), 7.48-7.37 (m, 3H), 7.32 (d, J=6.7Hz, 2H), 7.14
(s, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 6.71 (d, J=4.6Hz, 1H), 6.61 (s, 1H), 2.70 (s, 1H), 2.22
(s,1H).
Embodiment 3
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (3- fluorophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:455.1.
Embodiment 4
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (4- fluorophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:455.1.
Embodiment 5
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2,4 dichloro benzene base) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:505.1；1H NMR(300MHz,DMSO-d6)δ12.64(s,1H),11.64(s,1H),8.25
(s, 1H), 7.78 (d, J=7.5Hz, 2H), 7.63 (s, 1H), 7.46-7.38 (m, 2H), 7.21 (d, J=7.2Hz, 2H),
7.17 (s, 1H), 6.95 (s, 1H), 6.65 (d, J=6.7Hz, 1H), 6.61 (s, 1H), 2.70 (s, 3H)
Embodiment 6
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (the bromo- 2- fluorophenyl of 4-) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:533.1.
Embodiment 7
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoro
Methyl) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:505.1.
Embodiment 8
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoro
Methoxyl group) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:521.1；1H NMR(300MHz,DMSO-d6)δ12.70(s,1H),12.04(s,1H),8.18
(d, J=9.5Hz, 1H), 7.99 (d, J=6.5Hz, 1H), 7.70 (d, J=7.7Hz, 1H), 7.61 (d, J=6.5Hz, 2H),
7.54 (d, J=6.6Hz, 1H), 7.49 (d, J=8.3Hz, 2H), 7.37 (s, 1H), 7.23 (d, J=7.5Hz, 2H), 6.73
(d, J=5.2Hz, 1H), 6.52 (s, 1H), 2.28 (s, 3H)
Embodiment 9
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(o-tolyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:465.2.
Embodiment 10
1- (2,5- 3,5-dimethylphenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygen
Base) phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:480.2
Embodiment 11
1- (4- fluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:469.2；1H NMR(300MHz,DMSO-d6)δ12.07(s,1H),8.97(s,1H),7.82(d,
J=10.4Hz, 2H), 7.63 (d, J=7.6Hz, 2H), 7.54 (d, J=6.1Hz, 2H), 7.08 (t, J=8.3Hz, 2H),
6.94(s,1H),6.87(s,1H),6.67(s,1H),6.62(s,1H),4.34(s,3H),2.51(s,3H).
Embodiment 12
1- (3,4- difluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup)
Phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:487.1.
Embodiment 13
1- (the bromo- 2- fluorophenyl of 4-) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygen
Base) phenyl) -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:547.1；1H NMR(300MHz,DMSO-d6) δ 10.64 (s, 1H), 8.13 (d, J=5.4Hz,
1H), 7.85 (d, J=9.7Hz, 1H), 7.78 (d, J=8.8Hz, 2H), 7.71-7.63 (m, 2H), 7.41 (d, J=3.3Hz,
1H), 7.20 (d, J=8.8Hz, 2H), 7.10 (s, 1H), 6.45 (d, J=5.4Hz, 1H), 6.18 (d, J=3.4Hz, 1H),
3.80(s,3H),2.40(s,3H).
Embodiment 14
1- (3- bromophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:529.1.
Embodiment 15
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(2- (trifluoromethoxy) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:535.1.
Embodiment 16
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1-
(4- methoxyl group) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:481.2.
Embodiment 17
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2,5- 3,5-dimethylphenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:483.2.
Embodiment 18
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2- fluorophenyl) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:473.1；1H NMR(300MHz,DMSO-d6)δ12.39(s,1H),10.90(s,1H),8.21
(d, J=5.7Hz, 1H), 8.11 (d, J=3.6Hz, 1H), 8.00 (d, J=12.8Hz, 1H), 7.75 (d, J=11.7Hz,
1H), 7.57-7.43 (m, 3H), 7.34 (d, J=8.2Hz, 2H), 7.15 (s, 1H), 6.91 (d, J=4.2Hz, 1H), 6.70
(d, J=5.4Hz, 1H), 2.47 (s, 3H)
Embodiment 19
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3,4- difluorophenyl) -4-
Methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:491.1；1H NMR(300MHz,DMSO-d6)δ12.34(s,1H),11.76(s,1H),9.17
(s, 1H), 8.21 (d, J=12.6Hz, 1H), 7.94 (d, J=13.4Hz, 1H), 7.56 (d, J=8.2Hz, 1H), 7.43 (d, J
=7.9Hz, 2H), 7.32 (d, J=7.9Hz, 2H), 6.87 (s, 1H), 6.68 (d, J=13.3Hz, 1H), 6.55 (s, 1H),
2.55(s,3H).
Embodiment 20
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (the chloro- 4- fluorophenyl of 3-) -4-
Methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:507.1.
Embodiment 21
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3- bromophenyl) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:533.1.
Embodiment 22
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (2-
(trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:523.2；1H NMR(300MHz,DMSO-d6)δ12.83(s,1H),12.16(s,1H),8.12-
8.04 (m, 3H), 7.89 (d, J=7.6Hz, 1H), 7.80 (s, 1H), 7.75 (d, J=7.5Hz, 1H), 7.63 (d, J=
10.6Hz, 1H), 7.54 (d, J=9.4Hz, 1H), 7.40 (s, 1H), 7.31 (d, J=8.3Hz, 1H), 6.72 (d, J=
5.7Hz,1H),6.57(s,1H),2.26(s,3H).
Embodiment 23
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (4-
(methoxyl group) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:485.2.
Embodiment 24
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- phenyl -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:469.2.
Embodiment 25
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2- fluorophenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:487.1.
Embodiment 26
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (3- fluorophenyl) -
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:487.1.
Embodiment 27
1- (the chloro- 4- fluorophenyl of 3-)-N- (fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup)
Phenyl) -4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:521.1.
Embodiment 28
1- (2,4 dichloro benzene base)-N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:537.1.
Embodiment 29
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- (2- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:537.1.
Embodiment 30
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxygen
Generation -1- (3- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide
ESI-MS m/z:537.1；1H NMR(300MHz,DMSO-d6)) δ 12.82 (s, 1H), 8.29 (d, J=5.0Hz,
1H), 8.08 (d, J=12.1Hz, 2H), 7.89 (d, J=7.6Hz, 1H), 7.84-7.72 (m, 2H), 7.63 (d, J=7.8Hz,
1H), 7.54 (d, J=7.0Hz, 1H), 7.30 (s, 1H), 7.20 (d, J=1.7Hz, 1H), 6.71 (d, J=6.1Hz, 1H),
6.65(s,1H),4.31(s,3H),2.26(s,3H).
The pharmacological research of product of the present invention
Extracorporeal anti-tumor cell activity
External suppression has been carried out to the 7- azaindoles containing dihydrogen dazin structure of general formula I according to the invention
Lung carcinoma cell H460, colon cancer cell HT-29, gastric carcinoma cells MKN-45, human umbilical vein endothelial cell and bladder cancer cell U- processed
87MG screening active ingredients.
(1) after 2~3 stabilizations of cell recovery and passage, make it from culture bottle bottom with trypsin solution (0.25%)
Digestion is got off.After cell dissociation buffer is poured into centrifuge tube, culture solution is added later to terminate digestion.By centrifuge tube in 800r/
It is centrifuged 10min under min, 5mL culture solution is added after discarding supernatant liquid, piping and druming mixes cell, draws 10 μ L cell suspensions and is added
It is counted in cell counting board, adjustment cell concentration is 104A/hole.Except the hole A1 is that blank well is not added extracellularly in 96 orifice plates, remaining
100 μ L cell suspensions are all added.96 orifice plates are put into incubator and are cultivated for 24 hours.
(2) with 50 μ L dmso solution given the test agent, appropriate culture solution is then added, sample is made to be dissolved into 2mg/mL
Then sample is diluted to 20,4,0.8,0.16,0.032 μ g/mL in 24 orifice plates by medical fluid.
3 holes are added in each concentration, wherein surrounding two rows, two column cell growing way is affected by environment larger, it only and is blanc cell
Hole uses.96 orifice plates are put into incubator and cultivate 72h.
(3) band medicine culture solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole
Middle 100 μ L of addition MTT (tetrazole) (0.5mg/mL) is put into incubator after 4h, discards MTT solution, and dimethyl sulfoxide is added
100μL.Oscillation dissolves survivaling cell sufficiently with MTT reaction product formazan on magnetic force oscillator, is put into microplate reader and measures
As a result.Drug IC can be found out by Bliss method50Value.
Inhibition lung carcinoma cell H460, colon cancer cell HT-29, the gastric carcinoma cells MKN-45, lung adenocarcinoma cell of compound
A549 and bladder cancer cell U-87MG Activity Results are as shown in table 2.
The test of c-Met enzymatic activity
Test for measuring c-Met kinase activity is based on enzyme-linked immunosorbent assay (ELISA).Concrete operations are:
At room temperature, on the coated plate of 0.25mg/mL PGT, by embodiment compound, 50pM c-Met, (His- is marked
Recombined human Met (end amino acid 974-), by baculovirus expression and 5 μM of ATP in test buffer (25mM MOPS,
pH 7.4,5mM MgCl2,0.5raM MnCl2, 100 μM of sodium orthovanadates, 0.01%TritonX-100,1mM DTT, last DMSO
Concentration 1% (v/v)) it incubates 20 minutes.By rinsing removing reaction mixture and horseradish peroxidase being conjugated with 0.2 μ g/mL
(HRP) phosphotyrosine monoclonal antibody specific (PY20) detects phosphorylated polymer substrate.It is aobvious that the termination of 1M phosphoric acid is added
After color, pass through the color of the substrate (TMB) of spectrophotometry quantitative chromogenic at 450nm.Embodiment compound is to c-Met kinases
Inhibition data it is as shown in table 2.
Table 2:
From above-mentioned test result it can be clearly seen that the compound of the claimed general formula I of the present invention, has good
Anti tumor activity in vitro, quite or better than the anti-tumor drug cis-platinum listed.
The compound of formula of I of the present invention can be administered alone, but usually give with pharmaceutical carrier mixture, described medicinal
The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various drug agent of such compound
Type, such as the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment,
Illustrate its new opplication in pharmaceutical field.
Application examples 1: tablet
100 are pressed into, often after adding auxiliary material 20g to mix according to the general pressed disc method of pharmacy with 1 compound 10g of embodiment
Slice weight 300mg.
Application examples 2: capsule
With 10 compound 10g of embodiment be packed into hollow glue after auxiliary material 20g being mixed according to the requirement of pharmacy capsule
Capsule, each capsule weight 300mg.
Application examples 3: injection
Activated carbon adsorption is carried out according to pharmacy conventional method with 13 compound 10g of embodiment, is filtered through 0.65 μm of micropore
After film filtering, hydro-acupuncture preparation is made in filling nitrogen gas tank, and every dress 2mL is filling 100 bottles total.
Application examples 4: aerosol
It after distilled water and other spoke material are added, is made after the dissolution of appropriate propylene glycol with 20 compound 10g of embodiment
The clear solution of 500mL to obtain the final product.
Application examples 5: suppository
With 19 compound 10g of embodiment, by finely ground addition glycerol it is appropriate, the glycerin gelatine melted is added after grinding well,
Grinding uniformly, is poured into the model for having applied lubricant, and suppository 50 is made.
Application examples 6: film
With 28 compound 10g of embodiment, will be dissolved by heating after the stirrings such as polyvinyl alcohol, medicinal glycerin, water expansion, 80 meshes
Net filtration, then 18 compound of embodiment is added to stirring and dissolving in filtrate, film applicator is film-made 100.
Application examples 7: pill
It is instilled in cryogenic liquid paraffin after being mixed with matrix 50g heating fusings such as gelatin with 17 compound 10g of embodiment,
1000 ball of dripping pill is made altogether.
Application examples 8: externally-applied liniment
With 21 compound 10g of embodiment, according to the auxiliary materials 2.5g mixed grinding such as conventional dose method and emulsifier, then plus
Distilled water is obtained to 200mL.
Application examples 9: ointment
With 26 compound 10g of embodiment, ground well after finely ground with oleaginous bases 500g such as vaseline obtained.
Although describing the present invention by specific embodiment, modification and equivalent variations are for being proficient in this field
It will be apparent from for technical staff, and they are included within the scope of the invention.
Claims (7)
1. a kind of 7- azaindoles containing dihydrogen dazin structure, which is characterized in that structure such as the following general formula I institute
Show:
Wherein:
R1For hydrogen, methyl, ethyl or cyano；
R2The hydrogen or fluorine identical or different selected from 1~4；
X is O or S；
R3 be selected from hydrogen, halogen, (C1~C6) alkyl, (C1~C6) alkoxy, by halogenated (C1~C4) alkyl or (C1~C4)
Alkoxy, (C1~C6) alkyl sulfenyl, the amino replaced by single or double (C1~C6 alkyl), (C1~C6) alkyl amido, (C1
~C6) alkyl sulphinyl, (C1~C6) alkyl acyl, by single or double (C1~C6 alkyl) replace carbamoyl in 1
It is a；
R4 be 1~2 selected from hydrogen, halogen, (C1~C6) alkyl, (C1~C6) alkoxy, by halogenated (C1~C4) alkyl or
(C1~C4) alkoxy, (C1~C6) alkyl sulfenyl, the amino replaced by single or double (C1~C6 alkyl), (C1~C6) alkyl acyl
Amino, (C1~C6) alkyl sulphinyl, (C1~C6) alkyl acyl, the carbamyl replaced by single or double (C1~C6 alkyl)
Base, (C1~C3) alkylenedioxy group.
2. the 7- azaindoles containing dihydrogen dazin structure according to claim 1, it is characterised in that:
R1For hydrogen or methyl；
R2For F, replace position by the ortho position on phenyl ring with X even carbon atom；
X is O；
R3For CH3Or CF3,
R4Fluorine, chlorine, methyl, methoxyl group, trifluoromethyl or trifluoromethoxy are selected from for 1~2.
3. the 7- azaindoles containing dihydrogen dazin structure according to claim 1, it is characterised in that: described logical
The compound of Formulas I is selected from one of following compounds:
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- phenyl -1,6- dihydro
Pyridazine -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (o-tolyl) -1,
6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) oxo-1-1- (3- fluorophenyl)-4- methyl-6-,
6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) oxo-1-1- (4- fluorophenyl)-4- methyl-6-,
6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2,4 dichloro benzene base) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (the bromo- 2- fluorophenyl of 4-) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoromethyl)
Phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1- (3- (trifluoro methoxy
Base) phenyl) -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1- (adjacent first
Phenyl) -1,6- dihydrogen dazin -3- formamide,
1- (2,5- 3,5-dimethylphenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (4- fluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -
6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (3,4- difluorophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (the bromo- 2- fluorophenyl of 4-) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (3- bromophenyl) -4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6-
Oxo -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1- (2- (three
Fluorine methoxyl group) phenyl) -1,6- dihydrogen dazin -3- formamide,
4- methyl-N- (4- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -6- oxo -1- (4- first
Oxygroup) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2,5- 3,5-dimethylphenyl) -4- first
Base -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (2- fluorophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3,4- difluorophenyl) -4- methyl -
6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (the chloro- 4- fluorophenyl of 3-) -4- first
Base -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -1- (3- bromophenyl) -4- methyl -6- oxygen
Generation -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (2- (trifluoro
Methyl) phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (4- ((1H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) -3- fluorophenyl) -4- methyl -6- oxo -1- (4- (methoxy
Base) -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1-
Phenyl -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (2- fluorophenyl) -4- first
Base -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -1- (3- fluorophenyl) -4- first
Base -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (the chloro- 4- fluorophenyl of 3-)-N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) benzene
Base) -4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
1- (2,4 dichloro benzene base)-N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl)-
4- methyl -6- oxo -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1-
(2- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide,
N- (the fluoro- 4- of 3- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) oxygroup) phenyl) -4- methyl -6- oxo -1-
(3- (trifluoromethyl) phenyl) -1,6- dihydrogen dazin -3- formamide.
4. a kind of pharmaceutical composition, comprising compound described in one of claims 1 to 3 and its pharmaceutically acceptable salt as work
Property ingredient and pharmaceutically acceptable excipients.
5. application of the pharmaceutical composition in preparation treatment and/or prevention proliferative disease drug according to claim 4.
6. application of the pharmaceutical composition in the drug of preparation treatment and/or pre- anti-cancer according to claim 4.
7. pharmaceutical composition is in preparation treatment and/or prevention lung cancer, liver cancer, gastric cancer, colon cancer, cream according to claim 4
Application in the drug of gland cancer.
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| Discovery of Pyrrolopyridine-Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities;Kyoung Soon Kim et al.;《J. Med. Chem.》;20081231;第51卷;5330-5341 |
| Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress;J. Jean Cui;《J. Med. Chem.》;20130909;第57卷;4427-4453 |
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