CN107311983A - Indoles micromolecular C MET inhibitor - Google Patents
Indoles micromolecular C MET inhibitor Download PDFInfo
- Publication number
- CN107311983A CN107311983A CN201710544705.3A CN201710544705A CN107311983A CN 107311983 A CN107311983 A CN 107311983A CN 201710544705 A CN201710544705 A CN 201710544705A CN 107311983 A CN107311983 A CN 107311983A
- Authority
- CN
- China
- Prior art keywords
- compound
- bases
- methyl
- pyrroles
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/14—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 three or more hetero rings
Abstract
The invention belongs to pharmaceutical technology field, there is provided the Benzazole compounds for treating the cancers such as lung cancer, breast cancer, kidney, cancer of pancreas, colorectal cancer and stomach cancer.
Description
Technical field
The application belongs to pharmaceutical technology field, and in particular to the high activity indoles C-MET that a class acts on C-MET suppresses
Agent.
Background technology
C-MET is the member of tyrosine kinase growth factor receptor family, and it, which is expressed, occurs in endothelial cell, epithelial cell
In mesenchymal cell.Different from other kinases, positive receptor tyrosine kinase c-Met is used as the pass in tumor signal network path
Key node albumen, can with cell surface other kinases, acceptor interaction and receive much concern.Cancers of the c-Met in the overwhelming majority
And height is expressed and abnormal activation in the sarcoma of part, played in links such as tumor development, invasion and attack transfer, chemoresistants
Key effect.
Now it has been reported that a variety of C-MET inhibitor, however, for not it has been found that have and suppress C-MET effects
Compound stills need constantly to be explored, to hope effect improve.This application provides being considered to have by suppressing C-MET and
The new indole compound of the clinical application for the treatment of cancer.
The content of the invention
This application provides the compound or pharmaceutically acceptable salt thereof of Formulas I.
The compound of following structural formula：
,
Wherein：
R1It is H or methyl；
R2It is H or methyl；
R3It is phenyl or contraposition F, amino or methyl substituted phenyl；
R4It is H or methyl；
R5It is H or F；
X and Y are O, S, amide groups or ester group, and the two can be with identical, also can be different；
Z is amino, dimethylamino, fluorine, cyclopropyl, the pyrroles optionally replaced by amino-substituent or 1-2 methyl substituents
Base, the pyrazolyl optionally replaced by two methyl substituents, 2- methoxy-pyrimidine -5- bases, 4- methylsulfonyl phenyls, tetrahydrochysene -
2H- pyrans -4- bases-amino,（Tetrahydrochysene -2H- pyrans -4- bases）Amino carbonyl or morpholine -4- base substituents：
,
Wherein Ra、RbAnd RcIndependently selected from H or methyl.
Compound or pharmaceutically acceptable salt thereof provided herein can be used for treatment lung cancer, breast cancer, colorectal cancer, kidney,
Cancer of pancreas, head cancer, heredity Papillary Renal Cell Carcinoma, childhood hepatocellular carcinoma and stomach cancer in cancer.
The compound of the application is amine, and the compound of most of or whole the application can be with many inorganic acids and having
Machine acid reaction formation medicinal acid addition salt.This medicinal acid addition salt and its common preparation method are in this area many institute's weeks
Know, the preferred pharmaceutical salts of the application are mesylates.
It is preferred that compound of formula I, wherein：
(a1)R1It is H；
(a1)R1It is methyl；
(b1)R2It is H；
(b2)R2It is methyl；
(c)R1It is H, and R2It is H；
(d1)R3It is phenyl；
(d2)R3It is 4- fluorophenyls；
(d3)R3It is 4- aminophenyls；
(d4)R3It is 4- aminomethyl phenyls；
(e)R1It is H, R2It is H, R3It is 4- fluorophenyls；
(f1)R4It is H；
(f2)R4It is methyl；
(g)R1It is H, R2It is H, R3It is 4- aminomethyl phenyls, R4It is methyl；
(h1)R5It is H；
(h2)R5It is F；
(i)R1It is H, R2It is H, R3It is 4- fluorophenyls, R4It is methyl, R5It is H；
(j1) Z is the morpholine -4- bases of amino, dimethylamino, cyclopropyl, pyrroles -3- bases, pyrazoles -4- bases or following formula：
；
(j2) Z is amino, dimethylamino, pyrroles -3- bases, pyrazoles -4- bases or morpholine -4- bases；
(j3) Z is pyrroles -3- bases, pyrazoles -4- bases；
(j4) Z is pyrroles's -3- bases；
(k)R1It is H, R2It is H, R3It is 4- fluorophenyls, R4It is methyl, R5It is H, Z is pyrroles's -3- bases；
(l1) X is methylene, O, NH, S, amide groups or carboxyl；
(l2) X is amide groups, carboxyl；
(l4) X is amide groups；
(l5) X is ester group；
(m1) Y is O, S, amide groups or ester group；
(m2) Y is O, S, amide groups or carboxyl；
(m3) Y is O, S；
(m4) Y is O；
(m5) Y is amide groups；
(n)R1It is H, R2It is H, R3It is 4- fluorophenyls, R4It is methyl, R5It is H, Z is pyrroles's -3- bases, and X is amide groups, and Y is O；
(o) R1It is H, R2It is H, R3It is 4- fluorophenyls, R4It is methyl, R5It is H, Z is pyrroles's -3- bases, and X is amide groups, and Y is ester
Base.
The compound of the application can pass through side that is known in this field and understanding completely according to following synthetic reaction route
Prepared by method, suitable reaction condition the step of these reaction schemes is well known in the art.Prepare the compound of the application
Required particular step order depends on the relative of the specific compound, initial compounds and substitution structure division to be synthesized
Tendentiousness, this is that skilled chemist fully understands.Unless otherwise indicated, all substituents are as defined above, and
All reagents are well known in the present art.
The compound of the application can be synthesized as shown in following reaction scheme, and group is as defined above.
Reaction scheme I：
。
Compound 8 can be prepared as shown in above-mentioned reaction scheme, wherein R4’, Z ' and R5As defined above.
Compound 1 is reacted in the presence of suitable alkali at high temperature with compound 2, can obtain compound 3, compound 3
Methylated with appropriate methylating reagent such as methyl iodide in suitable solvent in suitable alkali, so that compound 4 is obtained, its
Middle R4’It is methyl.Compound 3 can also be with the protection reagent such as DHP being adapted in appropriate solvent such as THF, in acid such as methyl sulphur
Protected in the presence of acid, so as to obtain compound 4, wherein R4’It is that (protection group is introduced and removed protection group such as 2- THP trtrahydropyranyls
Method is well known in the present art).
Compound 4 can react under the coupling condition that various transition metal promote, so as to provide with as determined above
The appropriate substituted Z ' of justice compound 5.More specifically, if carbon-to-carbon is coupled, compound 5 can be in such as Suzuki
With suitable boric acid, appropriate catalyst such as PdCl under the coupling condition of coupling etc2(dppf) fitted with the appropriate CsF such as that subtracts
Prepared at high temperature in the solvent such as 1,4- dioxanes of conjunction.If carbon-to-nitrogen is coupled, compound 5 can be in such as Buchwald-
With appropriate nitrogenous reaction reagent such as morpholine, suitable part such as 2- under the coupling condition of Hartwig coupling reactions etc
- 2 '-methyl biphenyl of di-t-butyl phosphino-, alkali such as potassium hydroxide and catalyst such as Pd (dba)3In appropriate solvent such as the tert-butyl alcohol
Prepare at high temperature.Coupling reaction can be again under the conditions of common heating or well known to a person skilled in the art microwave reaction bar
Carried out under part.
Compound 5 can be reduced to amino-compound under well known to a person skilled in the art various reducing conditions.More
Say, compound 5 can such as ethyl acetate/ethanol reacts at high temperature in suitable solvent with stannous chloride body, so that
To required compound 6.If R4’It is nitrogen-protecting group, protection group will be split off, R4’To be proton after the reduction.
Compound 5 can also be by reacting or palladium carbon catalytic hydrogenation with N, N- Dimethylhydrazines and iron chloride in appropriate solvent
Reduction.Nitro is only reduced to amino by both reducing conditions, and nitrogen-protecting group R4’Keep constant.
The compound of the application can be by preparing well known to a person skilled in the art standard peptide coupling condition.Compound
6 react to obtain compound 8 with compound 7 under peptide coupling reagent effect.If R4’Be suitable nitrogen protection group or
Z ' is the functional group protected with nitrogen-protecting group, then needs to be deprotected to obtain the compound of the application.
Reaction scheme II：
。
Compound 7 can be prepared as shown in above-mentioned reaction scheme, wherein R4’’、Z’’And R5As defined above.
Compound 1 and appropriate methylating reagent such as methyl iodide methylate acquisition in suitable solvent in the alkali being adapted to
Compound 2, wherein R4’It is methyl；Compound 1 can also protect reagent such as DHP in appropriate solvent such as THF with what is be adapted to,
Protected in the presence of acid such as pyrovinic acid, so as to obtain compound 2, wherein R4’It is protection group, such as 2- THP trtrahydropyranyls, protection group is drawn
The method for entering and removing is well known in the present art.Compound 2 can obtain compound 3 in reaction under suitable alkali.
Compound 3 can react under the coupling condition that various transition metal promote, so as to provide with as determined above
The appropriate substituted Z ' of justice compound 4.More specifically, if carbon-to-carbon is coupled, compound 4 can be in such as Suzuki
With suitable boric acid, appropriate catalyst such as PdCl under the coupling condition of coupling etc2(dppf) fitted with appropriate alkali such as CsF
Prepared at high temperature in the solvent such as 1,4- dioxanes of conjunction.If carbon-to-nitrogen is coupled, compound 4 can be in such as Buchwald-
With appropriate nitrogenous reaction reagent such as morpholine, suitable part such as 2- under the coupling condition of Hartwig coupling reactions etc
- 2 '-methyl biphenyl of di-t-butyl phosphino-, alkali such as potassium hydroxide and catalyst such as Pd (dba)3In appropriate solvent such as the tert-butyl alcohol
Prepare at high temperature.Coupling reaction can be again under the conditions of common heating or well known to a person skilled in the art microwave reaction bar
Carried out under part.
Compound 4 can be reduced to amino-compound under well known to a person skilled in the art various reducing conditions.More
Say, compound 4 can such as ethyl acetate/ethanol reacts at high temperature in suitable solvent with stannous chloride body, so that
To required compound 5.If R4’It is nitrogen-protecting group, protection group will be split off, R4’To be proton after the reduction.
Compound 4 can also be by reacting or palladium carbon catalytic hydrogenation with N, N- Dimethylhydrazines and iron chloride in appropriate solvent
Reduction.Nitro is only reduced to amino by both reducing conditions, and nitrogen-protecting group R4’Keep constant.
The compound of the application can be by preparing well known to a person skilled in the art condition.Compound 5 and compound 6
Reaction is so as to obtain compound 7 under the effect of suitable reagent.If R4’’It is the protection group or Z of suitable nitrogen’’It is to be protected with nitrogen
The functional group of base protection is protected, then needs to be deprotected to obtain the compound of the application.
Example is embodied
The application is described in more detail below in conjunction with example, but not as the limitation to the application.
Embodiment 1：6- bromo- 5- (4-nitrophenoxy) -1H- indoles
By the bromo- 5- hydroxyls -1H- indoles of 7.5g 6-, 4.7g4- fluoronitrobenzenes, 2.8gNaHCO3It is added in DMF, heat temperature raising
To 80 DEG C of stirring reaction 5h.10% lithium chloride is added, ethyl acetate extraction, anhydrous magnesium sulfate is dried organic phase, filtered, concentration.Post
Chromatographic purification is separated（Petroleum ether：Dichloromethane=1:1）, obtain product 6.2g, yield 56%.MS(m/z)：334.1（M+H）.
Embodiment 2：6- bromo- 5- (4-nitrophenoxy) -1- Methyl-1H-indoles
Weigh the bromo- 5- of 6.0g6- (4-nitrophenoxy) -1H- indoles and 1.3g potassium hydroxide is added in 150ml acetone, ice-water bath
Cooling, is added dropwise 1ml methyl iodides, and completion of dropping is reacted 3h in 0 DEG C, is stirred overnight at room temperature.Except molten, gained solid column chromatography point
From purification, product 5.2g, yield 84% are obtained.MS(m/z)：348.2（M+H）.
Embodiment 3：6- bromo- 5- (4-nitrophenoxy) -1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- indoles
Into the 40ml tetrahydrofuran solutions added with 5.0g6- bromo- 5- (4-nitrophenoxy) -1H- indoles add 2.5gDHP and
1.0g pyrovinic acids, at room temperature stirring reaction 1.5h.Ethyl acetate and sodium bicarbonate aqueous solution are added, organic phase is separated, it is anhydrous
Magnesium sulfate is dried, and is filtered, and concentration, column chromatography purification ＆ isolation obtains product 5.6g, yield 89%.MS(m/z)：418.3（M+H）.
Embodiment 4：5- (4-nitrophenoxy) -6- (1H- pyrroles -3- bases) -1- Methyl-1H-indoles
By 5.0g6- bromo- 5- (4-nitrophenoxy) -1- Methyl-1H-indoles, 4.0g3- pyrrol boronic acids, 2.3gPdCl2(dppf)
80ml1 is dissolved in 6.5gCsF, 4- dioxanes are heated at 110 DEG C and are stirred overnight.Add aqueous ammonium chloride solution and acetic acid
Ethyl ester is extracted, and separates organic phase, and anhydrous magnesium sulfate is dried, and is filtered, concentration, and column chromatography for separation purification obtains product 3.8g, yield
79%.MS(m/z)：334.3（M+H）.
Embodiment 5：3- (1- methyl -5- (4-nitrophenoxy) -1H- indoles -6- bases) -1H- pyrroles's -1- t-butyl formates
Added into the 80mlTHF solution of 3.5g5- (4-nitrophenoxy) -6- (1H- pyrroles -3- bases) -1- Methyl-1H-indoles
3.5g di-tert-butyl dicarbonates and 15ml triethylamines, stirring reaction 4h, adds ethyl acetate and saturated ammonium chloride is water-soluble at room temperature
Liquid, separates organic phase, and anhydrous magnesium sulfate is dried, and is filtered, concentration, and column chromatography purification obtains product 3.3g, yield 73%.MS(m/z)：
434.5（M+H）.
Embodiment 6：3- (1- methyl -5- (4- amino-benzene oxygens) -1H- indoles -6- bases) -1H- pyrroles's -1- t-butyl formates
2.5g3- (1- methyl -5- (4-nitrophenoxy) -1H- indoles -6- bases) -1H- pyrroles's -1- t-butyl formates are dissolved in
THF, adds 0.25g5%Pd/C, in being heated to 45 DEG C of reaction 10h under hydrogen environment, cools, filters, concentration obtains product 2.1g,
Yield 91%.MS(m/z)：404.5（M+H）.
Embodiment 7：5- (4-nitrophenoxy) -6- (1H- pyrroles -3- bases) -1H- indoles（Deprotection）
3.0g5- (4-nitrophenoxy) -6- (1H- pyrroles -3- bases) -1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- indoles（Prepare
With reference to embodiment 4）20ml ethanol is dissolved in, 7ml concentrated hydrochloric acids is slowly added to, finishes, 80 DEG C of reaction 2h.Add sodium bicarbonate aqueous solution
And ethyl acetate, point liquid, anhydrous magnesium sulfate drying organic phase, concentrate, column chromatography for separation purification obtains product 2.1g, yield 88%.
MS(m/z)：320.3（M+H）.
Embodiment 8：4- ((6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) aniline (example 41)（Nitro is reduced）
2.0g5- (4-nitrophenoxy) -6- (1H- pyrroles -3- bases) -1H- indoles and 11.0g stannous chloride dihydrates exist
The mixed solution of 150ml ethyl acetate and ethanol（1/1）In in 80 DEG C of stirring reaction 15h, add sodium bicarbonate aqueous solution and second
Acetoacetic ester, point liquid, anhydrous magnesium sulfate dries organic phase, filters, concentration, column chromatography for separation purification, obtains product 1.2g, yield 67%.
MS(m/z)：290.3（M+H）.
Embodiment 9：The bromo- 5- hydroxyls -1- Methyl-1H-indoles of 6-
Weigh the bromo- 5- hydroxyls -1H- indoles of 5.0g6- and 2.0g potassium hydroxide is added in 50ml acetone, ice-water bath cooling is added dropwise
2ml methyl iodides, completion of dropping reacts 2h in 0 DEG C, at room temperature stirring reaction 20h.Except molten, gained solid column chromatography for separation is carried
It is pure, obtain product 4.3g, yield 81%.MS(m/z)：227.1（M+H）.
Embodiment 10：The bromo- 5- hydroxyls -1- of 6- (tetrahydrochysene -2H- pyrans -2- bases) -1H- indoles
4.0gDHP and 1.5g pyrovinic acids are added into the 40ml tetrahydrofuran solutions of the bromo- 5- hydroxyls -1H- indoles containing 5.0g6-,
Stirring reaction 1h at room temperature.Ethyl acetate and sodium bicarbonate aqueous solution are added, organic phase is separated, anhydrous magnesium sulfate is dried, filtering,
Concentration, column chromatography purification ＆ isolation obtains product 5.9g, yield 84%.MS(m/z)：297.2（M+H）.
Embodiment 11：(the bromo- 1- Methyl-1H-indoles -5- bases of 6-) paranitrobenzoic acid ester
0.5g dicyclohexylcarbodiimides are added into the 50ml acetone solns of the bromo- 5- hydroxyls -1- Methyl-1H-indoles of 5.0g6-
With 7.4g paranitrobenzoic acids, heat temperature raising, back flow reaction 13h, concentration adds ethyl acetate, is heated to backflow, while hot mistake
Filter, filtrate concentration, dichloromethane mashing is filtered, dries, obtain product 5.9g, yield 74%.MS(m/z)：362.2（M+H）.
Embodiment 12：(1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) paranitrobenzoic acid ester
By 3.0g (the bromo- 1- Methyl-1H-indoles -5- bases of 6-) paranitrobenzoic acid ester, 1.8g3- pyrrol boronic acids 110.9,
1.3gPdCl2(dppf) and 3.8gCsF is dissolved in 100ml1,4- dioxanes are heated at 110 DEG C and are stirred overnight.Add chlorine
Change aqueous ammonium and ethyl acetate extraction, separate organic phase, anhydrous magnesium sulfate is dried, and is filtered, concentration, column chromatography for separation purification,
Obtain product 2.0g, yield 67%.MS(m/z)：362.1（M+H）.
Embodiment 13：(1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) P aminobenzoates
1.0g (1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) paranitrobenzoic acid ester is dissolved in 15mlTHF, plus
Enter 0.1g5%Pd/C（Removed water before adding）, in being heated to 65 DEG C of reaction 5h under hydrogen environment, cool, filter, concentration obtains product
0.8g, yield 84%.MS(m/z)：332.4（M+H）.
Embodiment 14：2- oxo -1,2- dihydropyridine -3- methyl formates
8g2- hydroxy niacins, the 2ml concentrated sulfuric acids, 300ml methanol and 70ml toluene are added into reaction bulb, backflow, reaction is heated to
Overnight.Cooling down is filtered to room temperature, concentration, and 150ml dichloromethane dissolving, saturated sodium bicarbonate aqueous solution is neutralized, 150ml
Dichloromethane is extracted, and is dried, and concentration obtains product 6.5g, yield 74%.MS(m/z)：154.0（M+H）.
Embodiment 15：1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- methyl formates
250ml dichloromethane, 5.0g 2- oxo -1,2- dihydropyridine -3- methyl formates, 14.0g4- fluorine are added into reaction bulb
Phenylboric acid, 12.0g copper acetates, 10.0g pyridines, add 4g4A molecular sieves, are stirred overnight at room temperature, filter, water washing, filtrate
Extract, anhydrous magnesium sulfate dries organic phase, filter through 100ml dichloromethane, concentration, column chromatography for separation purification obtains product 8.0g,
Yield 99.6%.MS(m/z)：248.1（M+H）.
Embodiment 16：1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formic acid
Weigh 5.0g1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- methyl formates be dissolved in 100ml75% methanol it is water-soluble
In liquid, 1.0gKOH is added, reaction 0.5h is stirred at room temperature.Distillation removes methanol, and concentrated hydrochloric acid to white solid precipitation is slowly added dropwise and does not exist
Increase, filtering, water washing is dried, product 4.4g, yield 94% needed for obtaining.MS(m/z)：234.2（M+H）.
Embodiment 17：N- (4- ((1- methyl -6- (- 1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) phenyl) -1-
(4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides
Weigh 1.4g 3- (1- methyl -5- (4- amino-benzene oxygens) -1H- indoles -6- bases) -1H- pyrroles -1- t-butyl formates and
1.3g1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formic acid, 1.5gEDCl, 0.8gHOBt adds to reaction bulb, measured
15mlDMF, 2mlDIPEA, reaction solution at room temperature stay overnight by stirring reaction.Add the dilution of 300ml ethyl acetate, saturated sodium-chloride
Solution is washed, ethyl acetate aqueous phase extracted, merges organic phase, and anhydrous magnesium sulfate is dried, filtering, and revolving removes solvent, column chromatography point
From purification.
50ml dichloromethane dissolving gained is measured, triethyl silicane 2ml, 18mlTFA is added, at room temperature stirring reaction 2h.
Except molten, 150ml dichloromethane is added, saturated sodium bicarbonate aqueous solution is washed twice, point liquid, anhydrous sodium sulfate drying, decompression is steamed
Distillation is molten, and gained residue purifies to obtain target product 1.0g through column chromatography for separation, in pale solid shape, yield 57%.MS(m/
z)：519.5（M+H）.
Embodiment 18：N- (4- ((1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) phenyl) -1-
(4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides
By 4- (6- (1H- pyrroles -3- bases) -1H- indoles -5- bases epoxide) aniline（9mmol）With 1- (4- fluorophenyls) -2- oxygen
Generation -1,2- dihydropyridine -3- formic acid（11.2mmol）Add in 50mlDMF, add HOBt（10mmol）、EDCl（10mmol）With
5mlN- methyl morpholines.It is heated to 60 DEG C of reactions to stay overnight, adds ethyl acetate and saturated aqueous ammonium chloride, point liquid is organic
Mutually dry, concentration, ethyl acetate mashing is filtered, dries, obtain target product, yield 50%.MS(m/z)：519.5（M+H）.
Embodiment 19：N- (4- ((1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) phenyl) -1-
(4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- carboxamide mesylate salts
By above-mentioned gained N- (4- ((1- methyl -6- (- 1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) phenyl) -1- (4- fluorine
Phenyl) -2- oxo -1,2- dihydropyridine -3- formamides are dissolved in acetone solvent, and pyrovinic acid is added, reaction is stirred at room temperature
1h, except molten, ether elution, dries, obtains the mesylate of target product, yield 95%.MS(m/z)：615.2（M+H）.
Embodiment 20：(1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) -4- (1- (4- fluorophenyls) -2- oxygen
Generation -1,2- dihydropyridine -3- formamidos) benzoic ether
By (1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) P aminobenzoates（9mmol）With 1- (4- fluorobenzene
Base) -2- oxo -1,2- dihydropyridine -3- formic acid（15mmol）Add in 70mlDMF, add HOBt（12mmol）、EDCl
（11mmol）With 6mlN- methyl morpholines.It is heated to 50 DEG C of reactions to stay overnight, adds ethyl acetate and saturated ammonium chloride is water-soluble
Liquid, point liquid, organic phase is dried, concentration, ethyl acetate mashing, is filtered, is dried, obtain target product, yield 50%.MS(m/z)：
547.6（M+H）.
Application content define compound refer to give way of example preparation, but be not limited to the method.
The general principle of the application, principal character and advantage has been shown and described above.The technical staff of the industry should
Understand, the application is not restricted to the described embodiments, the original for simply illustrating the application described in above-described embodiment and specification
Reason, on the premise of spirit and scope is not departed from, the application also has various changes and modifications, and these change and changed
Enter and both fall within claimed scope.This application claims scope by appended claims and its equivalent thereof.
Following experiment proves that the compound of some the application effectively suppresses the c-Met phosphorylations in cell, effectively
Suppress in vivo c-Met, and demonstrate in some heteroplastic transplantation models dose-dependent antitumor activity.
C-Met protein expressions and purification
People c-Met kinase domain is cloned into pFastBacHT carriers.Using Bac-to-Bac systems by His-c-Met
KD structure swivel bases are into baculovirus DNA.SF9 cell recombinate shape virus infections.The infected cell by centrifuge come
Harvest, collects cell granulations, is stored at -80 DEG C.Cell dissolves in buffer A.By cell dissolved matter homogeneity and centrifugation.
Supernatant is incubated with NTA nickel resin, is loaded into post.Protein is eluted with buffer B, by the level containing c-Met
Divide and pool together, be filled into Superdex®In 200 posts, buffer solution C elutions.
The Met that HGF is stimulated（pY1349）NCI-H460 cellular types ELISA
NCI-H460 cells are cultivated in the culture mediums of RPMI 1640 for be supplemented with 10% hyclone, with 20000 cells/wells
Density and 80 μ L volumes platings are into 96 hole level land plates.Cell and then the overnight incubation in cell culture couveuse, and make
Be attached on plate.Next morning, cell is washed with the low blood serum medium of two volumes.Remove last time washing lotion it
Afterwards, 80 μ L RSM is added in each hole of cell plates.Cell plates are incubated 2.5h in cell culture couveuse, it is fixed
Amount adds compound.Compound inhibitor is dissolved in 100% dimethyl sulfoxide with 10mM first, then with 2%DMSO RSM dilutions
To 100 μM.Then, the series of compounds dilution in the range of 100 μM -0.005 μM is prepared（1:3）20 μ are added in cytolytic dose
L compound is got the raw materials ready, to produce final compound concentration dose between 0.4% final DMSO concentration and 20-0.001 μM.Fixed
After amount addition compound, cell plates are gently agitated for mix, then 30min are incubated in cell culture couveuse.Fixed
After the completion of amount addition, pierced by adding the HGF in 20 μ L/ holes with the ultimate density of the 100ng/ml in RMS
Swash cell.After being incubated 10 minutes in cell culture couveuse, liquid is removed from cell plate hole, phosphoric acid is supplemented with by addition
50 μ L of enzyme I and II and protease inhibitors ice-cold MesoScale Discovery®1X dissolves buffer solution to make cell
Dissolving.After dissolving 30 minutes at room temperature, dissolved matter is shifted and captured the MSD of BSA closings®The hole 4- of Multi-Spot 96
On spot PhosphoMet plates, then it washed once with Tris lavation buffer solutions.Captured at 2 hours（At room temperature）Afterwards,
From MSD®Dissolved matter is removed on plate, then plate is washed with 1X Tris lavation buffer solutions.After trace, by 25 μ L 5nM
Sulfo-Tag Anti-Total Met antibody is added to MSD®In the hole of plate.After 1 hour captures, MSD®Plate hole 1X
Tris lavation buffer solutions are washed, and then add 150 μ L 1X Read Buffer T.After addition Read Buffer, immediately
With the MSD of SECTOR 6000®Imager plate reader analysis plates.With respect to IC50Value uses MSD®Active unit by calculate relative to
The suppression percentage of " MIN " and " MAX " tester on plate, then will suppress fraction values and ten dose point response datas is fitted to
Four parameter logistics this base of a fruit equations is determined.The experiment has 2.06 minimum significance ratio（MSR）.For all embodiments
Compound, IC50Value is less than 0.2 μM.For example, embodiment 1 in this experiment is averaged（n=6）IC50Value is 0.0352 μM, indicates it
Effectively suppress the c-Met phosphorylations in cell.
In vivo target spot suppresses experiment to c-Met
S114 cells are cultivated and extended in the growth medium for being supplemented with 10% hyclone.Harvesting, uses phosphate-buffered
Salt solution is washed twice, by 2*106Individual cell and isometric BD MatrigelTMMatrix is mixed, and is subcutaneously injected into the flank of nude mice
In.8 days after the implants, by oral gavage, compound is delivered medicine into animal with 50mg/kg.Put to death within 2 hours upon administration
Animal, gathers tumour, keeps in cold storage to when needing.
Tumour is freezed to crush using mortar-pestle.The crushing tissue is transferred to equipped with Lysing Matrix D beads and
In the pipe of 600 μ L dissolving buffer solutions.Come disrupting tissue and cell lysis using FastPrep cell crushing instruments.Dissolved matter passes through 20
Number pin, is transferred in cleaning pipe.Protein concentration is determined by Bradford methods.
Tumor lysis thing is loaded into MSD®On phosphor-Met ELISA plates, phosp-
Hor-c-Met levels are determined using with H460 cellular types ELISA identicals operational procedure.For all embodiment chemical combination
Thing, in vivo inhibiting value is equal to or more than 50% to S114 under 50mg/kg dosage.For example, the compound of embodiment is c-
Effective suppression machine of Met phosphorylations, the ED with 2.9mg/kg50Value, it is effective in vivo c-Met inhibitor to indicate it.
Xenograft Tumor Models
People's Malignant glioma cells U87MG, gastric carcinoma cells MKN45, Non-small cell lung carcinoma cell H441 and people's kidney is thin
Born of the same parents' Caki-1 amplification cultivations, collection, and be subcutaneously injected on the hind flank of nude mouse.Test compound is in appropriate carrier
Prepare, be administered when setting up tumour by oral gavage.Tumor response is swollen by what is carried out twice a week over the course for the treatment of
Knurl cubing is determined.Gross tumor volume suppresses to calculate with vehicle Control group by comparison therapy group.Body weight is used as toxicity
General criterion.The compound of embodiment demonstrates excellent dose-dependent antitumor activity in these models.When
When dosage is 1.5mg/kg, the compound of embodiment can result in 56% growth inhibition of U87MG tumours.In 4.5mg/kg dosage
When, obtain 80% growth inhibition.Reached in 12.5mg/kg dosage 88% growth inhibition.
C-Met related neoplasms and heteroplastic transplantation model
C-Met overexpressions are to include lung tumors, tumor of breast, colorectal tumours, tumor stomach, tumor of kidney, pancreas
The common trait of many human tumors including tumour, head and tumor colli.C-Met activated mutants in kinase domain are dark
The reason for being shown as several tumours.
The compound of the application is prepared preferably as the pharmaceutical composition being administered by all means.Most preferably, this group
Compound is used to be administered orally.This pharmaceutical composition and preparation method thereof is known in the field.
The general compound of the application is effective in wide dosage range.For example, daily dose is normally to about in about 1mg
200mg total daily doses, preferably 1mg to 150mg total daily doses.In some cases, the dosage below the lower limit of above range
Level may be more than sufficient, and in other cases, can use bigger dosage.Above dosage range is not intended to any
Mode is left unused scope of the present application.The amount of the compound of administration should determine according to correlation circumstance, including to be treated disease, institute
The method of administration of selection, one or more compounds, the age of individual patient, body weight and the reaction of actual administration and patient's disease
The order of severity of shape.
Claims (10)
1. following formula: compound or its pharmaceutical salts：
,
Wherein：
R1It is H or methyl；
R2It is H or methyl；
R3It is phenyl or contraposition F, amino or methyl substituted phenyl；
R4It is H or methyl；
R5It is H or F；
X and Y are O, S, amide groups or ester group, and the two can be with identical, also can be different；
Z is amino, dimethylamino, fluorine, cyclopropyl, the pyrroles optionally replaced by amino-substituent or 1-2 methyl substituents
Base, the pyrazolyl optionally replaced by two methyl substituents, 2- methoxy-pyrimidine -5- bases, 4- methylsulfonyl phenyls, tetrahydrochysene -
2H- pyrans -4- bases-amino,（Tetrahydrochysene -2H- pyrans -4- bases）Amino carbonyl or morpholine -4- base substituents：
,
Wherein Ra、RbAnd RcIndependently selected from H or methyl.
2. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z be amino, dimethylamino, cyclopropyl, optionally
Pyridine radicals, pyrroles -3- bases, pyrazoles -4- bases or the morpholine -4- bases replaced by amino-substituent or 1-2 methyl substituents.
3. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z be amino, pyrroles -3- bases, pyrazoles -4- bases or
Quinoline -4- bases.
4. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z are pyrroles's -3- bases.
5. the compound or pharmaceutically acceptable salt thereof according to claim any one of 1-4, wherein X and Y are amide groups and O or S respectively
Or ester group or amide groups.
6. the compound or pharmaceutically acceptable salt thereof according to claim any one of 1-5, wherein X and Y are amide groups and O or ester respectively
Base.
7. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is
(1- methyl -6- (1H- pyrroles -3- bases) -1H- indoles -5- bases) -4- (1- (4- fluorophenyls) -2- oxo -1,2- dihydro pyrroles
Pyridine -3- formamidos) benzoic ether,
。
8. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is N- (4- ((1- methyl -6-
(1H- pyrroles -3- bases) -1H- indoles -5- bases) epoxide) phenyl) -1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- first
Acid amides,
。
9. the compound or pharmaceutically acceptable salt thereof according to claim any one of 1-4, wherein the pharmaceutical salts are mesylates.
10. the compound or pharmaceutically acceptable salt thereof according to claim any one of 1-9 is used for treating cancer, the cancer is selected from lung
Cancer, breast cancer, kidney, cancer of pancreas, colorectal cancer and stomach cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710544705.3A CN107311983A (en) | 2017-07-06 | 2017-07-06 | Indoles micromolecular C MET inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710544705.3A CN107311983A (en) | 2017-07-06 | 2017-07-06 | Indoles micromolecular C MET inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107311983A true CN107311983A (en) | 2017-11-03 |
Family
ID=60180667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710544705.3A Pending CN107311983A (en) | 2017-07-06 | 2017-07-06 | Indoles micromolecular C MET inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107311983A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010126530A (en) * | 2008-12-01 | 2010-06-10 | Takeda Chem Ind Ltd | Condensed heterocyclic derivative and application thereof |
| CN102105462A (en) * | 2008-07-24 | 2011-06-22 | 伊莱利利公司 | Amidophenoxyindazoles useful as inhibitors of C-MET |
| US20160375142A1 (en) * | 2013-10-28 | 2016-12-29 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
-
2017
- 2017-07-06 CN CN201710544705.3A patent/CN107311983A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102105462A (en) * | 2008-07-24 | 2011-06-22 | 伊莱利利公司 | Amidophenoxyindazoles useful as inhibitors of C-MET |
| JP2010126530A (en) * | 2008-12-01 | 2010-06-10 | Takeda Chem Ind Ltd | Condensed heterocyclic derivative and application thereof |
| US20160375142A1 (en) * | 2013-10-28 | 2016-12-29 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
| CN105237515B (en) | Deuterated pyrimidines, its preparation method, pharmaceutical composition and purposes | |
| CN106883213B (en) | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) | |
| CN106831730B (en) | A kind of substituted diaminopyrimidines and its preparing the purposes in anti-malignant tumor medicine | |
| CN102105462A (en) | Amidophenoxyindazoles useful as inhibitors of C-MET | |
| CN103491960A (en) | Therapeutic compounds and compositions | |
| CN103420977A (en) | Acetylene derivative with anti-tumor activity | |
| CN106995437A (en) | Substituted indole or indazole pyrimidine derivatives and its production and use | |
| CN111303123B (en) | 2- (2,4, 5-substituted anilino) pyrimidine compound and application thereof | |
| CN105669564A (en) | Urea compound and preparation method, medicine composition, intermediate and application thereof | |
| JP2021523168A (en) | Cancer treatments that target cancer stem cells | |
| JP4716996B2 (en) | Sulfopyrrole | |
| CN111732575B (en) | N- (3- (pyrimidine-2-yl) phenyl) benzene sulfonamide derivative, pharmaceutical composition, preparation method and application | |
| CN103382182B (en) | Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage | |
| CN111362925A (en) | 4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application | |
| CN107739368B (en) | N-substituted-5- ((4-substituted pyrimidine-2-yl) amino) indole derivatives, and preparation method and application thereof | |
| CN110642837A (en) | Pyridine amide compound containing triazole or quinolinone structure and application thereof | |
| CN107474039A (en) | Ketone containing triazole and the 4- phenoxy groups substituted quinoline derivatives of imidazoles and its application | |
| CN111116585A (en) | Compound with c-MET kinase inhibitory activity, preparation method, composition and application | |
| CN107311983A (en) | Indoles micromolecular C MET inhibitor | |
| CN113956234B (en) | N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application of antitumor activity | |
| CN109988110A (en) | 4- phenoxyquinolines and sulfonyl urea compound, the intermediate for synthesizing the compound and its preparation method and application | |
| CN106146468B (en) | Pyridone protein kinase inhibitors | |
| CN104277028A (en) | Acridine-1,2,4-triazole-5-thioketone compound and preparation method and applications of acridine-1,2,4-triazole-5-thioketone compound | |
| CN102216280B (en) | Bisarylurea derivatives and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171103 |