CN108033965A - ALK/C-MET double inhibitors and its application - Google Patents
ALK/C-MET double inhibitors and its application Download PDFInfo
- Publication number
- CN108033965A CN108033965A CN201810003122.4A CN201810003122A CN108033965A CN 108033965 A CN108033965 A CN 108033965A CN 201810003122 A CN201810003122 A CN 201810003122A CN 108033965 A CN108033965 A CN 108033965A
- Authority
- CN
- China
- Prior art keywords
- compound
- prodrug
- crystallization
- pharmaceutically acceptable
- solvate
- 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
- GXVXFNAQWFFVMN-UHFFFAOYSA-N C(C(Cc1c2)Cc1c1[n]2ncnc1-c1c[n](C2CCNCC2)nc1)OCc1cnccc1 Chemical compound C(C(Cc1c2)Cc1c1[n]2ncnc1-c1c[n](C2CCNCC2)nc1)OCc1cnccc1 GXVXFNAQWFFVMN-UHFFFAOYSA-N 0.000 description 1
- HKPKZDXQLORHEG-ILDGXJFMSA-O CC1NN(C2CCNCC2)C=C1/C(/c1c(CC(COCc2cccnc2)C2)c2c[nH]1)=N/C(C)=[NH2+] Chemical compound CC1NN(C2CCNCC2)C=C1/C(/c1c(CC(COCc2cccnc2)C2)c2c[nH]1)=N/C(C)=[NH2+] HKPKZDXQLORHEG-ILDGXJFMSA-O 0.000 description 1
- 0 F/C(/C=C/C(/Cl)=C\C(C*CC(Cc1c2)Cc1c1[n]2ncnc1-c1c[n](C2CCNCC2)nc1)C1)=C1/Cl Chemical compound F/C(/C=C/C(/Cl)=C\C(C*CC(Cc1c2)Cc1c1[n]2ncnc1-c1c[n](C2CCNCC2)nc1)C1)=C1/Cl 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to medicinal chemistry arts, it is related to a kind of ALK/C MET double inhibitors and its application, ALK/C MET double inhibitors compound shown in formula I or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, and the pharmaceutical composition containing these compounds and application of these compound or compositions in medicine preparation, the compound has good ALK kinases and C MET inhibitory activity, can effectively reduce Tumor incidence, extend tumor patient life.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of ALK/C-MET double inhibitors and its application, and in particular to one
Class has the compound or its medicine of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor (c-Met) inhibitory activity
Learn acceptable salt, solvate, crystallization or prodrug, and the pharmaceutical composition containing these compounds and these compounds or
Application of the composition in medicine preparation.
Background technology
Receptor type tyrosine kinase anaplastic lymphoma kinase (Anaplastic lymphomakinase, ALK) is sent out earliest
Now in primary cutaneous type (Anaplastic large cell lymphoma, ALCL), by No. 2 and No. 5 dyeing
The fused protein that body transposition is formed, contains 3 ' the end intracellular domain of ALK, and nuclear phosphoprotein
The domain at the 5 ' ends of (Nucleophosmin, NPM).Research is found, in non-small cell lung cancer, ALK positive rates are about
Specific chromosome translocation can occur for 3%-5%, patient, form EML4 and ALK fusion proteins, cause tumour cell because of gene table
Breed and survive up to misregistration signal.
C-MET is a kind of protein product encoded by C-MET proto-oncogenes, is hepatocyte growth factor (HGF) acceptor, tool
There is tyrosine kinase activity, it is related with a variety of oncoproteins and regulatory protein, participate in cellular informatics conduction, cytoskeleton rearrangement
Regulation and control, be cell Proliferation, differentiation and movement an important factor for.Research shows that C-MET and the generation and transfer of a variety of cancers are close
Correlation, massive tumor patient have C-MET transition expression and gene magnification in the mode and transfer process of its tumour.
Gram azoles of U.S. FDA approval listing in 2011 replaces Buddhist nun (Crizotinib), can dose-dependent inhibition tumour cell
C-MET and ALK, the tumour cell that transposition or inversion occurs to ALK gene also have potent inhibitory action.Clinical research shows gram
Azoles replaces Survival be significantly improved effect of the Buddhist nun to ALK positive Patients with Non-small-cell Lung, and tolerance is good, security compared with
Height, can effectively treat the Locally Advanced of the ALK positives or the non-small cell lung cancer of transfer.
Therefore, medicine of the exploitation with C-MET and ALK dual restraining activities, will clinically there is good application
Prospect.
The content of the invention
It is an object of the present invention to provide general formula I one kind have ALK/C-MET dual restraining activities compound or
Its pharmaceutically acceptable salt, solvate, crystallization or prodrug,
Wherein：
X is selected from O, S, N (R3), wherein R3Selected from hydrogen and alkyl；
R1Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, ammonia
Base, cyano group, nitro, alkyl, hydroxy alkyl, carboxyalkyl, alkoxy substitution；
R2Selected from Heterocyclylalkyl, the Heterocyclylalkyl can be by one or more halogens, hydroxyl, carboxyl, amino, cyanogen
Base, nitro, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxy alkyl, carboxyalkyl, alkoxy, alkoxy acyl substitution.
It is a further object to provide comprising the present invention compounds of formula I or its pharmaceutically acceptable salt,
The composition of solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and comprising the present invention compounds of formula I or
The combination of its pharmaceutically acceptable salt, solvate, crystallization or prodrug and one or more protein tyrosine kinase inhibitors
Thing.
The present invention's a further object is the compounds of formula I or its pharmaceutically acceptable salt, solvent for providing the present invention
Compound, crystallization or the method for prodrug treatment and/or pre- preventing tumor, and the compounds of formula I of the present invention or its pharmacy can connect
Application of salt, solvate, crystallization or the prodrug received in preparing for the medicine for the treatment of and/or pre- preventing tumor.
For above-mentioned purpose, the present invention provides following technical scheme：
In a first aspect, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, solvate, crystallization or preceding
Medicine,
Wherein：
X is selected from O, S, N (R3), wherein R3Selected from hydrogen and alkyl；
R1Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, ammonia
Base, cyano group, nitro, alkyl, hydroxy alkyl, carboxyalkyl, alkoxy substitution；
R2Selected from Heterocyclylalkyl, the Heterocyclylalkyl can be by one or more halogens, hydroxyl, carboxyl, amino, cyanogen
Base, nitro, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxy alkyl, carboxyalkyl, alkoxy, alkoxy acyl substitution.
In some preferred embodiments, compound of the invention is compounds of formula I and its pharmaceutically acceptable
Salt, solvate, crystallization or prodrug, wherein：
X is O；
R1Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, C1-6Alkyl, C1-6Alkane
Epoxide substitutes；
R2Selected from azacycloalkyl, the azacycloalkyl can be by one or more halogens, C1-6Alkyl, alcoxyl acyl
Base substitutes.
In some highly preferred embodiments, compound of the invention can connect for compounds of formula I and its pharmacy
Salt, isomers, solvate, crystallization or the prodrug received, wherein：
X is O；
R1Selected from phenyl, pyridine radicals, indyl, furyl, benzofuranyl, the phenyl, pyridine radicals, indyl,
Furyl, benzofuranyl can be by one or more halogens, C1-3Alkyl, alkoxy substitution；
R2For piperidyl, the piperidyl can be substituted by alkoxy acyl.
The present invention provides compound in detail below：
Present invention also offers the following key intermediate for preparing the compounds of this invention：
On the other hand, the present invention provide pharmaceutical composition, it includes the present invention compound or its pharmaceutically acceptable salt,
Solvate, crystallization or prodrug.
In some embodiments, the present invention provide pharmaceutical composition, it includes the present invention compound, solvate,
Crystallization or prodrug, also include the one or more selected from following composition：Tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR
Inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, histone deacetylase
Enzyme inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..
Can by the present invention compound, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, diluent or
Excipient is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to it is intracutaneous,
It is intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as be passed through
It is transfused or injects, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) is applied.Administration can be with
It is whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including tablet, pill,
Granula, pulvis, capsule, syrup, emulsion, supensoid agent etc..The preparation can be prepared by methods known in the art, and comprising
The conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
The third aspect, the present invention provide compound, solvate, crystallization or the prodrug of the present invention or the medicine group of the present invention
Compound treats or prevents the method for tumour and the application in prevention or tumor is prepared, including easily sends out crowd to tumour
Or tumor patient applies compound, isomers, solvate, crystallization or the prodrug of the present invention or includes the chemical combination of the present invention
Thing, isomers, solvate, the pharmaceutical composition of crystallization or prodrug, effectively to reduce Tumor incidence, extend tumor patient life
Life.
Term explanation
" alkyl " of the present invention refers to the saturated hydrocarbyl of straight or branched.
" alkoxy " of the present invention refers to-O- alkyl.
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine.
" alkoxy acyl " of the present invention refers to-C (O)-O- alkyl.
" aryl " of the present invention refers to the aromatic hydrocarbon group containing one or more phenyl ring.Suitable aryl includes phenyl, naphthalene
Base.
" heteroaryl " of the present invention refers to the aromatic radical that at least one carbon atom is substituted by hetero atom in aryl.Institute
The hetero atom stated is O, S, N.
The present invention " solvate " refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and
The compound that solvent (such as water) combination is formed.Solvent refers to solvent known to those of skill in the art or easily definite.Such as
Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the present invention refers to that the various solid forms that compound of the present invention is formed, including crystal form, nothing are determined
Shape.
" prodrug " of the present invention refer under the physiological condition of organism, due to the reaction such as enzyme, hydrochloric acid in gastric juice and conversion cost
The compound of the compound of invention, i.e., the compound for the compound invented by conversion costs such as the oxidations, reduction, hydrolysis of enzyme
And/or the compound of the compound of the conversion cost such as hydrolysis by hydrochloric acid in gastric juice etc. invention.
" the pharmaceutically acceptable salt " of the present invention refers to the pharmaceutically acceptable salt that the compound of the present invention is formed with acid,
The acid include but not limited to phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, butanedioic acid,
Fumaric acid, acetic acid, lactic acid, nitric acid etc..
" pharmaceutical composition " of the present invention refers to include any type compound as described herein, including isomers, prodrug,
Solvate, pharmaceutically acceptable salt or its chemical forms of protection, and one or more pharmaceutically acceptable carriers are mixed
Compound.
" pharmaceutically acceptable carrier " of the present invention refer to not cause obvious irritation to organism and do not disturb to
Give the bioactivity of compound and the carrier of property, comprising solvent, diluent or other excipient, dispersant, surfactant,
Isotonic agent, thickener or emulsifying agent, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention
Compound is incompatible.It can include, but are not limited to carbohydrate as some examples of pharmaceutically acceptable carrier, such as lactose, Portugal
Grape sugar and sucrose；Starch, such as cornstarch and farina；Cellulose and its derivates, such as sodium carboxymethylcellulose and
Cellulose and cellulose acetate；Malt, gelatin etc..
" excipient " of the present invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound.
Excipient can include calcium carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, gelatin, plant
Oil, polyethylene glycol.
The life for referring to that tumour can be suppressed " preparing the application in being used to treat or prevent the medicine of tumour " of the present invention
Long, development and/or transfer, mainly give to required human or animal and control the compound of the invention for giving treatment effective dose to press down
Make, slow down or reverse the growth, development or expanding of subject's tumour.
Embodiment
Representational embodiment is in order to which the present invention is better described, not for the protection model of the limitation present invention below
Enclose.
Embodiment 1
The synthesis of chloro- penta rings of 6,7- dihydros -5H- of 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methanol
The synthesis of the iodo- 2- p-toluenesulfonyls -4- methyl formates-pentamethylene of step 1 1-
At -5 DEG C -5 DEG C, 5g 3- cyclopentene -1- methyl formates and 12.6g sodium toluene sulfinate are weighed in reaction bulb,
Add 300mL methylene chloride/waters mixed solvent (volume ratio 1:1) after, reacting 1.5h, 10g I are added2, it is small to be warmed to room temperature reaction 2
When, reaction finishes, and separates organic phase, and water mutually extracts, and merges, molten with aqueous solution of sodium bisulfite, saturated sodium bicarbonate water successively
Liquid and saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains title compound, without purifying, directly
For reacting in next step.
ESI-MS m/z:409[M+H]+,447[M+K]+。
The synthesis of step 2 1- p-toluenesulfonyls -4- methyl formates-cyclopentene
10.6g step 1 gained compounds are weighed in reaction bulb, are slowly added to 3.5g triethylamines, 200mL acetonitriles, 70 DEG C
When lower reaction 2.5 is small, reaction finishes, and is spin-dried for, and adds the dissolving of 100mL ethyl acetate, successively with saturated sodium bicarbonate aqueous solution and
Saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains title compound, without further purification, be directly used in down
Single step reaction.
ESI-MS m/z:281[M+H]+。
The synthesis of-penta ring of step 3 2,4- dicarboxylic acid methyl esters simultaneously [3,4] pyrroles
1g NaH are weighed in reaction bulb, add the anhydrous THF of 70mL, 100mL is added portionwise at 0-5 DEG C walks dissolved with 2.8g
The anhydrous THF solution of rapid 2 gained compound and 1.88g Methyl isocyanoacetates, the reaction was continued at 0-5 DEG C 1.5 it is small when, reacted
Finish, add 1mL absolute methanols, stirring, is spin-dried for, and ethyl acetate dissolving, diatomite filtering, filter cake acetic acid second are added in residue
Ester washs, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains dark oil thing, column chromatography
Purifying, obtains title compound.
ESI-MS m/z:224[M+H]+,262[M+K]+。
The synthesis of-penta ring of step 4 N- amino -2,4- dicarboxylic acid methyl esters simultaneously [3,4] pyrroles
24mgNaH is weighed in reaction bulb, adds 5mL anhydrous DMFs, instilling 2mL at 0-5 DEG C is dissolved with 90mg steps 3 institute
Compound anhydrous DMF solution, 120mg diphenyl phosphono azanols are added portionwise, at room temperature in the reaction was continued at 0-5 DEG C 0.5h
The reaction was continued 0.5h, reaction finish, and add ethyl acetate and frozen water extraction, take organic layer, aqueous layer with ethyl acetate extraction, merges
Organic layer, saturated salt solution washed once, and anhydrous sodium sulfate drying, filtering, is spin-dried for, column chromatography purifies to obtain title compound.
ESI-MS m/z:239[M+H]+。
Penta rings of step 5 4- hydroxyl -6,7- dihydros -5H- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formic acid first
The synthesis of ester
0.7g step 4 gained compounds are weighed in reaction bulb, 5mL formyl amine solvents is added, reacts 2 at 180-200 DEG C
Hour, reaction finishes, reaction solution is poured into 10mL frozen water, ethyl acetate extraction, combined ethyl acetate, saturated common salt washing
Wash, anhydrous sodium sulfate drying, filtering, is spin-dried for, and column chromatography purifying, obtains title compound.
1H NMR(300M Hz,DMSO-d6):δ12.45(s,1H),7.68(s,1H),7.26(s,1H),3.72-3.66
(m,1H),3.63(s,3H),3.20-3.02(m,4H)。
ESI-MS m/z:234[M+H]+。
Chloro- penta rings of 6,7- dihydros -5H- of step 6 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methyl formates
Synthesis
100mg step 5 gained compounds are weighed in reaction bulb, the dissolving of 20mL toluene is added, sequentially adds 5 equivalent trichlorines
Oxygen phosphorus, 5 equivalent n,N-diisopropylethylamine, when reaction 6 is small at 110 DEG C, reaction finishes, and is spin-dried for, and adds ethyl acetate dissolving, ice
Bath is lower to add saturated sodium bicarbonate aqueous solution adjusting pH to 6-7, separates organic layer, saturated common salt water washing, anhydrous sodium sulfate is done
Dry, filtering, is spin-dried for obtaining title compound.
ESI-MS m/z:252[M+H]+。
The conjunction of chloro- penta rings of 6,7- dihydros -5H- of step 7 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methanol
Into
20mL tetrahydrofurans and 54mg Lithium Aluminium Hydrides are added in reaction bulb, stirs the lower 20mL that is added dropwise dissolved with 400mg steps
The anhydrous tetrahydrofuran solution of rapid 6 gained compound, stirs 0.5h, and reaction is finished, is quenched, ethyl acetate extraction, anhydrous slufuric acid
Sodium dries organic phase, and filtering, is spin-dried for, and title compound is made.
1H NMR(300M Hz,DMSO-d6):δ10.05(s,1H),6.11(s,1H),3.65-3.62(m,2H),3.40-
3.36(m,1H),2.55-2.52(m,3H),2.28-2.25(m,2H)。
ESI-MS m/z:224[M+H]+。
Embodiment 2
The synthesis of the iodo- 1H- pyrazoles of 1- (N-Boc- piperidin-4-yls) -3-
The synthesis of step 1 piperidin-4-yl methanesulfonates
10g4- hydroxy piperidines are weighed in reaction bulb, anhydrous tetrahydro furan 200mL is added and dissolves, at 0 DEG C, be slowly added dropwise
100mL is dissolved with 25g (Boc)2The anhydrous tetrahydrofuran solution of O, drop finish, and react at room temperature 12h, are spin-dried for, and it is molten to add dichloromethane
Liquid, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, is spin-dried for obtaining title compound, without purifying, is directly used in next
Step.
ESI-MS m/z:180[M+H]+。
The synthesis of step 2 N-BOC piperidin-4-yl methanesulfonates
5.4g step 1 gains are weighed in reaction bulb, 100mL dichloromethane is added and dissolves, at 0 DEG C, be slowly added dropwise
4.2mL triethylamines, drop finish, and mesyl chloride 2.32mL and DMAP 40mg is slowly added dropwise, and drop finishes, and reacts at room temperature 8h, and reaction terminates,
Add water, dichloromethane extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, is spin-dried for titled
Compound, without purifying, is directly used in next step.
ESI-MS m/z:218[M+H]+。
The synthesis of the iodo- 1H- pyrazoles of step 3 1- (N-Boc- piperidin-4-yls) -3-
9.7g 4- iodine pyrazoles is weighed in reaction bulb, adds 100mL DMF dissolving, is added portionwise 2.4g sodium hydrogen at 0 DEG C, 0
After reacting 1h at DEG C, 15.3g step 2 gains are added, react 12h at 100 DEG C, reaction terminates, and adds water to be quenched, ethyl acetate extraction
Take, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, is spin-dried for, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):7.53(s,1H),7.47(s,1H),4.23(m,3H),2.85-2.88
(m,2H),2.07-2.09(m,2H),1.88(m,2H),1.44(s,9H)。
ESI-MS m/z:378[M+H]+。
Embodiment 3
The chloro- 3- benzyls 4- of 2,6- bis- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4]
The synthesis of triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
The synthesis of the chloro- 3- fluorophenyl methanols of step 1 2,6- bis-
1.5g 2 is weighed, the chloro- 3- fluorobenzaldehydes of 6- bis- add absolute methanol 10mL dissolvings, be added dropwise at 0 DEG C in reaction bulb
5mL is stirred at room temperature 10min, adds frozen water, rotation removes methanol, ethyl acetate extraction dissolved with the absolute methanol solution of 0.36g sodium borohydrides
Take, saturated common salt water washing, anhydrous magnesium sulfate drying.Filtering, rotation, without purifying, are directly used in next except the grease of solvent
Step.
ESI-MS m/z:194[M+H]+。
The chloro- 5,6,7,8- tetrahydrochysenes of the chloro- 3- benzyls 4- of step 2 2,6- bis--[1,2,4] triazine simultaneously [6,1-a] different Yin
Diindyl -7- methyl ethers
1 gains of 0.5g embodiments are weighed in reaction bulb, add the dissolving of 50mL tetrahydrofurans, sequentially add 0.43g steps
Rapid 1 gains and 0.93g triphenylphosphines, after reacting at room temperature 2h, are cooled to 0 DEG C, add 0.75mLDIAD, react 12h at 0 DEG C,
Reaction finishes, and is spin-dried for, and column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),7.26-7.28(m,1H),7.05-7.08(m,1H),
6.10(s,1H),4.63(s,2H),3.44-3.48(m,1H),3.19-3.22(m,1H),2.50-2.54(m,3H),2.23-
2.27(m,2H)。
ESI-MS m/z:400[M+H]+。
The chloro- 3- benzyls 4- of step 3 2,6- bis- (- 3 base of 1- (N-Boc- piperidin-4-yls) 1H- pyrazoles) -5,6,7,8-
Tetrahydrochysene-[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Weigh 4.09g PdCl2(dppf) in reaction bulb, 2 gains of 9.4g embodiments, 9.5g connection boric acid frequency are added where
Alcohol ester, 9.7g potassium acetates and 150mL dimethyl sulfoxides, react 3h at 80 DEG C, are cooled to room temperature, and add 30mL and are dissolved with 8.3g steps
Dimethyl sulfoxide solution, the 20mL of 2 gains are dissolved with the aqueous solution of 6.6g sodium carbonate, 80 DEG C of reaction 4h, and reaction is finished, is cooled to
Room temperature, filtering, ethyl acetate washing filter cake, takes filtrate, adds water, ethyl acetate extraction, merges organic layer, saturated common salt washing
Wash, anhydrous sodium sulfate drying, is filtered, concentration, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),7.93-7.96(m,2H),7.26-7.28(m,1H),
7.05-7.08(m,1H),6.11(s,1H),4.63(s,2H),3.68-3.70(m,1H),3.27-3.40(m,6H),2.50-
2.54(m,2H),2.25-2.27(m,1H),2.03-2.06(m,3H),1.79-1.83(m,3H),1.37(s,9H)。
ESI-MS m/z:615[M+H]+。
The chloro- 3- benzyls 4- of step 4 2,6- bis- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes -
[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
1.0g step 3 gains are weighed in reaction bulb, add dichloromethane 2mL, add trifluoracetic acid 5mL, room temperature is stirred
8h is mixed, solvent and trifluoracetic acid is evaporated off, adds dichloromethane dissolving, pH to 12-13 is adjusted with 20% sodium hydrate aqueous solution, point
From organic layer, water layer continues to be extracted with dichloromethane, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, concentration, column chromatography purify to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),7.93-7.96(m,2H),7.26-7.28(m,1H),
7.05-7.08(m,1H),6.11(s,1H),4.63(s,2H),3.68-3.70(m,1H),3.41-3.44(m,1H),3.27-
3.30(m,1H),2.75-2.81(m,5H),2.53-2.68(m,3H),2.23-2.24(m,1H),2.03-2.06(m,3H),
1.79-1.83(m,2H)。
ESI-MS m/z:515[M+H]+。
Embodiment 4
Pyridine -3- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,
1-a] iso-indoles -7- methyl ethers synthesis
The chloro- 5,6,7,8- tetrahydrochysenes of step 1 pyridine -3- methyl 4--[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Using nicotinic alcohol and 1 gains of embodiment as raw material, title compound is made in the method with 3 step 2 of embodiment.
ESI-MS m/z:315[M+H]+。
Step 2 pyridine -3- methyl 4- (- 3 base of 1- (N-Boc- piperidin-4-yls) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,
4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Using step 1 gains and 2 gains of embodiment as raw material, title compound is made in the method with 3 step 3 of embodiment
Thing.ESI-MS m/z:530[M+H]+。
Step 3 pyridine -3- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] three
Piperazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Using step 2 gains as raw material, title compound is made in the method with 3 step 4 of embodiment.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),8.61(s,1H),8.41-8.43(m,1H),7.94-
7.97(m,2H),7.88-7.91(m,1H),7.40-7.44(m,1H),6.10(s,1H),4.63(s,2H),3.68-3.71(m,
1H),3.43-3.46(m,1H),3.21-3.24(m,1H),2.75-2.81(m,4H),2.68-2.71(m,3H),2.53-2.58
(m,2H),2.03-2.06(m,3H),1.79-1.83(m,2H)。
ESI-MS m/z:430[M+H]+。
Embodiment 5
Chloro- pyridine -3- methyl the 4- of 2- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine
And the synthesis of [6,1-a] iso-indoles -7- methyl ethers
Using 2- chlorine nicotinic alcohol, 1 gains of embodiment and 2 gains of embodiment as raw material, title is made in the method with embodiment 4
Compound.
1H NMR(400MHz,CDCl3,δppm):10.04(s,1H),8.32-8.34(m,1H),8.07-8.09(m,1H),
7.94-7.98(m,2H),7.45-7.49(m,1H),6.09(s,1H),4.63(s,2H),3.69-3.71(m,1H),3.43-
3.46(m,1H),3.21-3.24(m,1H),2.75-2.83(m,4H),2.69-2.71(m,3H),2.53-2.57(m,2H),
2.03-2.06(m,3H),1.79-1.83(m,2H)。
ESI-MS m/z:464[M+H]+。
Embodiment 6
1- methyl indol -6- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] three
The synthesis of piperazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Using 1- methyl -6- skatoxyls, 1 gains of embodiment and 2 gains of embodiment as raw material, with embodiment 4
Title compound is made in method.
1H NMR(400MHz,CDCl3,δppm):10.04(s,1H),8.16-8.18(m,1H),7.94-7.98(m,3H),
7.33-7.35(m,1H),7.10-7.11(m,1H),6.41-6.42(m,1H),6.08(s,1H)4.65(s,2H),3.69-
3.70(m,4H),3.45-3.46(m,1H),3.21-3.24(m,1H),2.74-2.83(m,4H),2.52-2.69(m,3H),
2.27-2.34(m,2H),2.03-2.06(m,3H),1.79-1.83(m,2H)。
ESI-MS m/z:482[M+H]+。
Embodiment 7
Furans -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,
1-a] iso-indoles -7- methyl ethers synthesis
Using 2- hydroxymethylfurans, 1 gains of embodiment and 2 gains of embodiment as raw material, the method with embodiment 4 is made
Title compound.
1H NMR(400MHz,CDCl3,δppm):9.98(s,1H),7.94-7.97(m,2H),7.67-7.68(m,1H),
6.39-6.50(m,2H),6.05(s,1H)4.48(s,2H),3.69-3.70(m,1H),3.45-3.46(m,1H),3.21-
3.24(m,1H),2.74-2.85(m,4H),2.52-2.70(m,3H),2.27-2.34(m,2H),2.03-2.06(m,3H),
1.79-1.83(m,2H)。
ESI-MS m/z:419[M+H]+。
Embodiment 8
1- benzofuran -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] three
The synthesis of piperazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Using 1- benzofuran -2- methanol, 1 gains of embodiment and 2 gains of embodiment as raw material, with the side of embodiment 4
Legal system obtains title compound.
1H NMR(400MHz,CDCl3,δppm):9.98(s,1H),7.88-7.97(m,3H),7.66-7.68(m,1H),
7.32-7.38(m,2H),7.03(s,1H),6.06(s,1H)4.48(s,2H),3.69-3.71(m,1H),3.44-3.47(m,
1H),3.21-3.24(m,1H),2.74-2.85(m,4H),2.52-2.70(m,3H),2.27-2.34(m,2H),2.03-2.05
(m,3H),1.79-1.82(m,2H)。
ESI-MS m/z:469[M+H]+。
The Compound ira vitro enzymatic activity evaluation of the present invention
ALK kinases behaviours source recombinant protein used, the enzyme are containing 50mM HEPES (pH7.5), 10mM MgCl2,2M
Test-compound in the buffer solution of DTT (1000x) and the reaction system of 30 μM of ATP with peptide substrate and various concentrations is total to
With being reacted (25 DEG C, 45min), substrate is marked in subsequent FAM labelled antibodies, finally in a manner of time-resolved fluorescence pair
ALK kinase activity is quantitative determined, the IC measured50It is worth (required change during for by certain density inhibition of enzyme activity to 50%
Compound concentration) it is shown in Table 1.
Table 1
| Compound | ALK kinase inhibitions IC50It is worth (nM) |
| Gram azoles replaces Buddhist nun | 0.55 |
| 3 compound of embodiment | 0.24 |
| 4 compound of embodiment | 1.59 |
| 5 compound of embodiment | 1.88 |
| 6 compound of embodiment | 20.31 |
| 7 compound of embodiment | 0.33 |
| 8 compound of embodiment | 19.64 |
The compound that can be seen that the present invention from above experimental result has preferable inhibitory activity to ALK kinases, especially
It is 7 compound of 3 compound of embodiment and embodiment.
NCI-H1975 cells and A431 cell growth inhibition assays
Using suppression of the method test compound of CellTiter-Glo to NCI-H1975 cells, A431 cells and propagation
Effect, is inoculated with the H1975 cell suspensions of 90 μ L in 96 porocyte culture plates, and density is 1~5 × 103Cell/ml, will cultivate
Plate when incubator culture 16~24 is small (37 DEG C, 5%CO2)；The various concentrations of gradient dilution are added into culture plate cell
Testing compound solution, by culture plate incubator be incubated 72 it is small when (37 DEG C, 5%CO2)；50~100 μ L are added per hole
CellTiter-Glo reagents, and vibrate 10 minutes, it is stored at room temperature 10 minutes；Microplate reader measures the chemiluminescence signal value of each plate,
And inhibiting rate is calculated by chemiluminescence signal value, carried out curve fitting according to the inhibiting rate of various concentrations and draw compound
IC50, the results are shown in Table 2.
Table 2
The compound that can be seen that the present invention from above experimental result has very strong suppression to the propagation of NCI-H1975
Activity.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
On the premise of bright spirit and scope various modifications and change can be carried out to the present invention.The interest field of the present invention is not limited to
The detailed description made above, and claims should be belonged to.
Claims (10)
1. compound or its pharmaceutically acceptable salt, solvate, crystallization or prodrug shown in a kind of general formula I,
Wherein：
X is selected from O, S, N (R3), wherein R3Selected from hydrogen and alkyl；
R1Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, amino, cyanogen
Base, nitro, alkyl, hydroxy alkyl, carboxyalkyl, alkoxy substitution；
R2Selected from Heterocyclylalkyl, the Heterocyclylalkyl can be by one or more halogens, hydroxyl, carboxyl, amino, cyano group, nitre
Base, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxy alkyl, carboxyalkyl, alkoxy, alkoxy acyl substitution.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：X is O.
3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：R1Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, C1-6Alkyl, C1-6Alkoxy
Substitution.
4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：R1Selected from phenyl, pyridine radicals, indyl, furyl, benzofuranyl, the phenyl, pyridine radicals, indyl, furans
Base, benzofuranyl can be by one or more halogens, C1-3Alkyl, C1-3Alkoxy substitutes.
5. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：R2Selected from azacycloalkyl, the azacycloalkyl can be by one or more halogens, C1-6Alkyl, alkoxy acyl take
Generation.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：R2For piperidyl, the piperidyl can be substituted by alkoxy acyl.
7. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, crystallization or prodrug, its feature exist
In：Wherein described compound is selected from following compound：
8. prepare claim 1-6 any one of them compound or its pharmaceutically acceptable salt, isomers, solvate,
Crystallization or the intermediate of prodrug：
9. a kind of pharmaceutical composition, it includes any one of them compound of claim 1-6 or its pharmaceutically acceptable salt,
Isomers, solvate, crystallization or prodrug and pharmaceutical acceptable carrier.
It is 10. a kind of as any one of them compound of claim 1-6 or its pharmaceutically acceptable salt, isomers, solvent are closed
Pharmaceutical composition described in thing, crystallization or prodrug or claim 7 is being prepared for treating or preventing answering in the medicine of tumour
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810003122.4A CN108033965A (en) | 2018-01-02 | 2018-01-02 | ALK/C-MET double inhibitors and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810003122.4A CN108033965A (en) | 2018-01-02 | 2018-01-02 | ALK/C-MET double inhibitors and its application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108033965A true CN108033965A (en) | 2018-05-15 |
Family
ID=62098595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810003122.4A Pending CN108033965A (en) | 2018-01-02 | 2018-01-02 | ALK/C-MET double inhibitors and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108033965A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725381A (en) * | 2013-12-19 | 2015-06-24 | 南京圣和药业股份有限公司 | Growth factor receptor inhibitor and application thereof |
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
-
2018
- 2018-01-02 CN CN201810003122.4A patent/CN108033965A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725381A (en) * | 2013-12-19 | 2015-06-24 | 南京圣和药业股份有限公司 | Growth factor receptor inhibitor and application thereof |
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| YONGFEI CHEN 等: "Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR a", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113527335A (en) | Macrocyclic compound as EGFR inhibitor and application thereof | |
| AU2015276699B2 (en) | Pyridino[1,2-a]pyrimidone analogue used as PI3K inhibitor | |
| CN105732615B (en) | Cdk kinase inhibitors | |
| CN107922348A (en) | Bicyclic heterocycle amide derivatives | |
| CN107619388A (en) | Heterocyclic compound as FGFR inhibitor | |
| CN102875570A (en) | Quinazoline derivative, and preparation method and application thereof | |
| CN105592850A (en) | Inhibitors of ACK1/TNK2 tyrosine kinase | |
| CN110467638A (en) | A kind of double amino Chloropyrimide class compounds containing m-chloroaniline class substituent group, preparation method and applications | |
| CN112105609A (en) | Substituted imidazolidin-2-one derivatives as PRMT5 inhibitors | |
| CN117447449A (en) | PARP1 inhibitor and application thereof | |
| CN112867717A (en) | Compounds useful as kinase inhibitors and uses thereof | |
| CN104230954A (en) | 2,4-diaminopyrimidine compounds and medical applications thereof | |
| CN111269229B (en) | Compound for treating cancer | |
| CN110804059B (en) | Carbamate compound, pharmaceutical composition and application thereof | |
| CN109384784B (en) | Sulfonamide derivative, preparation method thereof and application thereof in medicine | |
| CN103613591B (en) | As the compound and its production and use of cMet inhibitor | |
| CN108033965A (en) | ALK/C-MET double inhibitors and its application | |
| CN109384785B (en) | Pyrrolopyridinone derivatives, preparation method and medical application thereof | |
| CN105601631A (en) | 2,4-disubstituted-5-chloropyrimidine derivative, preparation method and medical applications thereof | |
| KR20240021239A (en) | Compounds used as CDK kinase inhibitors and their uses | |
| CN110294742A (en) | And ring class ASK1 inhibitor and its application | |
| CN108689997A (en) | Cell cycle protein dependent kinase inhibitor 4- amino -2- pyrimidinecarboxylic acids derivative, it is prepared and purposes | |
| CN111410662B (en) | Tyrosine kinase inhibitor | |
| CN111875583A (en) | Triazole derivative and preparation method and application thereof | |
| CN114853752A (en) | Preparation and application of BTK inhibitor pyridine heterocyclic compound |
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: 20180515 |