CN106496232B - A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof - Google Patents
A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof Download PDFInfo
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- CN106496232B CN106496232B CN201610843513.8A CN201610843513A CN106496232B CN 106496232 B CN106496232 B CN 106496232B CN 201610843513 A CN201610843513 A CN 201610843513A CN 106496232 B CN106496232 B CN 106496232B
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- oxinanes
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- 0 N=Cc(c(*C1OCCCC1)ncn1)c1Cl Chemical compound N=Cc(c(*C1OCCCC1)ncn1)c1Cl 0.000 description 5
- CCHMIEBDQWHKQA-UHFFFAOYSA-N Cc1c(cn[nH]2)c2ncn1 Chemical compound Cc1c(cn[nH]2)c2ncn1 CCHMIEBDQWHKQA-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N C1COC=CC1 Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- WJPJKQUWUXWCDZ-UHFFFAOYSA-N CCCc1c(C(C)=O)c(C)ncn1 Chemical compound CCCc1c(C(C)=O)c(C)ncn1 WJPJKQUWUXWCDZ-UHFFFAOYSA-N 0.000 description 1
- BVBPJBBOSPUULV-UHFFFAOYSA-O Nc(cc1)ccc1Oc1c(C=N)c([NH2+]C2OCCCC2)ncn1 Chemical compound Nc(cc1)ccc1Oc1c(C=N)c([NH2+]C2OCCCC2)ncn1 BVBPJBBOSPUULV-UHFFFAOYSA-O 0.000 description 1
- NBJZEUQTGLSUOB-UHFFFAOYSA-N O=C=Nc(cc1C(F)(F)F)ccc1Cl Chemical compound O=C=Nc(cc1C(F)(F)F)ccc1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 description 1
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- 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
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with anti-tumor activity, general formula (I) is as follows.Invention also discloses the synthetic methods of the compound, and the Pharmaceutical composition containing the compound.The invention also discloses the pharmaceutical composition in treatment because of the application of protein kinase activity exception diseases caused.The present invention develops a kind of structure novel, pyrazolo [3 with notable antitumor activity, 4-d] pyrimidines, the compound may serve as double target spot inhibitor of BRAF/VEGFR-2 kinases, have good effect and wide application prospect in terms for the treatment of is because of protein kinase activity exception diseases caused.
Description
Technical field
The present invention relates to a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines with anti-tumor activity
Object and preparation method thereof is closed, field of medicaments is belonged to.
Background technology
The treatment of malignant tumour is a global problem for a long time.It is in the past swollen by finding to the treatment of tumour
Tumor is simultaneously destroyed to realize, deepens continuously now with what is studied cell signaling pathway, people are to inside tumor cells
Having acted on of oncogene and antioncogene solves more and more deep so that for new anti-of the specific molecular shot design of tumour
Tumour medicine is possibly realized.It is well known that the increasing of mitogen original activated protein kinase (MAPK) signal path and tumour cell
Grow, break up, migrate it is related with apoptosis.BRAF is one of tri- hypotypes of RAF, is the important transduced element of MAPK accesses, and BRAF
BRAF mutation occur for the frequency of mutation highest in 3 hypotypes, about 7%~8% human tumor, ARAF and CRAF then less hair
Raw mutation.BRAF mutation occur for BRAF mutation rates highest in melanoma, about 40%~68% pernicious (metastatic) melanoma.
The mutation is first high-frequency mutator being found in melanoma, has become the therapeutic target of melanoma at present
Mark.
Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and its receptor
" budding formula angiogenesis (sprouting angiogenesis) " that VEGFR (VEGF receptor) is mediated, in physiology and
Pathologic vessels play important role in generating, and crucial effect is especially played in terms of Tumor Angiongesis.Targeting
The drug of VEGF and VEGFR is continuously developed out, such as bevacizumab, sorafenib, aflibercept,
These drugs inhibit VEGF/VEGFR signal paths in different ways, clinically have been demonstrated effectively inhibit kinds of tumors
Growth, be successfully realized the clinical conversion of related drugs.Research thinks that the signal transduction pathway of VEGF is likely to be
VEGFR-2 is by activating PLC (phospholipase C), and hydrolysis generates second messenger DAG (diacylglycerol), and then (albumen swashs activation PKC
Enzyme), PKC reactivations RAF, RAF finally activate MAPK by activating MEK.Two target spots of BRAF and VEGFR-2 are shown in tumour
Occurrence and development during have certain synergistic effect.
Domestic and international present Research and analysis:Sorafenib is II A type BRAF kinase inhibitors of the 1st report.But
In III clinical trial phase of metastasis melanin tumor, there is no significant curative effects by Sorafenib.One kind may be, melanoma according to
New vessels around relying are shifted, and alternatively possible to be, in melanoma, Sorafenib is not special to RAF kinases
The effect of property.And BRAF in 2011V600EThe listing of inhibitor Vemurafenib becomes an important breakthrough.There are about the evenings of half
Phase melanoma has variation, and the response rate of Vemurafenib reaches 50% in this crowd, and extending 3 months than chemotherapy survives
Phase.This product was considered as the impressive progress of melanoma treatment and a success model of individualized treatment at that time.But
Unfortunately, start drug resistance occur in or so half a year.And another kind RAF inhibitor RAF265 is also reported as RAF/VEGFR and swashs
The double target spot inhibitor of enzyme inhibit the angiogenesis and mutation BRAF of VEGF inductions, act on A375M (BRAFV600E) human melanin
Oncocyte system can effectively reduce tumour glycometabolism and FDG accumulations.Therefore, with BRAFV600EIt is target spot, design with VEGFR-2
Synthesize BRAFV600EDouble target spot inhibitor of/VEGFR-2 kinases, by making BRAFV600EIt expresses and reduces with VEGFR-2, block it
Signal transduction pathway exhausts the vascular endothelial growth factor of tumour cell generation and inhibits tumor vascular generation, cuts off tumour
Blood supply is then expected to achieve the purpose that inhibit tumour growth, development and transfer.And double target spot inhibitor have more in anti-tumor aspect
High selectivity and better activity.
Therefore, there is an urgent need in the art to develop structure novel, double target spots suppression of active strong BRAF/VEGFR-2 kinases
Preparation.
Invention content
The purpose of the present invention is to provide a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4- with anti-tumor activity
D] pyrimidines and its derivative and the substance synthetic method and application.
Technical scheme is as follows:
A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines lead to
Formula (I) is as follows:
Wherein X is oxygen, sulphur or nitrogen;
Linking group Linker be substituted in parent benzene 2,3 or 4 Wherein N atoms one end is connected with parent;
R1For-H, halogen, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Alkylthio group or-NO2;R2It is substituted 4~12 yuan
Aromatic heterocyclic,Substituent group in the substitution heteroaromatic is-H, C1~C6Alkyl, aryl ,-
CF3Or 5~10 yuan of aromatic heterocyclics;Hetero atom number on the aromatic heterocyclic is 1~4, hetero atom O, S or N;R3For-H,
Halogen, alkyl ,-CF3、-NO2Or-CN;R4For-H or alkyl.
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines chemical combination with anti-tumor activity
Object, X is oxygen in general formula (I);Linking group Linker be substituted in parent benzene 2,3 or 4Wherein N atoms one end is connected with parent;R1For-H, halogen, C1~C4Alkyl, C1~C4Alkane
Oxygroup, C1~C4Alkylthio group or-NO2;R2For 4~12 yuan of substituted aromatic heterocyclics,The substitution
Substituent group in heteroaromatic is-H, C1~C6Alkyl, aryl ,-CF3Or 5~10 yuan of aromatic heterocyclics;It is miscellaneous on the aromatic heterocyclic
Atom number is 1~4, and hetero atom is O or S;R3For-H, halogen, alkyl ,-CF3、-NO2Or-CN;R4For-H;R3、R4It is contained
Hydrogen atom each independently by one or more identical or different G1Or G2Substitution;G1Or G2Be each independently selected from H ,-
OH、-NH2、-CN、-CF3, halogen, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl, C6Aryl, 5-6 circle heterocyclic rings aryl,
C3-6Heteroalicyclyl, C1-6Alkoxy, C3-6Cycloalkyloxy, C6Aryloxy group, 5-7 members heteroaryloxy, C3-6Heterolipid epoxy group, C1-6Alkane
Amino, C3-6Naphthene amino, C6Fragrant amino, 5-7 circle heterocyclic rings fragrant amino, C3-6Heterolipid ring type amidogen, C1-6Alkoxy -C O-, C3-6Cycloalkanes
Oxygroup-CO-, C6Aryloxy group-CO-, 5-7 circle heterocyclic ring aryloxy group-CO-, C3-6Heterolipid epoxy group-CO-, C1-6Alkylamino-CO-, C3-6
Naphthene amino-CO-, C6Fragrant amino-CO-, 5-7 circle heterocyclic ring fragrant aminos-CO-, C3-6One of which in heterolipid ring type amidogen-CO-.
General formula (I) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, mutually
Tautomeric or prodrug, the compound be selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,
4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,
4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos
[3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrroles
Azoles simultaneously [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- tetra-
Hydrogen pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- tetrahydrochysenes
Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) -
1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- tetrahydrochysenes
Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1-
(2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (tri- fluoro- 5- trifluoromethyls of 3-) -
3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- chlorphenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the chloro- 3- trifluoromethylbenzenes of 2-
Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- cyclohexyl -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- aminomethyl phenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (4- chlorphenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- trifluoromethyl -4- chlorobenzenes
Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- fluoroforms
Base phenyl) in -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide wherein
It is a kind of.
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with anti-tumor activity
Synthetic method:Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are subjected to ring-closure reaction and generate the chloro- 1H- pyrazolos [3,4-d] of 4-
Pyrimidine is reacted with 3,4- dihydro -2H- pyrans under the action of catalyst, generates 4- chloro- 1- (2- oxinanes) -1H- pyrazolos
Amine intermediate 4- [[1- (2- oxinanes)-are obtained by the reaction with p-aminophenol under protective gas protection in [3,4-d] pyrimidine
1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] aniline, targeted finally is obtained by the reaction with isocyanates or sulphur isocyanates etc.
Close object.
The catalyst is at least one of acidic catalyst and saline catalyst.
The protective gas is at least one of nitrogen and inert gas.
At least one of a kind of pharmaceutical composition, including following ingredients:A) compound, b) compound pharmaceutically may be used
The polymorph of the solvate of the hydrate of the salt of receiving, c) compound, d) compound, e) compound, f) change
The prodrug of the tautomer of conjunction object, g) compound;Wherein, the compound is general formula (I) compound represented.
A kind of pharmaceutical composition is in treatment because of the application of protein kinase activity exception diseases caused.
The disease is cancer.
The disease be melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, skin or
Intraocular melanoma, uterine cancer, oophoroma, the carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer, breast cancer, carcinoma of fallopian tube, endometrium
Cancer, cervical carcinoma, carcinoma of vagina, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid gland
Cancer, soft tissue sarcoma, carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute leukemia, carcinoma of urinary bladder, kidney or carcinoma of ureter, ridge
Axis of a cylinder tumour, pituitary adenoma, gastrointestinal stromal, colorectal cancer, non-small cell lung cancer, Small Cell Lung Cancer, mast cell increase
One kind in more diseases, glioma, sarcoma, lymthoma or arbitrary several combination.
The beneficial effects of the invention are as follows:
The present invention develops a kind of structure novel, pyrazolo [3,4-d] miazines chemical combination with notable antitumor activity
Object, the compound may serve as double target spot inhibitor of BRAF/VEGFR-2 kinases, in treatment because of protein kinase activity exception
There are good effect and wide application prospect in terms of diseases caused.
Specific implementation mode
A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines lead to
Formula (I) is as follows:
Wherein X is oxygen, sulphur or nitrogen;
Linking group Linker be substituted in parent benzene 2,3 or 4 Wherein N atoms one end is connected with parent;
R1For-H, halogen, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Alkylthio group or-NO2;R2It is substituted 4~12 yuan
Aromatic heterocyclic,Substituent group in the substitution heteroaromatic is-H, C1~C6Alkyl, aryl ,-
CF3Or 5~10 yuan of aromatic heterocyclics;Hetero atom number on the aromatic heterocyclic is 1~4, hetero atom O, S or N;R3For-H,
Halogen, alkyl ,-CF3、-NO2Or-CN;R4For-H or alkyl.
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines chemical combination with anti-tumor activity
Object, X is oxygen in general formula (I);Linking group Linker be substituted in parent benzene 2,3 or 4Wherein N atoms one end is connected with parent;R1For-H, halogen, C1~C4Alkyl, C1~C4Alkane
Oxygroup, C1~C4Alkylthio group or-NO2;R2For 4~12 yuan of substituted aromatic heterocyclics,The substitution
Substituent group in heteroaromatic is-H, C1~C6Alkyl, aryl ,-CF3Or 5~10 yuan of aromatic heterocyclics;It is miscellaneous on the aromatic heterocyclic
Atom number is 1~4, and hetero atom is O or S;R3For-H, halogen, alkyl ,-CF3、-NO2Or-CN;R4For-H;R3、R4It is contained
Hydrogen atom each independently by one or more identical or different G1Or G2Substitution;G1Or G2Be each independently selected from H ,-
OH、-NH2、-CN、-CF3, halogen, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl, C6Aryl, 5-6 circle heterocyclic rings aryl,
C3-6Heteroalicyclyl, C1-6Alkoxy, C3-6Cycloalkyloxy, C6Aryloxy group, 5-7 members heteroaryloxy, C3-6Heterolipid epoxy group, C1-6Alkane
Amino, C3-6Naphthene amino, C6Fragrant amino, 5-7 circle heterocyclic rings fragrant amino, C3-6Heterolipid ring type amidogen, C1-6Alkoxy -C O-, C3-6Cycloalkanes
Oxygroup-CO-, C6Aryloxy group-CO-, 5-7 circle heterocyclic ring aryloxy group-CO-, C3-6Heterolipid epoxy group-CO-, C1-6Alkylamino-CO-, C3-6
Naphthene amino-CO-, C6Fragrant amino-CO-, 5-7 circle heterocyclic ring fragrant aminos-CO-, C3-6One of which in heterolipid ring type amidogen-CO-.
General formula (I) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, mutually
Tautomeric or prodrug, the compound be selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,
4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,
4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos
[3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrroles
Azoles simultaneously [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- tetra-
Hydrogen pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- tetrahydrochysenes
Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) -
1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- tetrahydrochysenes
Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1-
(2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (tri- fluoro- 5- trifluoromethyls of 3-) -
3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- chlorphenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the chloro- 3- trifluoromethylbenzenes of 2-
Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- cyclohexyl -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- aminomethyl phenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (4- chlorphenyls) -3- [4-
[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- trifluoromethyl -4- chlorobenzenes
Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- fluoroforms
Base phenyl) in -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide wherein
It is a kind of.
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with anti-tumor activity
Synthetic method:Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are subjected to ring-closure reaction and generate the chloro- 1H- pyrazolos [3,4-d] of 4-
Pyrimidine is reacted with 3,4- dihydro -2H- pyrans under the action of catalyst, generates 4- chloro- 1- (2- oxinanes) -1H- pyrazolos
Amine intermediate 4- [[1- (2- oxinanes)-are obtained by the reaction with p-aminophenol under protective gas protection in [3,4-d] pyrimidine
1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] aniline, targeted finally is obtained by the reaction with isocyanates or sulphur isocyanates etc.
Close object.Specific synthetic line is as follows:
A in formula:Et3N,MeOH;b:PPTs,EtOAc;c:Substituted phenol, Cs2CO3,DMF,N2;d:Isocyanic acid or sulphur are different
Cyanate, CH2Cl2。
Last product is general formula (I) compound represented in synthesis formula.
Preferably, the catalyst is at least one of acidic catalyst and saline catalyst;It is further preferred that
The catalyst is saline catalyst;Still further preferably, the catalyst is para-methylbenzenepyridinsulfonate sulfonate.
Preferably, the protective gas is at least one of nitrogen and inert gas;It is further preferred that described
Protective gas is the one of which in nitrogen, argon gas;Still further preferably, the protective gas is nitrogen.
At least one of a kind of pharmaceutical composition, including following ingredients:A) compound, b) compound pharmaceutically may be used
The polymorph of the solvate of the hydrate of the salt of receiving, c) compound, d) compound, e) compound, f) change
The prodrug of the tautomer of conjunction object, g) compound;Wherein, the compound is general formula (I) compound represented.
It is further preferred that the pharmaceutical composition further includes auxiliary material;Still further preferably, the auxiliary material includes
At least one of following substance:Solvent, propellant, solubilizer, stabilizer, glidant, corrigent, preservative, suspending agent, packet
Clothing material, aromatic, anti-binder, integrated agent, penetration enhancer, pH adjusting agent, buffer, plasticizer, cosolvent, emulsification
Agent, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, surfactant, foaming agent,
Antifoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retarding agent.
The pharmaceutical composition of the present invention can be made into various dosage forms:
Classify according to the decentralized system of dosage form, specifically, following dosage form can be made:Solution-type, colloidal solution
Type, emulsion-type, suspension type, gas dispersing type, microdispersed form, solid dispersing;
According to typoiogical classification, specifically, following dosage form can be made:Liquid dosage form (such as aromatic waters, solution, note
Penetrate agent, mixture, lotion, liniment etc.), gas formulation (such as aerosol, spray), solid dosage forms (such as powder, pill, tablet,
Film etc.), semisolid dosage form (such as ointment, suppository, paste);
Classify according to administration route, specifically, following dosage form can be made:Dosage form through gastrointestinal administration, without stomach
The dosage form of intestinal canal administration.
A kind of pharmaceutical composition is in treatment because of the application of protein kinase activity exception diseases caused.Preferably,
The disease is cancer;It is further preferred that the disease is melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, pancreas
Cancer, cutaneum carcinoma, head and neck cancer, skin or intraocular melanoma, uterine cancer, oophoroma, the carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer,
Breast cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical carcinoma, carcinoma of vagina, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, endocrine
System cancer, thyroid cancer, parathyroid carcinoma, soft tissue sarcoma, carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute white blood
Disease, carcinoma of urinary bladder, kidney or carcinoma of ureter, spinal column axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal cancer, non-small cell lung
One kind in cancer, Small Cell Lung Cancer, mastocytosis, glioma, sarcoma, lymthoma or arbitrary several combination.
Preferably, general formula (I) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline
The application of type object, tautomer or prodrug in preparing BRAF/VEGFR-2 kinase inhibitors.
It is further preferred that general formula (I) compound represented or its pharmaceutically acceptable salt, hydrate, solvent conjunction
Object, polymorph, tautomer or prodrug are preparing treatment and/or are preventing and/or delay and/or auxiliary treatment and/or place
Reason and the application in the drug of the excessively high relevant disease of BRAF/VEGFR-2 kinase activities;Still further preferably, general formula (I) institute
The compound shown or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug exist
Prepare the application in antitumor drug;Still more preferably, at least one of following compounds or its can pharmaceutically connect
Salt, hydrate, solvate, polymorph, tautomer or the prodrug application in preparation of anti-tumor drugs received, such as exist
The application in antiprostate cancer is prepared, or prepares the application in anti-melanin tumor medicine.
" pharmaceutically acceptable salt " refers to the form for the basic group in parent compound being converted into salt in the present invention.
Pharmaceutically acceptable salt is include but are not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.The present invention
Pharmaceutically acceptable salt can be synthesized by parent compound, i.e. the acid of basic group in parent compound and 1-4 equivalents exists
It is reacted in one solvent system.Suitable salt is enumerated in Remington ' s Pharmaceutical Sciences, 17th
Ed., Mack Publishing Company, Easton, Pa., 1985,1418 and Journal of Pharmaceutical
Science, in 66,2,1977.
Pharmaceutically acceptable acid-addition salts can be prepared as follows by inorganic and organic acid:By the inorganic of derivative acid-addition salts
Acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..Organic acid by derivative acid-addition salts includes acetic acid, propionic acid, ethyl alcohol
Acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Chinese cassia tree
Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, benzene sulfonic acid etc..The inorganic acid of derivative acid-addition salts and organic
Acid is especially selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, acetic acid, benzoic acid and p-methyl benzenesulfonic acid.
Present disclosure is described in further detail below by way of specific embodiment.
Embodiment 1:
The synthesis of chloro- 1H- pyrazolos [3,4-d] pyrimidines of 4-
In 100mL three-necked flasks, 1.0g 4, bis- chloro- 5- pyrimidinecarboxaldehydes of 6-, 20mL methanol, stirring and dissolving, cooling is added
To -65 DEG C, the triethylamine of 0.97mL (1.2eq) is added dropwise.0.274mL (1.0eq) hydrazine hydrate 10mL methanol dilutions, use dropping liquid
Funnel slowly drips.Bi Huifu is dripped to room temperature, reacts 2~3h, TLC monitorings.Reaction terminates, and revolves solvent evaporated, dry.Use acetic acid
Ethyl ester dissolved solid (30mL × 3), filtering are washed (60mL × 3) after merging with saturation NaCl solution.Anhydrous MgSO4Dry, rotation
Solvent, drying is evaporated off, obtains faint yellow solid, yield 68.9%.1H NMR(400MHz,DMSO-d6)δ14.51(s,1H),
8.84(s,1H),8.45(s,1H).ESI-MS m/z:153[M-H]-。
Embodiment 2:
The synthesis of the chloro- 1- of 4- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine
In 100mL three-necked flasks, chloro- 1H- pyrazolos [3, the 4-d] pyrimidines of 1.88g 4- are added, 50mL ethyl acetate rises
Temperature is to 50 DEG C.PPTs (para-methylbenzenepyridinsulfonate sulfonate, catalytic amount), the 1.37mL 3 of 50mg, 4- dihydro -2H- pyrroles are put into successively
It mutters (1.2eq).50 DEG C of insulation reaction 20-22h, TLC monitorings.Reaction terminates, and is down to room temperature, uses water (60mL × 1), saturation respectively
NaCl solution (50mL × 2) washs mixture.Anhydrous MgSO4Dry, revolving is except solvent, drying.It is solid obtained by petroleum ether extraction
Body (60mL × 2), solvent evaporated obtain faint yellow oily solid, yield 76.5% after dry.1H NMR(400MHz,DMSO-d6)δ
8.92 (s, 1H), 8.55 (s, 1H), 6.02 (dd, J=10.4,2.4Hz, 1H), 3.97 (d, J=12.0Hz, 1H), 3.76-
3.70(m,1H),2.49–2.42(m,1H),2.07-2.08(m,1H),1.98–1.94(m,1H),1.85–1.73(m,1H),
1.64–1.58(m,2H).ESI-MS m/z:261[M+Na]+。
Embodiment 3:
The synthesis of 4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] aniline
In 100mL three-necked flasks, 0.28g p-aminophenols, 1.51g Cs is added2CO3(1.2eq) powder, N2The lower drop of protection
Enter 2mL DMF, 1.5-2h is stirred at room temperature.The chloro- 1- of 0.56g 4- (2- the oxinanes) -1H- pyrazoles that will be dissolved in appropriate DMF afterwards
And [3,4-d] pyrimidine (1.0eq) instills, and reacts 22-24h, TLC monitorings.Reaction terminates, after being diluted with 50mL ethyl acetate, according to
It is secondary to be washed with the NaOH solution (60mL × 1) of 1M, water (80mL × 1), 5%LiCl solution (50mL × 2), MgSO4Dry, revolving
Except solvent, dry sepia oily solid, yield 79.5%.1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.75
(s, 1H), 6.99-6.95 (m, 2H), 6.67-6.31 (m, 2H), 5.96 (dd, J=10.0,2.4Hz, 1H), 5.19 (s, 2H),
3.96 (d, J=12.4Hz, 1H), 3.73-3.67 (m, 1H), 2.48-2.40 (m, 1H), 2.06-2.00 (m, 1H), 1.92-
1.88(m,1H),1.79-1.71(m,1H),1.61–1.56(m,2H).ESI-MS m/z:310[M-H]-。
Embodiment 4:
1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] benzene
Base] urea synthesis
In 100mL three-necked flasks, chloro- 1H- pyrazolos [3, the 4-d] pyrimidines of 4-, appropriate CH is added2Cl2, ice bath cooling, drop
Add the CH of the 3- methylphenyl isocyanates of 1.0eq amounts2Cl2.Ice bath is removed, overnight, TLC is monitored for reaction at room temperature.Reaction knot
Beam is added 60mL petroleum ethers, crude product, acidic alumina column chromatography for separation (ethyl acetate/first is obtained after filtering, drying
Alcohol) obtain target compound, yield 80.0%.1H NMR(400MHz,DMSO-d6)δ14.13(s,1H),8.82(s,1H),
8.66 (s, 1H), 8.51 (s, 1H), 8.01 (s, 1H), 7.56 (d, J=8.9Hz, 2H), 7.32 (s, 1H), 7.25 (d, J=
8.9Hz, 3H), 7.17 (t, J=7.7Hz, 1H), 6.80 (d, J=7.7Hz, 1H), 2.29 (s, 3H)13C NMR(101MHz,
DMSO-d6)δ163.68,157.13,155.39,153.00,146.77,139.99,138.36,138.11,132.26,
129.04,123.02,122.66,120.47,119.63,117.67,117.24,102.01.ESI-MS m/z:445[M+H]+。
Implement 5:
1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups]
Phenyl] urea
With reference to the preparation method of embodiment 4.Yield 67.0%.1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),
8.97 (s, 1H), 8.58 (s, 1H), 8.14 (s, 1H), 7.90 (s, 1H), 7.58-7.52 (m, 3H), 7.37 (d, J=8.4Hz,
1H), 7.27 (d, J=8.8Hz, 2H), 5.99 (d, J=9.6Hz, 1H), 3.97 (d, J=10.8Hz, 1H), 3.71 (s, 1H),
2.05 (d, J=12.8Hz, 1H), 1.93 (d, J=12.4Hz, 1H), 1.79 (s, 1H), 1.59 (s, 2H), 1.24 (s, 1H)13C
NMR(101MHz,DMSO-d6)δ163.71,155.73,152.81,147.00,140.36,137.71,132.26,131.45,
131.00,123.56,122.66,120.18,119.76,118.82,102.73,82.70,67.55,29.14,25.02,
22.59.ESI-MS m/z:499[M+H]+。
Embodiment 6:
1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 69.4%.1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),
8.59 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=8.8Hz, 2H), 7.34 (d, J=
8.0Hz, 1H), 7.28 (d, J=8.8Hz, 2H), 6.87 (d, J=8.0Hz, 1H), 5.99 (d, J=10.0Hz, 1H), 3.97
(d, J=11.2Hz, 1H), 3.75-3.68 (m, 1H), 2.30 (s, 3H), 2.08-2.00 (m, 1H), 1.93 (d, J=11.6Hz,
1H),1.77(s,1H),1.60(s,2H),1.24(s,1H).13C NMR(101MHz,DMSO-d6)δ163.71,155.73,
155.68,152.58,146.87,137.90,137.47,135.92,132.26,129.20,124.47,122.72,122.20,
119.75,119.45,102.72,82.70,67.54,29.14,25.02,22.59,21.32.ESI-MS m/z:477[M-
H]-。
Embodiment 7:
1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 65.5%.1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),
8.58 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.56 (t, J=8.6Hz, 3H), 7.25 (d, J=8.4Hz, 1H), 7.05
(t, J=7.8Hz, 1H), 6.92 (d, J=7.2Hz, 1H), 5.99 (d, J=9.2Hz, 1H), 3.97 (d, J=11.2Hz, 1H),
3.75-3.68 (m, 1H), 2.45 (d, J=10.4Hz, 1H), 2.27 (s, 3H), 2.16 (s, 3H), 2.05 (d, J=10.8Hz,
1H), 1.93 (d, J=12.0Hz, 1H), 1.79 (s, 1H), 1.60 (s, 2H), 1.46 (s, 1H)13C NMR(101MHz,DMSO-
d6))δ155.74,153.38, 146.51,138.49,137.31,137.00,132.26,128.07,125.65,125.42,
122.60,120.92,119.50,102.70,82.69,67.54,29.14,25.02,22.59,20.75,14.05.ESI-MS
m/z:481[M+Na]+。
Embodiment 8:
1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 79.4%.1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),
8.69 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.38 (dd, J=6.8,2.4Hz,
1H), 7.30-7.24 (m, 3H), 7.06 (t, J=9.2Hz, 1H), 5.98 (dd, J=10.4,2.4Hz, 1H), 3.97 (d, J=
10.8Hz, 1H), 3.74-3.658 (m, 1H), 2.22 (s, 3H), 2.05 (d, J=11.6Hz, 1H), 1.95-1.90 (m, 1H),
1.80-1.76(m,1H),1.59(s,2H),1.24(s,1H).13C NMR(101MHz,DMSO-d6)δ163.76,155.70,
155.54,153.17,146.71,137.99,135.73,132.25,124.79,124.61,122.58,121.94,120.04,
118.10,118.03,115.44,115.21,102.65,82.68,67.65,29.10,24.92,22.54,14.72.ESI-MS
m/z:485[M+Na]+。
Embodiment 9:
1- (3- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] benzene
Base] urea
With reference to the preparation method of embodiment 4.Yield 62.3%.1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),
9.11(s,1H),8.59(s,2H),8.16(s,1H),7.85(s,1H),7.74(s,1H),7.59(s,2H),7.29–7.00
(m, 2H), 5.99 (d, J=12.4Hz, 1H), 5.31 (s, 1H), 3.96 (s, 2H), 3.72 (s, 2H), 2.02 (s, 2H), 1.77
(s,1H),1.59(s,1H).13C NMR(101MHz,DMSO-d6)δ167.36,163.69,155.70,152.91,148.58,
147.07,141.45,137.66,132.23,131.95,130.46,129.04,124.77,122.64,120.27,116.72,
112.61,102.74,82.72,67.82,28.77,22.79.ESI-MS m/z:474[M-H]-。
Embodiment 10:
[[[1- (2- oxinanes) -1H- pyrazolos [3,4-d] are phonetic by 4- by -3- by 1- (2- fluoro- 5- (trifluoromethyl) phenyl)
Pyridine] -4- oxygroups] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 70.2%.1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),
8.96 (s, 1H), 8.61 (d, J=22.8Hz, 2H), 8.16 (s, 1H), 7.55 (d, J=26.4Hz, 3H), 7.41 (s, 1H),
7.29 (d, J=5.6Hz, 2H), 5.98 (d, J=8.8Hz, 1H), 3.95 (s, 1H), 3.71 (s, 1H), 2.03 (s, 1H), 1.92
(d, J=12.4Hz, 2H), 1.78 (s, 1H), 1.59 (s, 2H)13C NMR(101MHz,DMSO-d6)δ163.65,155.73,
155.64,152.54,147.08,137.40,132.27,129.13,128.99,122.79,119.92,116.94,116.62,
116.39,115.63,102.71,82.65,67.55,29.13,25.01,22.60.ESI-MS m/z:517[M+H]+。
Embodiment 11:
1- (3- cyano-phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] benzene
Base] urea
With reference to the preparation method of embodiment 4.Yield 69.8%.1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),
9.00 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.00 (t, J=1.8Hz, 1H), 7.71 (ddd, J=3.2,2.0,
1.2Hz, 1H), 7.59 (d, J=2.4Hz, 1H), 7.57 (d, J=2.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.43
(dt, J=7.6,1.2Hz, 1H), 7.29-7.27 (m, 2H), 5.99 (dd, J=10.0,2.4Hz, 1H), 3.18 (d, J=
5.2Hz,2H),1.99(s,6H).13C NMR(101MHz,DMSO-d6)δ163.68,155.73,152.89,146.93,
140.99,137.71,132.27,130.61,125.76,123.33,122.68,121.18,120.12,119.29,111.98,
102.70,82.65,67.56,60.18,29.13,25.01,22.60,21.17,14.48.ESI-MS m/z:456[M+H]+。
Embodiment 12:
1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4-
Oxygroup] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 61.8%.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),
9.71 (s, 1H), 8.58 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 8.04 (d, J=8.4Hz, 1H), 7.61 (d, J=
8.8Hz, 2H), 7.29 (d, J=8.4Hz, 2H), 7.03 (d, J=8.8Hz, 1H), 5.98 (d, J=9.6Hz, 1H), 3.97 (d,
J=11.2Hz, 1H), 3.71 (dd, J=12.8,6.4Hz, 1H), 2.40 (s, 4H), 2.03 (s, 1H), 1.92 (d, J=
12.0Hz,1H),1.78(s,1H),1.59(s,2H).13C NMR(101MHz,DMSO-d6)δ163.70,155.76,155.70,
152.24,147.09,146.76,137.68,135.52,132.28,125.95,123.53,122.76,122.58,120.21,
102.74,82.70,67.60,29.14,25.02,22.60,21.94.ESI-MS m/z:488[M-H]-。
Embodiment 13:
1- (2- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] benzene
Base] urea
With reference to the preparation method of embodiment 4.Yield 74.5%.1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),
7.95 (s, 1H), 7.81 (t, J=8.4Hz, 2H), 7.49 (d, J=7.2Hz, 1H), 7.36 (t, J=7.6Hz, 1H), 7.19
(t, J=7.6Hz, 1H), 7.00 (s, 3H), 6.89 (t, J=7.8Hz, 2H), 6.74 (d, J=8.0Hz, 1H), 5.37 (d, J=
6.0Hz, 2H), 4.54 (s, 3H), 3.05 (s, 1H), 1.67 (d, J=5.2Hz, 5H)13C NMR(101MHz,DMSO-d6)δ
167.01,159.65,151.08,141.82,141.36,140.59,135.03,133.47,129.50,128.93,128.22,
126.97,125.17,123.42,122.12,119.87,113.33,112.36,55.14,43.52,24.14.ESI-MS m/
z:443[M-H]-。
Embodiment 14:
1- (3- fluorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl]
Urea
With reference to the preparation method of embodiment 4.Yield 61.2%.1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),
8.89 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.51 (dt, J=11.6,2.4Hz,
1H), 7.35-7.26 (m, 3H), 7.15 (d, J=8.0Hz, 1H), 6.80 (td, J=8.4,2.4Hz, 1H), 5.98 (dd, J=
10.0,2.4Hz, 1H), 3.97 (d, J=11.2Hz, 1H), 3.71 (ddd, J=11.6,6.4,4.8Hz, 1H), 2.06-2.03
(m,1H),1.95–1.91(m,1H),1.80–1.72(m,1H),1.63–1.57(m,2H),1.23(s,1H).13C NMR
(101MHz,DMSO-d6)δ163.71,155.72,152.85,146.87,142.00,137.84,132.24,130.77,
130.67,122.63,120.02,116.25,114.39,114.36,108.69,108.48,105.44,102.72,82.69,
67.54,29.14,25.02,22.59,21.52.ESI-MS m/z:447[M-H]-。
Embodiment 15:
1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl]
Urea
With reference to the preparation method of embodiment 4.Yield 66.3%.1H NMR(400MHz,CDCl3)δ8.57(s,1H),7.88
(s, 1H), 7.59 (d, J=7.6Hz, 4H), 7.54 (d, J=7.7Hz, 4H), 7.49 (s, 2H), 7.41 (d, J=8.5Hz,
4H), 7.20 (d, J=7.1Hz, 13H), 7.13-7.07 (m, 13H), 6.56 (s, 3H), 6.06 (d, J=9.1Hz, 1H), 4.14
(d, J=11.3Hz, 2H), 3.89-3.77 (m, 2H), 2.22 (d, J=9.3Hz, 13H)13C NMR(101MHz,DMSO-d6)δ
167.35,163.77,155.72,153.11,146.61,138.36,137.74,132.14,131.93,130.58,129.04,
128.06,126.55,122.61,121.57,119.56,102.72,82.71,67.81,28.77,22.79,14.26.ESI-
MS m/z:447[M-H]-。
Embodiment 16:
1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 71.2%.1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),
8.59 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=6.8Hz, 2H), 7.26 (d, J=
6.7Hz, 2H), 7.05 (s, 1H), 6.77 (s, 1H), 5.98 (d, J=9.2Hz, 1H), 3.97 (d, J=10.0Hz, 1H), 3.71
(s, 1H), 2.24 (d, J=9.2Hz, 6H), 2.02 (s, 1H), 1.92 (d, J=12.8Hz, 1H), 1.78 (s, 1H), 1.59 (s,
3H).13C NMR(101MHz,DMSO-d6)δ163.76,155.75,155.64,153.09,146.52,138.36,137.50,
135.49,132.27,130.40,124.87,123.80,122.65,122.06,119.49,102.69,99.92,82.65,
67.56,29.14,25.01,22.60,21.35,17.90.ESI-MS m/z:457[M-H]-。
Embodiment 17:
1- (3- trifluoromethyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 73.2%.1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),
9.01 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.62-7.51 (m, 4H), 7.30 (dd, J=20.0,
7.6Hz, 3H), 5.98 (d, J=9.2Hz, 1H), 3.97 (d, J=11.2Hz, 1H), 3.70 (s, 1H), 2.05-1.99 (m,
1H), 1.92 (d, J=11.6Hz, 1H), 1.76 (s, 1H), 1.59 (s, 3H)13C NMR(101MHz,DMSO-d6)δ163.70,
155.72,155.64,152.99,146.90,140.95,137.78,132.26,130.32,122.64,122.23,121.17,
120.11,118.53,115.57,114.53,102.70,82.65,67.56,29.13,25.01,22.59.ESI-MS m/z:
497[M-H]-。
Embodiment 18:
1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -
4- oxygroups] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 66.6%.1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),
8.99 (s, 1H), 8.58 (s, 1H), 8.14 (s, 2H), 7.69-7.57 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.98 (d, J
=10.0Hz, 1H), 3.97 (d, J=11.6Hz, 1H), 3.74-3.68 (m, 1H), 2.05 (d, J=12.4Hz, 1H), 1.93
(d, J=12.4Hz, 1H), 1.77 (d, J=8.0Hz, 1H), 1.59 (s, 3H)13C NMR(101MHz,DMSO-d6)δ163.7,
155.7,152.9,147.1,139.8,137.6,132.4,132.3,127.3,123.5,122.7,121.9,120.3,
117.3,102.7,82.7,67.5,29.1,25.0,22.6.ESI-MS m/z:531[M-H]-。
Embodiment 19:
1- (the fluoro- 5- trifluoromethyls of 3-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -
4- oxygroups] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 60.2%.1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),
9.06 (s, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.73 (s, 1H), 7.64 (d, J=11.2Hz, 1H) 7.58 (d, J=
8.8Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 5.99 (dd, J=10.1,2.1Hz, 1H),
3.97 (d, J=11.6Hz, 1H), 3.76-3.66 (m, 1H), 2.45 (dd, J=12.8,4.0Hz, 1H), 2.05 (d, J=
12.5Hz, 1H), 1.93 (dd, J=13.0,2.6Hz, 1H), 1.84-1.70 (m, 1H), 1.61 (d, J=10.0Hz, 2H)
.ESI-MS m/z:517[M+H]+。
Embodiment 20:
1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl]
Urea
With reference to the preparation method of embodiment 4.Yield 68.3%.1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),
8.85 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.56 (d, J=8.9Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 7.26
(d, J=8.8Hz, 2H), 7.26 (d, J=8.9Hz, 2H), 5.98 (dd, J=10.1,1.9Hz, 1H), 3.97 (d, J=
11.2Hz, 1H), 3.77-3.65 (m, 1H), 2.49-2.41 (m, 1H), 2.05 (d, J=12.5Hz, 1H), 1.93 (dd, J=
12.9,2.3Hz,1H),1.83-1.68(m,1H),1.67-1.53(m,2H).13C NMR(101MHz,DMSO-d6)163.72,
155.72,155.68,152.90,146.81,139.08,137.97,132.25,129.03,125.80,122.62,120.18,
119.94,102.72,82.70,67.54,29.14,25.03,22.59.13C NMR(101MHz,DMSO)δ164.56,
163.86,163.67,161.44,155.68,152.80,147.51,147.15,143.00,137.51,132.23,122.64,
120.42,114.97,114.77,110.95,109.05,108.79,102.73,82.70,67.53,29.14,25.02,
22.59.ESI-MS m/z:465[M+H]+。
Embodiment 21:
1- (the chloro- 5- trifluoromethyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -
4- oxygroups] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 74.5%.1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),
8.99 (s, 1H), 8.58 (s, 1H), 8.14 (s, 2H), 7.69-7.57 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.98 (d, J
=10.0Hz, 1H), 3.97 (d, J=11.6Hz, 1H), 3.74-3.68 (m, 1H), 2.05 (d, J=12.4Hz, 1H), 1.93
(d, J=12.4Hz, 1H), 1.77 (d, J=8.0Hz, 1H), 1.59 (s, 3H) .ESI-MS m/z:533[M+H]+。
Embodiment 22:
1- cyclohexyl -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea
With reference to the preparation method of embodiment 4.Yield 71.5%.1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),
8.46 (s, 1H), 8.06 (s, 1H), 7.47 (d, J=8.0Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 6.13 (d, J=
8.4Hz, 1H), 5.98 (d, J=9.2Hz, 1H), 5.59 (d, J=7.2Hz, 4H), 4.07 (s, 1H), 3.96 (d, J=
14.0Hz, 1H), 3.71 (s, 1H), 2.00 (s, 1H), 1.91 (d, J=14.0Hz, 1H), 1.80 (s, 2H), 1.72 (d, J=
12.0Hz,8H).ESI-MS m/z:437[M+H]+。
Embodiment 23:
1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] benzene
Base] thiocarbamide
With reference to the preparation method of embodiment 4.Yield 69.5%.1H NMR (400MHz, DMSO-d6) δ 9.86 (d, J=
7.6Hz, 2H), 8.60 (s, 1H), 8.15 (s, 1H), 7.60 (d, J=8.8Hz, 2H), 7.31 (d, J=8.0Hz, 4H), 7.24
(t, J=7.6Hz, 1H), 6.97 (d, J=10.8Hz, 1H), 5.99 (d, J=9.6Hz, 1H), 3.97 (d, J=11.2Hz,
1H),3.74–3.68(m,1H),2.31(s,3H),2.09(s,6H).13C NMR(101MHz,DMSO-d6)δ180.12,
163.54,155.68,148.71,139.58,138.20,138.05,137.94,132.31,128.77,128.65,125.65,
124.55,122.35,122.23,121.25,102.70,82.65,67.57,31.10,29.14,25.01,22.60,
21.47.ESI-MS m/z:461[M+H]+。
Embodiment 24:
1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygroups] phenyl]
Thiocarbamide
With reference to the preparation method of embodiment 4.Yield is 57.9%.1HNMR (400MHz, DMSO-d6) δ 9.97 (s, 1H),
9.95 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.59 (d, J=8.8Hz, 2H), 7.55 (d, J=8.8Hz, 2H), 7.41
(m, 2H), 7.32 (d, J=8.8Hz, 2H), 5.99 (dd, J=2.0Hz, 2.4Hz, 1H), 3.97 (d, J=11.6Hz, 1H),
3.72 (m, 1H), 2.46 (m, 1H), 2.05 (d, J=12.8Hz, 1H), 1.93 (dd, J=2.8Hz, 2.8Hz, 1H), 1.77 (m,
1H), 1.60 (m, 2H) .ESI-MS m/z:481[M+H]+。
Embodiment 25:
1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -
4- oxygroups] phenyl] thiocarbamide
With reference to the preparation method of embodiment 4.Yield is 60.3%.1HNMR (400MHz, DMSO-d6) δ 9.22 (s, 1H),
8.99 (s, 1H), 8.58 (s, 1H), 8.13 (d, J=3.2Hz, 2H), 7.68 (dd, J=2.0Hz, 2.0Hz, 1H), 7.62 (d, J
=8.8Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.28 (d, J=9.2Hz, 2H), 5.99 (dd, J=2.0Hz, 2.4Hz,
1H), 3.97 (d, J=11.2Hz, 1H), 3.71 (m, 1H), 2.46 (m, 1H), 2.05 (m, 1H), 1.93 (m, 1H), 1.77 (m,
1H), 1.60 (dt, 2H) .ESI-MS m/z:549[M+H]+。
Embodiment 26:
1- (3- trifluoromethyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- oxygen
Base] phenyl] thiocarbamide
With reference to the preparation method of embodiment 4.Yield is 69.9%.1HNMR (400MHz, DMSO-d6) δ 10.12 (s, 1H),
10.11 (s, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.79 (d, J=8.4Hz, 1H), 7.59 (q, J=
8.8Hz, 7.2Hz, 3H), 7.49 (d, J=7.6Hz, 1H), 7.34 (d, J=8.8Hz, 2H), 6.00 (dd, J=2.0Hz,
2.4Hz, 1H), 3.97 (d, J=11.2Hz, 1H), 3.72 (m, 1H), 2.46 (dd, J=4Hz, 4Hz, 1H), 2.05 (d, J=
13.6Hz, 1H), 1.93 (dd, J=2.8Hz, 2.8Hz, 1H), 1.79 (m, 1H), 1.61 (m, 2H) .ESI-MS m/z:515[M+
H]+。
Embodiment 27:
Cell in vitro strain inhibitory activity (IC50) test
Human umbilical vein endothelial cells HUVEC of the compound to high VEGF expression R-2, height expression BRAF are measured using mtt assay
The Human Prostate Cancer Cells PC-3 of (wild type) and high expression BRAFV600EPeople's Human melanoma cell line A375, people's colon
The external inhibitory activity of cancer cell HT-29, four kinds of Human Prostate Cancer Cells PC-3, human lung cancer cell A549 tumor cell lines, and
Set the cytotoxicity that normal cell canine kidney cells MDCK measures compound.
Cultured cell in vitro strain, after six kinds of cell strain cell dissociations of exponential phase, piping and druming divides at single cell suspension
It is not inoculated in 96 well culture plates;Per hole 5 × 103Culture medium 200 μ L, 37 DEG C, 5%CO are added per hole for a cell2It is trained in incubator
It supports overnight.After cell is adherent, it is separately added into the test-compound and positive control drug Sorafenib of various dose, configuration is different
The sample of concentration, using Sorafenib as positive controls, is further cultured for 48h in the incubator using blank group as negative control group.So
Afterwards, the MTT liquid that 20 μ L mass concentrations are 5mg/mL is added per hole, continuously cultivates 4h.Supernatant is sucked, 150 μ L bis- are added per hole
Culture plate is placed in micropore plate oscillator and vibrates 10min, crystal is made to dissolve by first sulfoxide.Microplate reader is used at 570nm wavelength
Absorbance A value is surveyed, inhibiting rate is calculated;IC is calculated by Bliss methods50.The result of cell in vitro active testing see the table below 1.
1 compound on tumor cell proliferation results of table
Cell in vitro active testing shows compound to high VEGF expression R-2, BRAF and BRAFV600ECell have compared with
Strong inhibitory activity can be used for preventing or treat and VEGFR-2, BRAF and BRAFV600ERelated clinical disease, these diseases can
To be melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, skin or intraocular melanoma, uterus
Cancer, oophoroma, the carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer, breast cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical carcinoma, vagina
Cancer, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid carcinoma, soft tissue sarcoma,
Carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute leukemia, carcinoma of urinary bladder, kidney or carcinoma of ureter, spinal column axis tumour, pituitary gland
Tumor, gastrointestinal stromal, colorectal cancer, non-small cell lung cancer, Small Cell Lung Cancer, mastocytosis, glioma, meat
Tumor, lymthoma etc..
Claims (8)
1. a kind of 1- with anti-tumor activity (2- oxinanes) -1HPyrazolo [3,4-d] pyrimidines, feature
It is:The compound is selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine]-
4- oxygroups] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine]-
4- oxygroups] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d] is phonetic
Pyridine] -4- oxygroups] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d]
Pyrimidine] -4- oxygroups] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-
D] pyrimidine]-4- oxygroups] phenyl] urea, 1- (2- fluoro- 5-(trifluoromethyl) phenyl)-3- [4- [[1- (2- oxinanes)-1HPyrrole
Azoles simultaneously [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H-
Pyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1HPyrrole
Azoles simultaneously [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazolo
[3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazoles
And [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- oxinanes) -1HPyrrole
Azoles simultaneously [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the fluoro- 5- trifluoromethyls of 3-) -3- [4- [[1- (2-
Oxinane) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- chlorphenyls) -3- [4- [[1- (2- tetrahydrochysenes
Pyrans) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (the chloro- 5- trifluoromethyls of 2-) -3- [4- [[1-
(2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- cyclohexyl -3- [4- [[1- (2- tetrahydrochysene pyrroles
Mutter) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] urea, 1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- tetra-
Hydrogen pyrans) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] thiocarbamide, 1- (3- trifluoromethyls) -3- [4- [[1-
(2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] phenyl] one of which in thiocarbamide.
2. a kind of 1- (2- oxinanes) -1 with anti-tumor activity described in claim 1HPyrazolo [3,4-d] is phonetic
Pyridine class compound synthesis method, it is characterised in that:Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are subjected to ring-closure reaction generation
4- chloro- 1HPyrazolo [3,4-d] pyrimidine is reacted with 3,4- dihydro -2H- pyrans under the action of catalyst, generates the chloro- 1- of 4-
(2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine is obtained by the reaction with p-aminophenol among amine under protective gas protection
Body 4- [[1- (2- oxinanes) -1HPyrazolo [3,4-d] pyrimidine] -4- oxygroups] aniline, finally with isocyanates or sulphur isocyanide
Target compound is obtained by the reaction in acid esters.
3. according to a kind of 1- (2- oxinanes) -1 with anti-tumor activity described in claim 2HPyrazolo [3,4-
D] pyrimidines synthetic method, it is characterised in that:The catalyst be in acidic catalyst and saline catalyst extremely
Few one kind.
4. according to a kind of 1- (2- oxinanes) -1 with anti-tumor activity described in claim 3HPyrazolo [3,4-
D] pyrimidines synthetic method, it is characterised in that:The protective gas is at least one of nitrogen and inert gas.
5. a kind of pharmaceutical composition, it is characterised in that:Including at least one of following ingredients:a)Compound, b)The compound
Pharmaceutically acceptable salt;Wherein, the compound is compound described in claim 1.
6. a kind of pharmaceutical composition described in claim 5 is preparing the drug because of protein kinase activity exception diseases caused
Using.
7. according to the application described in claim 6, it is characterised in that:The disease is cancer.
8. according to the application described in claim 7, it is characterised in that:The disease is melanoma, liver cancer, kidney, lung
Cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, uterine cancer, oophoroma, the carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer, mammary gland
Cancer, carcinoma of fallopian tube, cervical carcinoma, carcinoma of vagina, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid gland
Cancer, parathyroid carcinoma, soft tissue sarcoma, carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute leukemia, carcinoma of urinary bladder, backbone
In axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal cancer, mastocytosis, glioma, sarcoma, lymthoma
A kind of or arbitrary several combination.
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