CN106496232A - A kind of 1 (2 oxinane) 1H pyrazolos [3,4 d] pyrimidines with antitumor activity and preparation method thereof - Google Patents

A kind of 1 (2 oxinane) 1H pyrazolos [3,4 d] pyrimidines with antitumor activity and preparation method thereof Download PDF

Info

Publication number
CN106496232A
CN106496232A CN201610843513.8A CN201610843513A CN106496232A CN 106496232 A CN106496232 A CN 106496232A CN 201610843513 A CN201610843513 A CN 201610843513A CN 106496232 A CN106496232 A CN 106496232A
Authority
CN
China
Prior art keywords
pyrazolos
pyrimidine
oxinanes
phenyl
epoxides
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.)
Granted
Application number
CN201610843513.8A
Other languages
Chinese (zh)
Other versions
CN106496232B (en
Inventor
伍小云
付昱
王园园
万山河
李中皇
王广发
田元新
张婷婷
张嘉杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southern Medical University
Original Assignee
Southern Medical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Southern Medical University filed Critical Southern Medical University
Priority to CN201610843513.8A priority Critical patent/CN106496232B/en
Publication of CN106496232A publication Critical patent/CN106496232A/en
Application granted granted Critical
Publication of CN106496232B publication Critical patent/CN106496232B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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

Abstract

The invention discloses a kind of 1 (2 oxinane) 1H pyrazolos [3,4 d] pyrimidines with antitumor activity, its formula (I) is as follows.Invention also discloses the synthetic method of the compound, and the Pharmaceutical composition containing the compound.The invention also discloses the pharmaceutical composition is being treated because of the application of protein kinase activity exception diseases caused.It is novel that the present invention develops a kind of structure, there is the pyrazolo [3 of notable antitumor activity, 4 d] pyrimidines, the compound may serve as double target spot inhibitor of 2 kinases of BRAF/VEGFR, in terms for the treatment of is because of protein kinase activity exception diseases caused have good effect and wide application prospect.

Description

A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] with antitumor activity Pyrimidines and preparation method thereof
Technical field
The present invention relates to a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines with antitumor activity Compound and preparation method thereof, belongs to field of medicaments.
Background technology
The treatment of malignant tumour is a global difficult problem for a long time.It was swollen by finding in the past to the treatment of tumour Knurl is simultaneously destroyed to realize, now with deepening continuously that cell signaling pathway is studied, people are to inside tumor cells Having acted on of oncogene and antioncogene solves more and more deep so that for new anti-of 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 relevant with apoptosis.BRAF is one of tri- hypotypes of RAF, is the important transduced element of MAPK paths, and BRAF There is BRAF mutation, ARAF and CRAF then less in frequency of mutation highest in 3 hypotypes, about 7%～8% human tumor Raw mutation.There is BRAF mutation in 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 acceptor " formula of sprouting Angiogenesiss (sprouting angiogenesis) " that VEGFR (VEGF receptor) is mediated, in physiology and Pathologic vessels play important role in generating, and especially play the effect of key in terms of Tumor Angiongesis.Targeting The medicine of VEGF and VEGFR is continuously developed out, such as bevacizumab, sorafenib, aflibercept etc., These medicines suppress VEGF/VEGFR signal paths in a different manner, clinically have been demonstrated effectively suppress 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 By activating PLC (phospholipase C), hydrolysis produces second messenger DAG (diacylglycerol) to VEGFR-2, and then (albumen swashs to activate PKC Enzyme), PKC reactivations RAF, RAF finally activate MAPK by activating MEK.Two target spots of BRAF and VEGFR-2 are indicated in tumour Occur evolution in have certain synergy.
Present Research and analysis both at home and abroad：Sorafenib is II A type BRAF kinase inhibitors of the 1st report.But In III clinical trial phase of metastasis melanin tumor, Sorafenib does not have significant curative effect.One kind is probably, melanoma according to New vessels around relying is shifted, and alternatively possible is that, 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 evening of half Phase melanoma has variation, and in this crowd, the response rate of Vemurafenib reaches 50%, extends 3 months than chemotherapy and survives Phase.This product was considered as the impressive progress of melanoma treatment at that time, and one of individualized treatment successful model.But Unfortunately, start 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, suppress the Angiogenesiss 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 with VEGFR-2, designs Synthesis BRAFV600EDouble target spot inhibitor of/VEGFR-2 kinases, by making BRAFV600EReduce with VEGFR-2 expression, block which Signal transduction pathway is exhausted the VEGF of tumour cell generation and suppresses tumor vascular generation, cuts off tumour Blood supply, then be expected to reach the purpose for suppressing tumour growth, development and transfer.And double target spot inhibitor have more in anti-tumor aspect High selectivity and preferably activity.
Therefore, this area is in the urgent need to developing structure novelty, double target spots suppressions of the strong BRAF/VEGFR-2 kinases of activity Preparation.
Content of the invention
It is an object of the invention to provide a kind of 1- (2- oxinanes) -1H- pyrazolo [3,4- with antitumor activity D] pyrimidines and its derivative and the material synthetic method and application.
Technical scheme is as follows：
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with antitumor activity, its lead to Formula (I) is as follows：
Wherein X is oxygen, sulphur or nitrogen；
Linking group Linker is be substituted in parent benzene 2,3 or 4 Wherein N atoms one end is connected with parent；
R1For-H, halogen, C1～C4Alkyl, C1～C4Alkoxyl, C1～C4Alkylthio group or-NO2；R2For 4～12 yuan replaced Aromatic heterocyclic,Substituent in the replacement heteroaromatic is-H, C1～C6Alkyl, aryl ,- CF3Or 5～10 yuan of aromatic heterocyclics；Hetero atom number on the aromatic heterocyclic is 1～4, and hetero atom is O, S or N；R3For-H, Halogen, alkyl ,-CF3、-NO2Or-CN；R4For-H or alkyl.
A kind of described 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines chemical combination with antitumor activity Thing, in formula (I), X is oxygen；Linking group Linker is be substituted in parent benzene 2,3 or 4Wherein N atoms one end is connected with parent；R1For-H, halogen, C1～C4Alkyl, C1～C4Alkane Epoxide, C1～C4Alkylthio group or-NO2；R2For replace 4～12 yuan of aromatic heterocyclics,The replacement Substituent in heteroaromatic is-H, C1～C6Alkyl, aryl ,-CF3Or 5～10 yuan of aromatic heterocyclics；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、R4Contained Hydrogen atom independently of one another by one or more identical or different G1Or G2Replace；G1Or G2Be each independently selected from H ,- OH、-NH2、-CN、-CF3, halogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C6Aryl, 5-6 circle heterocycles aryl, C3-6Heteroalicyclyl, C1-6Alkoxyl, C3-6Cycloalkyloxy, C6Aryloxy group, 5-7 units heteroaryloxy, C3-6Heterolipid epoxy radicals, C1-6Alkane Amino, C3-6Naphthene amino, C6Fragrant amino, 5-7 circle heterocycles fragrant aminos, C3-6Heterolipid ring amino, C1-6Alkoxy -C O-, C3-6Cycloalkanes Epoxide-CO-, C6Aryloxy group-CO-, 5-7 circle heterocycles aryloxy group-CO-, C3-6Heterolipid epoxy radicals-CO-, C1-6Alkylamino-CO-, C3-6 Naphthene amino-CO-, C6Fragrant amino-CO-, 5-7 circle heterocycles fragrant amino-CO-, C3-6One of which in heterolipid ring amino-CO-.
Compound shown in formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, mutually Tautomeric or prodrug, the compound selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3, 4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3, 4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles And [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles And [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- tetra- Hydrogen pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) - 1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (tri- fluoro- 5- trifluoromethyls of 3-) - 3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 3- trifluoromethylbenzenes of 2- Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- cyclohexyl -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- trifluoromethyl -4- chlorobenzenes Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- fluoroforms Base phenyl) in -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide wherein A kind of.
A kind of described 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with antitumor activity Synthetic method：Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are carried out ring-closure reaction generation 4- chloro- 1H- pyrazolos [3,4-d] Pyrimidine, under catalyst action, is reacted with 3,4- dihydro -2H- pyrans, generates 4- chloro- 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine, protective gas protection under, with p-aminophenol reaction obtain amine intermediate 4- [[1- (2- oxinanes)- 1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] aniline, finally targeted is obtained with the reaction such as isocyanates or sulphur isocyanates Compound.
Described catalyst is at least one in acidic catalyst and saline catalyst.
Described protective gas is at least one in nitrogen and inert gas.
A kind of pharmaceutical composition, including following ingredients at least one：A) compound, b) compound pharmaceutically may be used The polymorph of the solvate of the hydrate of the salt of acceptance, c) compound, d) compound, e) compound, f) change The prodrug of the dynamic isomer of compound, g) compound；Wherein, described compound is the compound shown in formula (I).
A kind of described pharmaceutical composition is in treatment because of the application of protein kinase activity exception diseases caused.
Described disease is cancer.
Described disease be melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, skin or Intraocular melanoma, the cancer of the uterus, oophoroma, the carcinoma of the rectum, anal region cancer, cancer of the stomach, 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, ED-SCLC, mast cell increase Many diseases, glioma, sarcoma, the one kind in lymthoma or arbitrarily several combinations.
The invention has the beneficial effects as follows：
The present invention develops a kind of structure novelty, pyrazolo [3,4-d] the miazines chemical combination with notable antitumor activity Thing, 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 embodiment
A kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with antitumor activity, its lead to Formula (I) is as follows：
Wherein X is oxygen, sulphur or nitrogen；
Linking group Linker is be substituted in parent benzene 2,3 or 4 Wherein N atoms one end is connected with parent；
R1For-H, halogen, C1～C4Alkyl, C1～C4Alkoxyl, C1～C4Alkylthio group or-NO2；R2For 4～12 yuan replaced Aromatic heterocyclic,Substituent in the replacement heteroaromatic is-H, C1～C6Alkyl, aryl ,- CF3Or 5～10 yuan of aromatic heterocyclics；Hetero atom number on the aromatic heterocyclic is 1～4, and hetero atom is O, S or N；R3For-H, Halogen, alkyl ,-CF3、-NO2Or-CN；R4For-H or alkyl.
A kind of described 1- (2- oxinanes) -1H- pyrazolos [3,4-d] miazines chemical combination with antitumor activity Thing, in formula (I), X is oxygen；Linking group Linker is be substituted in parent benzene 2,3 or 4Wherein N atoms one end is connected with parent；R1For-H, halogen, C1～C4Alkyl, C1～C4Alkane Epoxide, C1～C4Alkylthio group or-NO2；R2For replace 4～12 yuan of aromatic heterocyclics,The replacement Substituent in heteroaromatic is-H, C1～C6Alkyl, aryl ,-CF3Or 5～10 yuan of aromatic heterocyclics；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、R4Contained Hydrogen atom independently of one another by one or more identical or different G1Or G2Replace；G1Or G2Be each independently selected from H ,- OH、-NH2、-CN、-CF3, halogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C6Aryl, 5-6 circle heterocycles aryl, C3-6Heteroalicyclyl, C1-6Alkoxyl, C3-6Cycloalkyloxy, C6Aryloxy group, 5-7 units heteroaryloxy, C3-6Heterolipid epoxy radicals, C1-6Alkane Amino, C3-6Naphthene amino, C6Fragrant amino, 5-7 circle heterocycles fragrant aminos, C3-6Heterolipid ring amino, C1-6Alkoxy -C O-, C3-6Cycloalkanes Epoxide-CO-, C6Aryloxy group-CO-, 5-7 circle heterocycles aryloxy group-CO-, C3-6Heterolipid epoxy radicals-CO-, C1-6Alkylamino-CO-, C3-6 Naphthene amino-CO-, C6Fragrant amino-CO-, 5-7 circle heterocycles fragrant amino-CO-, C3-6One of which in heterolipid ring amino-CO-.
Compound shown in formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, mutually Tautomeric or prodrug, the compound selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3, 4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3, 4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles And [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- nitrobenzophenones) -3- [4- [[1- (2- oxinanes) -1H- pyrazoles And [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) -3- [4- [[1- (2- tetra- Hydrogen pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) - 1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- tetrahydrochysene pyrroles Mutter) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyl-4-chlorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (tri- fluoro- 5- trifluoromethyls of 3-) - 3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 3- trifluoromethylbenzenes of 2- Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- cyclohexyl -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- trifluoromethyl -4- chlorobenzenes Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- fluoroforms Base phenyl) in -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide wherein A kind of.
A kind of described 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with antitumor activity Synthetic method：Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are carried out ring-closure reaction generation 4- chloro- 1H- pyrazolos [3,4-d] Pyrimidine, under catalyst action, is reacted with 3,4- dihydro -2H- pyrans, generates 4- chloro- 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine, protective gas protection under, with p-aminophenol reaction obtain amine intermediate 4- [[1- (2- oxinanes)- 1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] aniline, finally targeted is obtained with the reaction such as isocyanates or sulphur isocyanates Compound.Concrete 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.
In synthesis type, last product is the compound shown in formula (I).
Preferably, described catalyst is at least one in acidic catalyst and saline catalyst；It is further preferred that Described catalyst is saline catalyst；Still further preferably, described catalyst is para-methylbenzenepyridinsulfonate sulfonate.
Preferably, described protective gas is at least one in nitrogen and inert gas；It is further preferred that described Protective gas is nitrogen, the one of which in argon gas；Still further preferably, described protective gas is nitrogen.
A kind of pharmaceutical composition, including following ingredients at least one：A) compound, b) compound pharmaceutically may be used The polymorph of the solvate of the hydrate of the salt of acceptance, c) compound, d) compound, e) compound, f) change The prodrug of the dynamic isomer of compound, g) compound；Wherein, described compound is the compound shown in formula (I).
It is further preferred that described pharmaceutical composition also includes auxiliary material；Still further preferably, described auxiliary material includes At least one in following material：Solvent, propellant, solubilizer, stabilizer, glidant, flavouring, preservative, suspending agent, bag Clothing material, aromatic, anti-binder, integrated agent, penetration enhancer, pH value regulator, buffer, plasticizer, cosolvent, emulsification Agent, colouring agent, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, surfactant, foaming agent, Defoamer, thickener, inclusion agents, NMF, absorbent, diluent, flocculant and deflocculant, filter aid, release retarding agent.
The pharmaceutical composition of the present invention can be made into various formulations：
Decentralized system according to formulation is classified, and specifically, can make following formulation：Solution-type, colloidal solution Type, emulsion-type, suspension type, gas decentralized, microdispersed form, solid dispersing；
According to typoiogical classification, specifically, following formulation can be made：Liquid dosage form is (such as aromatic waters, solution, note Penetrate agent, mixture, lotion, liniment etc.), gas formulation (such as aerosol, spray etc.), solid dosage forms (as powder, pill, tablet, Film etc.), semisolid dosage form (such as ointment, suppository, paste etc.)；
Classify according to method of administration, specifically, following formulation can be made：Through the formulation of gastrointestinal administration, without stomach The formulation of intestinal canal administration.
A kind of described pharmaceutical composition is in treatment because of the application of protein kinase activity exception diseases caused.Preferably, Described disease is cancer；It is further preferred that described disease is melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, pancreas Cancer, cutaneum carcinoma, head and neck cancer, skin or intraocular melanoma, the cancer of the uterus, oophoroma, the carcinoma of the rectum, anal region cancer, cancer of the stomach, 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, ED-SCLC, mastocytosis, glioma, sarcoma, lymthoma or arbitrarily several combinations.
Preferably, shown in formula (I) compound or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline The application of type thing, dynamic isomer or prodrug in BRAF/VEGFR-2 kinase inhibitors are prepared.
It is further preferred that the compound or its pharmaceutically acceptable salt, hydrate, solvent conjunction shown in formula (I) Thing, polymorph, dynamic isomer or prodrug are preparing treatment and/or prevention and/or are delaying and/or auxiliary treatment and/or place Application in the medicine of reason related disease too high to BRAF/VEGFR-2 kinase activities；Still further preferably, formula (I) institute The compound for showing or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, dynamic isomer or prodrug exist Prepare the application in antineoplastic；Still more preferably, at least one in following compounds or its can pharmaceutically connect Salt, hydrate, solvate, polymorph, dynamic isomer or prodrug the applying in antineoplastic is prepared that receives, such as exists The application in antiprostate cancer is prepared, or prepares the application in melanoma medicine.
In the present invention, " pharmaceutically acceptable salt " refers to the form for the basic group in parent compound being converted into salt. Pharmaceutically acceptable salt include but 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 basic group in parent compound is existed with the acid of 1-4 equivalents React in one solvent system.Suitable salt is set forth 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..Acetic acid, propionic acid, ethanol are included by the organic acid of derivative acid-addition salts Acid, pyruvic acid, oxalic acid, malic acid, malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Chinese cassia tree Acid, mandelic acid, methanesulfonic acid, ethyl sulfonic 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 4- chloro- 1H- pyrazolos [3,4-d] pyrimidine
In 100mL there-necked flasks, 1.0g 4, bis- chloro- 5- pyrimidinecarboxaldehydes of 6-, 20mL methyl alcohol, 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.Drop Bi Huifu reacts 2～3h to room temperature, and TLC is monitored.Reaction terminates, and revolves solvent evaporated, dries.Use acetic acid Ethyl ester dissolved solid (30mL × 3), filters, washs (60mL × 3) with saturation NaCl solution after merging.Anhydrous MgSO4Dry, revolve Solvent, drying is evaporated off, faint yellow solid, yield 68.9% is obtained.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 there-necked flasks, 1.88g 4- chloro- 1H- pyrazolos [3,4-d] pyrimidine, 50mL ethyl acetate is added to rise Temperature is to 50 DEG C.PPTs (para-methylbenzenepyridinsulfonate sulfonate, catalytic amount), the 1.37mL 3 of 50mg, 4- dihydro -2H- pyrrole are put into successively Mutter (1.2eq).50 DEG C of insulation reactions 20-22h, TLC are monitored.Reaction terminates, and is down to room temperature, uses water (60mL × 1), saturation respectively NaCl solution (50mL × 2) washs mixture.Anhydrous MgSO4Dry, revolving removes solvent, drying.Solid with petroleum ether extraction gained Body (60mL × 2), solvent evaporated obtain faint yellow oily solid, yield 76.5% after drying.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- epoxides] aniline
In 100mL there-necked flasks, 0.28g p-aminophenols, 1.51g Cs is added2CO3(1.2eq) powder, N2Protection is lower to drip Enter 2mL DMF, 1.5-2h is stirred at room temperature.Afterwards by the chloro- 1- of 0.56g 4- (2- the oxinanes) -1H- pyrazoles being dissolved in appropriate DMF And [3,4-d] pyrimidine (1.0eq) is instilled, 22-24h is reacted, TLC is monitored.Reaction terminates, with 50mL diluted ethyl acetates after, according to Secondary NaOH solution (60mL × 1) with 1M, water (80mL × 1), 5%LiCl solution (50mL × 2) are washed, MgSO4Dry, rotate 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- epoxides] benzene Base] urea synthesis
In 100mL there-necked flasks, 4- chloro- 1H- pyrazolos [3,4-d] pyrimidine, appropriate CH is added2Cl2, ice bath cooling, drop Plus the CH of the 3- methylphenyl isocyanates of 1.0eq amounts2Cl2.Remove and react under ice bath, room temperature overnight, TLC is monitored.Reaction knot Beam, adds 60mL petroleum ethers, obtains crude product, acidic alumina column chromatography for separation (ethyl acetate/first after filtration, 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- epoxides] Phenyl] urea
Preparation method with reference to 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
Preparation method with reference to 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
Preparation method with reference to 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
Preparation method with reference to 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- epoxides] benzene Base] urea
Preparation method with reference to 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] is phonetic for 4- for 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- Pyridine] -4- epoxides] phenyl] urea
Preparation method with reference to 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- epoxides] benzene Base] urea
Preparation method with reference to 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- Epoxide] phenyl] urea
Preparation method with reference to 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- epoxides] benzene Base] urea
Preparation method with reference to 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- epoxides] phenyl] Urea
Preparation method with reference to 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- epoxides] phenyl] Urea
Preparation method with reference to 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
Preparation method with reference to 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
Preparation method with reference to 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- epoxides] phenyl] urea
Preparation method with reference to 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- epoxides] phenyl] urea
Preparation method with reference to 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- epoxides] phenyl] Urea
Preparation method with reference to 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- epoxides] phenyl] urea
Preparation method with reference to 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- epoxides] phenyl] urea
Preparation method with reference to 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- epoxides] benzene Base] thiocarbamide
Preparation method with reference to 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- epoxides] phenyl] Thiocarbamide
Preparation method with reference to 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- epoxides] phenyl] thiocarbamide
Preparation method with reference to 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
Preparation method with reference to 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 are determined using mtt assay, high expression BRAF Human Prostate Cancer Cells PC-3 of (wild type) and high expression BRAFV600EPeople's Human melanoma cell line A375, people's colon Cancer cell HT-29, Human Prostate Cancer Cells PC-3, the external inhibitory activity of four kinds of tumor cell lines of human lung cancer cell A549, and Set the cytotoxicity that normal cell MDCK MDCK determines compound.
Cultured cell in vitro strain, six kinds of cell line cell dissociations of exponential phase after, blow and beat into single cell suspension, point 96 well culture plates are not inoculated in；Per hole 5 × 103Individual cell, adds 200 μ L of culture medium, 37 DEG C, 5%CO per hole2Train in incubator Support overnight.After cell attachment, the test-compound and positive control drug Sorafenib of various dose is separately added into, configuration is different The sample of concentration, with blank group as negative control group, with Sorafenib as positive controls, is further cultured for 48h in incubator.So Afterwards, 20 μ L mass concentrations are added to cultivate 4h for the MTT liquid of 5mg/mL, continuously per hole.Supernatant is sucked, and 150 μ L bis- are added per hole Culture plate is placed in vibration 10min in micropore plate oscillator by first sulfoxide, dissolves crystal.ELIASA is used at 570nm wavelength Absorbance A value is surveyed, inhibiting rate is calculated；Press Bliss methods and calculate IC50.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 that compound is to high VEGF expression R-2, BRAF and BRAFV600ECell have compared with Strong inhibitory activity, can be used to prevent or treat and VEGFR-2, BRAF and BRAFV600ERelevant clinical disease, these diseases can Being 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, cancer of the stomach, 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 Knurl, gastrointestinal stromal, colorectal cancer, non-small cell lung cancer, ED-SCLC, mastocytosis, glioma, meat Knurl, lymthoma etc..

Claims (10)

1. a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines with antitumor activity, its feature It is：Its formula (I) is as follows：
Wherein X is oxygen, sulphur or nitrogen；
Linking group Linker is be substituted in parent benzene 2,3 or 4 Wherein N atoms one end is connected with parent；
R1For-H, halogen, C1～C4Alkyl, C1～C4Alkoxyl, C1～C4Alkylthio group or-NO2；
R2For replace 4～12 yuan of aromatic heterocyclics,Substituent in the replacement heteroaromatic for- H、C1～C6Alkyl, aryl ,-CF3Or 5～10 yuan of aromatic heterocyclics；Hetero atom number on the aromatic heterocyclic is 1～4, miscellaneous Atom is O, S or N；R3For-H, halogen, alkyl ,-CF3、-NO2Or-CN；R4For-H or alkyl.
2. according to a kind of 1- (2- the oxinanes) -1H- pyrazolo [3,4- with antitumor activity described in claim 1 D] pyrimidines, it is characterised in that：
In formula (I), X is oxygen；
Linking group Linker is be substituted in parent benzene 2,3 or 4Wherein N atoms one end is connected with parent；
R1For-H, halogen, C1～C4Alkyl, C1～C4Alkoxyl, C1～C4Alkylthio group or-NO2；
R2For replace 4～12 yuan of aromatic heterocyclics,Substituent in the replacement heteroaromatic for- H、C1～C6Alkyl, aryl ,-CF3Or 5～10 yuan of aromatic heterocyclics；Hetero atom number on the aromatic heterocyclic is 1～4, miscellaneous Atom is O or S；R3For-H, halogen, alkyl ,-CF3、-NO2Or-CN；R4For-H；R3、R4Contained hydrogen atom independently of one another by One or more identical or different G1Or G2Replace；G1Or G2It is each independently selected from H ,-OH ,-NH2、-CN、-CF3, halogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C6Aryl, 5-6 circle heterocycles aryl, C3-6Heteroalicyclyl, C1-6Alkoxyl, C3-6Cycloalkyloxy, C6Aryloxy group, 5-7 units heteroaryloxy, C3-6Heterolipid epoxy radicals, C1-6Alkylamino, C3-6Naphthene amino, C6Fragrant ammonia Base, 5-7 circle heterocycles fragrant aminos, C3-6Heterolipid ring amino, C1-6Alkoxy -C O-, C3-6Cycloalkyloxy-CO-, C6Aryloxy group-CO-, 5-7 circle heterocycles aryloxy group-CO-, C3-6Heterolipid epoxy radicals-CO-, C1-6Alkylamino-CO-, C3-6Naphthene amino-CO-, C6Fragrant amino- CO-, 5-7 circle heterocycles fragrant amino-CO-, C3-6One of which in heterolipid ring amino-CO-.
3. according to a kind of 1- (2- the oxinanes) -1H- pyrazolo [3,4- with antitumor activity described in claim 1 D] pyrimidines, it is characterised in that：Compound shown in formula (I) or its pharmaceutically acceptable salt, hydrate, molten Agent compound, polymorph, dynamic isomer or prodrug, the compound are selected from 1- (3- aminomethyl phenyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3,4- dichlorophenyls) -3- [4- [[1- (2- tetrahydrochysenes Pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 5- aminomethyl phenyls of 2-) -3- [4- [[1- (2- tetra- Hydrogen pyrans) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,3- 3,5-dimethylphenyls) -3- [4- [[1- (2- Oxinane) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the fluoro- 3- aminomethyl phenyls of 4-) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- nitrobenzophenones) -3- [4- [[1- (2- Oxinane) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- fluoro- 5- (trifluoromethyl) phenyl) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- cyano-phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (5- methyl -2- nitrobenzophenones) - 3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2- aminomethyl phenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- fluorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- fluorophenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (2,5- 3,5-dimethylphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- trifluoromethyl -4- chlorobenzenes Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (tri- fluoro- 5- tri- of 3- Trifluoromethylphenyl) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (4- Chlorphenyl) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (the chloro- 3- of 2- Trifluoromethyl) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- rings Hexyl -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] urea, 1- (3- methylbenzenes Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (4- chlorobenzenes Base) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- fluoroforms Base -4- chlorphenyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide, 1- (3- trifluoromethyls) -3- [4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] phenyl] thiocarbamide In one of which.
4. a kind of 1- (2- oxinanes) -1H- pyrazolos [3,4-d] with antitumor activity described in claim 1 is phonetic Pyridine class compound synthesis method, it is characterised in that：Bis- chloro- 5- pyrimidinecarboxaldehydes of 4,6- and a hydrazine hydrate are carried out ring-closure reaction generation 4- chloro- 1H- pyrazolos [3,4-d] pyrimidine, under catalyst action, is reacted with 3,4- dihydro -2H- pyrans, generates the chloro- 1- of 4- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine, under protective gas protection, is obtained in the middle of amine with p-aminophenol reaction Body 4- [[1- (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidine] -4- epoxides] aniline, finally with isocyanates or sulphur isocyanide The reaction such as acid esters obtains target compound.
5. according to a kind of 1- (2- the oxinanes) -1H- pyrazolo [3,4- with antitumor activity described in claim 4 D] pyrimidines synthetic method, it is characterised in that：Described catalyst be in acidic catalyst and saline catalyst extremely Few one kind.
6. according to a kind of 1- (2- the oxinanes) -1H- pyrazolo [3,4- with antitumor activity described in claim 5 D] pyrimidines synthetic method, it is characterised in that：Described protective gas is at least one in nitrogen and inert gas.
7. a kind of pharmaceutical composition, it is characterised in that：At least one in including following ingredients：A) compound, b) compound The pharmaceutically polymorphic of acceptable salt, c) hydrate of the compound, d) solvate of the compound, the e) compound The prodrug of the dynamic isomer of thing, f) compound, g) compound；Wherein, described compound is in claim 1 or 2 Compound shown in formula (I).
8. a kind of pharmaceutical composition described in claim 7 is being treated because of the application of protein kinase activity exception diseases caused.
9. treated because of protein kinase activity exception diseases caused according to a kind of pharmaceutical composition described in claim 8 Application, it is characterised in that：Described disease is cancer.
10. treated because of protein kinase activity exception diseases caused according to a kind of pharmaceutical composition described in claim 9 Application, it is characterised in that：Described disease is melanoma, liver cancer, kidney, lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, neck Cancer, skin or intraocular melanoma, the cancer of the uterus, oophoroma, the carcinoma of the rectum, anal region cancer, cancer of the stomach, colon cancer, breast cancer, fallopian tubal Cancer, carcinoma of endometrium, 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, kidney or Carcinoma of ureter, spinal column axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal cancer, non-small cell lung cancer, ED-SCLC, One kind in mastocytosis, glioma, sarcoma, lymthoma or arbitrarily several combinations.
CN201610843513.8A 2016-09-22 2016-09-22 A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof Active CN106496232B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610843513.8A CN106496232B (en) 2016-09-22 2016-09-22 A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610843513.8A CN106496232B (en) 2016-09-22 2016-09-22 A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof

Publications (2)

Publication Number Publication Date
CN106496232A true CN106496232A (en) 2017-03-15
CN106496232B CN106496232B (en) 2018-11-09

Family

ID=58290531

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610843513.8A Active CN106496232B (en) 2016-09-22 2016-09-22 A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof

Country Status (1)

Country Link
CN (1) CN106496232B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112961158A (en) * 2020-03-05 2021-06-15 四川大学华西医院 Aminopyrimidinopyrazole/pyrrole derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014325A2 (en) * 2004-07-02 2006-02-09 Exelixis, Inc. C-met modulators and method of use
WO2008153947A2 (en) * 2007-06-07 2008-12-18 Amgen Inc. Heterocyclic compounds as raf kinase modulators
CN101605540A (en) * 2006-12-14 2009-12-16 埃克塞利希斯股份有限公司 Use the method for mek inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014325A2 (en) * 2004-07-02 2006-02-09 Exelixis, Inc. C-met modulators and method of use
CN101605540A (en) * 2006-12-14 2009-12-16 埃克塞利希斯股份有限公司 Use the method for mek inhibitor
WO2008153947A2 (en) * 2007-06-07 2008-12-18 Amgen Inc. Heterocyclic compounds as raf kinase modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NERMIN S. ABDOU等: "Synthesis and in vitro antiproliferative activity of novel pyrazolo[3,4-d]pyrimidine derivatives", 《MED. CHEM. COMMUN》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112961158A (en) * 2020-03-05 2021-06-15 四川大学华西医院 Aminopyrimidinopyrazole/pyrrole derivative and preparation method and application thereof
CN112961158B (en) * 2020-03-05 2022-07-01 四川大学华西医院 Aminopyrimidinopyrazole/pyrrole derivative and preparation method and application thereof

Also Published As

Publication number Publication date
CN106496232B (en) 2018-11-09

Similar Documents

Publication Publication Date Title
TWI343383B (en) Pyrazole derivatives and uses thereof
CN105461695B (en) Pyrimidine or pyrrolotriazine derivatives and its production and use
US9562060B2 (en) Heterocyclic pyridone compound, and intermediate, preparation method and use thereof
CN103965120B (en) Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application
ES2753386T3 (en) 2-Hydroxy-1- {4 - [(4-phenyl) phenyl] carbonyl} piperazin-1-yl} ethane-1-one derivatives and related compounds as fatty acid synthase inhibitors (FASN) for the treatment of cancer
IL303451A (en) Prmts inhibitors
CN1807413B (en) Carbazole sulfonamide derivative and its preparation method
BRPI0608160A2 (en) isolated antibody, host cell, method of inhibiting psma + cell growth, and use of a defucosylated anti-psma antibody
BRPI0616630A2 (en) substituted pyrazole compounds
WO2013170770A1 (en) Acetylene derivatives having antitumor activity
CN107698603B (en) Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof
CN104507936A (en) Pyridinyl and pyrimidinyl sulfoxide and sulfone derivatives
US20190144427A1 (en) Heterocyclic compounds used as fgfr inhibitors
CN103992326B (en) Indole hexahydropyrazine quinazolinone anti-tumor compounds and preparation method thereof
CN107922348A (en) Bicyclic heterocycle amide derivatives
KR20190058550A (en) Combination therapy
CN106478605A (en) Pyrimidines, its preparation method and medical usage
CN104557871B (en) Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof
BR112020006805A2 (en) epidermal growth factor receptor inhibitor
CN103214481B (en) Novel imidazole also [1,2-a] pyridine compounds and their, its preparation method, comprise the medical composition and its use of this compounds
CN109575045B (en) Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof
CN103755647A (en) C2-bit derivative of 4(3H)-quinazolinone and preparation method and application thereof
CN104557913B (en) Pyridopyrimidine compounds as well as preparation method and application thereof
KR20170043546A (en) Quinazoline Derivative
CN107383014B (en) A kind of 1H- pyrazolo [3,4-d] pyrimidines and its preparation method and application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant