CN107619407A - Double target spot inhibitor of HDAC and VEGFR based on pazopanib structure and its preparation method and application - Google Patents

Double target spot inhibitor of HDAC and VEGFR based on pazopanib structure and its preparation method and application Download PDF

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CN107619407A
CN107619407A CN201710677980.2A CN201710677980A CN107619407A CN 107619407 A CN107619407 A CN 107619407A CN 201710677980 A CN201710677980 A CN 201710677980A CN 107619407 A CN107619407 A CN 107619407A
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张颖杰
徐文方
臧杰
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Shandong University
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Abstract

The present invention relates to double target spot inhibitor of the HDAC based on pazopanib structure and VEGFR and its preparation method and application.The compound has the structure shown in formula I, II or III.The present invention also provides the preparation method of such compound and is preparing prevention or treatment and the application in tumor-related illness medicine.

Description

The double target spot inhibitor of HDAC and VEGFR based on pazopanib structure and its preparation side Method and application
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to based on pazopanib structure Double target spot inhibitor of HDAC and VEGFR and its preparation method and application.
Background technology
Pazopanib Pazopanib is a Mutiple Targets receptor tyrosine kinase inhibitors, to VEGF Acceptor VEGFR three hypotypes (VEGFR-1, VEGFR-2, VEGFR-3) and associated receptor tyrosine kinase (PDGFR β, c-Kit, FGF-R1, c-fms) show preferable inhibitory activity (IC50:10,30,47,84,74,140,146 nM) (Harris,pHilip A.etc.,Journal of Medicinal Chemistry 2008,51,4632).Pazopanib in It is used for having the late period kidney of the past chemotherapy experience patient thin in October, 2009 by food and medicine Surveillance Authority of U.S. FDA approval listings The treatment (Bukowski.etc., Nature Reviews Drug Discovery, 2010,9,17) of born of the same parents' cancer, at 2012 years 04 The moon is used for treatment (Wilky, the Breelyn A.etc., Current of late period soft tissue sarcoma by FDA approval listings again opinion in oncology,2013,25,373).But in recent years, pazopanib occurs low in process of clinical application It is the problem of response rate and drug resistance (Gotink K J.etc., Cellular Oncology, 2015,38,119), medication combined Using and research and development Mutiple Targets medicine be strengthen tumour to drug susceptibility and reduce drug resistance of tumor a strategy.
Histon deacetylase (HDAC) HDACs is to regulate and control one group of horizontal enzyme of acetylation of histone, the acetyl of histone in vivo Change level has important influence to the transcriptional regulatory of chromatinic structure and gene, HDACs mutation and unconventionality expression generally with The generation of tumour is closely related.HDACs inhibitor has been shown to have antitumor action, has 5 small molecule HDAC suppressions at present Preparation go through listing for a variety of blood tumors treatment (Li X.etc., Current Drug Targets, 2014,15, 622).With gradually illustrating for HDAC and VEGF/VEGFR signal path relations, pazopanib and hdac inhibitor use in conjunction Cause the interest of researcher.Research finds that the combination of pazopanib and hdac inhibitor (VPA, SAHA) is in soft tissue sarcoma In show outer antitumor action inside addition or collaboration, and drug combination can reverse pazopanib drug-resistant tumor strain Drug resistance (Tavallai S.etc., Cancer Biology＆Therapy, 2014,15,578).Hdac inhibitor AR-42 with The combination of pazopanib is shown in testing in vivo and in vitro to be made to dabrafenib/Sibutramine Hydrochloride for the killing of the melanoma of Buddhist nun's resistance With it acts synergistically (Booth L.etc., Oncotarget, 2017,8,16367) relevant with the more signal paths of activation. When one clinical I phase of report in 2015 studies display pazopanib with hdac inhibitor SAHA drug combinations, TP53 is mutated The especially tumour patient of metastatic sarcoma and metastatic colorectal carcinoma shows the effect of obvious, its middle position Progression free survival Phase and middle position Overall survival are obviously prolonged (Fu S.etc., Annals of Oncology, 2015,26,1012).2017 most The clinical I phase newly reported, which studies display hdac inhibitor abexinost and pazopanib combination, has good tolerance Property, and can effectively overcome pazopanib resistance (Aggarwal, Rahul, etc., Journal of Clinical Oncology, 2017,35,1231)。
Clinically, the antineoplastic use in conjunction of different mechanism of action has been considered as avoiding the standard side of drug resistance Case, but the problem of following be present in drug combination：(1) drug combination pharmacokinetics is complicated, and drug-drug interactions are bad Reaction is difficult to predict；(2) compatibility of different pharmaceutical and dosage, which are set, clinically has difficulties.Mutiple Targets medicine refers to make simultaneously For the single medicine molecule of multiple target spots, Mutiple Targets medicine not only possesses the advantages of drug combination, and overcomes joint and use Some defects of medicine.Mutiple Targets drug pharmacokineticses are simple, avoid medicine-drug interaction, safer, improve The compliance of patient, turn into popular direction of current antineoplastic medicine design.At present, based on pazopanib structure The double target spot inhibitor of HDAC and VEGFR have no relevant report in the prior art.
The content of the invention
In view of the shortcomings of the prior art, the invention provides the double target spot suppressions of the HDAC based on pazopanib structure and VEGFR Preparation, present invention also offers the preparation method of above-claimed cpd and purposes.
The technical scheme is that：
First, the double target spot inhibitor of HDAC and VEGFR based on pazopanib structure
For the present invention containing the double target spot inhibitor of the HDAC/VEGFR based on pazopanib structure, its is pharmaceutically acceptable Salt, solvate or prodrug, with the structure shown in below formula I, II or III：
Wherein：
X is
N is 0~9；
Y is
According to currently preferred,
X is in contraposition or meta in Y and II in formula I；
X is
N is 0~7；
Y is
It is further preferred that above-claimed cpd is one of following：
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first Acid amides (6a),
3- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first Acid amides (6b),
5- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyls -2- Methyl benzamide (6c),
N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6d),
N- (2- aminophenyls) -3- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6e),
(E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamides (10a),
(E) -3- (3- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamides (10b),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyls Amine) -2- oxoethyls) benzamide (13a),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (3- (hydroxyls Amine) -3- oxopropyls) benzamide (13b),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (4- (hydroxyls Amine) -4- oxos butyl) benzamide (13c),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (5- (hydroxyls Amine) -5- oxopentyls) benzamide (13d),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyls Amine) -6- oxo-hexyls) benzamide (13e),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (7- (hydroxyls Amine) -7- oxos heptyl) benzamide (13f),
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (8- (hydroxyls Amine) -8- oxos octyl group) benzamide (13g),
3- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyls Amine) -6- oxo-hexyls) benzamide (13h),
5- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyls Amine) -6- oxo-hexyls) -2- methyl benzamides (13i),
N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a),
N- (3- ((2- aminophenyls) amino) -3- oxopropyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14b),
N- (4- ((2- aminophenyls) amino) -4- oxos butyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14c),
N- (5- ((2- aminophenyls) amino) -5- oxopentyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14d),
N- (6- ((2- aminophenyls) amino) -6- oxo-hexyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14e),
N- (7- ((2- aminophenyls) amino) -7- oxos heptyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14f),
N- (8- ((2- aminophenyls) amino) -8- oxos octyl group) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzamide (14g),
2- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyl acetamides (19a),
3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxypropanamides (19b),
4- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxybutyrate amides (19c),
5- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyvaleramides (19d),
6- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyl hexanamides (19e),
7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyls heptamide (19f),
8- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxy capryloyls amine (19g),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N3- hydroxyl malonamide (23a),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N4- hydroxy-succinamide (23b),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N5- hydroxyl glutaramide (23c),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N6- hydroxyl adipamide (23d),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N7- hydroxyl heptanedioyl amine (23e),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N8- hydroxyl suberamide (23f),
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N9- hydroxyl nonanedioyl amine (23g),
2- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyl acetamides (28a)
3- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxypropanamides (28b)
4- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxybutyrate amides (28c)
5- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyvaleramides (28d)
6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyls amide (28e)
7- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyls heptamide (28f) or
8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxy capryloyls amine (28g).
2nd, the preparation method of the double target spot inhibitor of HDAC and VEGFR based on pazopanib structure
Preparation method of the present invention containing the double target spot inhibitor of the HDAC based on pazopanib structure and VEGFR, is following One of method：
(1) with 2,3- dimethyl -6- amino -2H- indazoles for initiation material, with 2,4- under sodium acid carbonate alkalescence condition Dichloro pyrimidine occurs nucleophilic substitution and obtains intermediate 2, and intermediate 2 is under cesium carbonate catalysis, in being obtained with iodomethane reaction Mesosome 3, intermediate 3 occur nucleophilic substitution from different substituted aniline under concentrated hydrochloric acid catalysis and obtain key intermediate 4, in Mesosome 4 is protected to obtain intermediate 5 through methyl esters, and ammonolysis reaction of the intermediate 5 through ester obtains end-product 6a-6c；In addition intermediate 4a- 4b obtains end-product 6d-6e with o-phenylenediamine through amide condensed.
Reaction equation is as follows：
Wherein 4a, 5a, 6a, 6d phenyl ring are contraposition substitutions, and 4b, 5b, 6b, 6e phenyl ring are meta substitutions.
Reagent and condition in above-mentioned reaction equation：(a) 2,4- dichloro pyrimidines, sodium acid carbonate, absolute ethyl alcohol, backflow, 4h； (b) cesium carbonate, iodomethane, DMF, room temperature, 2h；(c) isopropanol, concentrated hydrochloric acid, backflow, 4h；(d) O- benzos Triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, o-phenylenediamine, DMF, 0 DEG C-room temperature, Overnight；(e) absolute methanol, thionyl chloride, flow back, overnight；(f) hydroxylamine hydrochloride, potassium hydroxide, absolute methanol, room temperature, 2h.
The aniline of described different substitutions is：P-aminobenzoic acid, gavaculine or 5- amino-2-methyl benzene first Acid.
According to currently preferred, specific preparation process is as follows：
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first The preparation method of acid amides (6a), step are as follows：
(1) preparation of N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -6- amino -2H- indazoles (2)
By 2,3- dimethyl -6- amino -2H- indazole 5.00g, 2,4- dichloro pyrimidine 13.9g, and sodium acid carbonate 10.4g, It is dissolved in 100mL absolute ethyl alcohols, is heated to 79 DEG C, flow back after 4h, cool down to room temperature, filter, filter cake ethyl acetate is abundant Washing, filtrate is collected, is concentrated under reduced pressure, removed solvent, be filtrated to get pale solid after being fully beaten with ethyl acetate, use methanol 7.64g products 2 are obtained after recrystallization, are white solid.
(2) N- (2- chlorine pyrimidine-4-yl)-N, the preparation of 2,3- trimethyl -2H- indazole -6- amine (3)
The 1.00g of previous step product 2 and cesium carbonate 2.40g are added in 50mL DMFs, room temperature is anti- 20min is answered, iodomethane 0.78g is then slowly added into, finishes, 2h is reacted at room temperature, reaction solution is poured into frozen water, is separated out immediately big Faint yellow solid is measured, filtering, after drying, 1.06g products 3 is obtained with re-crystallizing in ethyl acetate, are light yellow crystal.
(3) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoic acid The preparation of (4a)
The 0.50g of intermediate 3 and p-aminobenzoic acid 0.36g are scattered in 30mL isopropanols, 2 drop concentrated hydrochloric acids is added, adds Heat back flow reaction 4h, is cooled to room temperature to 85 DEG C, filters, washs filter cake with isopropanol and ethyl acetate, be dried to obtain 0.53g Product 4a, it is white solid.
(4) methyl 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene first The preparation of acid esters (5a)
4a 0.50g are added in 50mL absolute methanols, thionyl chloride 0.60g is then added dropwise at 0 DEG C, finishes, After being incubated 30min, it is heated to flowing back after removing ice bath, after reacting 5h, solvent under reduced pressure is steamed, crude product recrystallisation from isopropanol 0.50g product 5a are obtained, are white solid.
(5) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyls The preparation of benzamide (6a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 5a 0.20g are dissolved in 30mL azanol potassium solutions, and after 1h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of molten Agent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 80.6mg product 6a, be White solid.
N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6d) preparation method, step is as follows：
(1) N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2- Base) amino) benzamide (6d) preparation
Intermediate 4a 0.50g are added in the anhydrous DMFs of 50mL, under ice bath, add O- benzos three Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.49g and triethylamine 0.26g, after activating 30min, then add adjacent benzene Diamines 0.17g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and DMF is removed in washing, Ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and removal of solvent under reduced pressure is residual Slag is purified to obtain 0.40g product 6d with silica gel column chromatography, is pale solid.
(2) it is initiation material with intermediate 4, with N, the generation of O- dimethyl hydroxylamine hydrochloride is amide condensed to obtain intermediate 7, Intermediate 7 is reduced to aldehyde intermediate 8 through tetrahydrochysene lithium aluminium, and with phosphonoacetate Huo Naer-Wo Ziwo occur for intermediate 8 Si-Ai Mengsi react to obtain intermediate 9, and ammonolysis of the intermediate 9 through ester obtains end-product 10.
Reaction equation is as follows：
Wherein 4a, 7a, 8a, 9a, 10a phenyl ring substitute for contraposition, 4b, 7b, 8b, 9b, and 10b phenyl ring substitutes for meta.
Reagent and condition in above-mentioned reaction equation：(a) N, O- dimethyl hydroxylamine hydrochloride, O- BTA-N, N, N', N'- tetramethylurea tetrafluoro boric acids, triethylamine, DMF, room temperature, overnight；(b) tetrahydrochysene lithium aluminium, tetrahydrofuran ,- 20℃,4h；(c) phosphonoacetate, sodium hydride, tetrahydrofuran, 0 DEG C-room temperature, overnight；(d) hydroxylamine hydrochloride, hydroxide Potassium, absolute methanol, room temperature, 2h.
According to currently preferred, specific preparation process is as follows：
(E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamides (10a) preparation：
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- methoxies The preparation of base-N-methyl-benzamide (7a)
Intermediate 4a 1.00g are added in anhydrous DMF, under ice bath, add the nitrogen of O- benzos three Azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add N, O- bis- Methyl hydroxylamine hydrochloride 0.30g and triethylamine 0.31g, at room temperature reaction add ethyl acetate dilution, washing overnight, after the completion of reaction DMF is removed, ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, anhydrous slufuric acid Magnesium is dried, removal of solvent under reduced pressure, residue dichloromethane:Methanol=35:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.78g product 7a, it is white solid.
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzaldehyde The preparation of (8a)
Compound 7a 1.00g are dissolved in 50mL anhydrous tetrahydro furans, and -40 DEG C are cooled in low-temp reaction instrument.To It is slowly added to tetrahydrochysene lithium aluminium 0.26g in batches, after maintaining this thermotonus 2h, reaction to terminate, is slowly carefully quenched with frozen water Reaction is to there is no bubble generation.Reaction solution is diluted with water, and is extracted with ethyl acetate, and merges organic layer, and saturation NaCl solution is washed Wash, anhydrous magnesium sulfate is dried, and be concentrated under reduced pressure solvent, residue dichloromethane:Methanol=40:The eluant, eluent of 1 volume ratio carries out post Chromatographic purifying obtains 0.61g product 8a, is white solid.
(3) ethyl (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl) acrylate (9a) preparation
Phosphonoacetate 0.32g is added into 50mL anhydrous tetrahydro furans, -5-0 DEG C is cooled to, is slowly added to NaH 0.16g, are finished, and stir 20min, 8a 0.52g tetrahydrofuran solution are then added dropwise, overnight, reaction finishes for room temperature reaction Afterwards, the ammonium chloride solutions of 50mL 10% are added, stir stratification after 30min, after organic phase is dried, filtering, are concentrated to give thick Product.Residue dichloromethane:Methanol=40:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.48g product 9a, is white Color solid.
(4) (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl)-N- hydroxyacrylamides (10a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 9a 0.50g, it is dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.29g product 10a, For white solid.
(3) it is initiation material with intermediate 4, the amino-alkane methyl esters of intermediate 4 and different chain length is through amide condensed reaction Intermediate 11 is obtained, ammonolysis reaction of the intermediate 11 through ester obtains end-product 13；Intermediate 11 is under the conditions of Sodium Hydroxide Alkaline Intermediate 12 is hydrolyzed to, intermediate 12 obtains end-product 14 with o-phenylenediamine through amide condensed reaction.
Reaction equation is as follows：
Wherein 4a, 11a-11g, 12a-12g, 13a-13g, 14a-14g phenyl ring substitute for contraposition, 4b, 11h, 13h benzene Ring substitutes for meta, and n is 1~7.
Reagent and condition in above-mentioned reaction equation：(a) the amino-alkane methyl esters of different chain length, O- BTA-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, DMF, room temperature, overnight；(b) hydroxylamine hydrochloride, hydroxide Potassium, absolute methanol, room temperature, 2h；(c) 3M NaOH, methanol, room temperature, 2h；(d) o-phenylenediamine, O- BTA-N, N, N', N'- tetramethylurea tetrafluoro boric acids, triethylamine, DMF, room temperature, overnight.
The amino-alkane methyl esters of described different chain length is：Glycine methyl ester, 3- aminopropanoates, 4-Aminobutanoicacid first Ester, 5- aminopentanoic acid methyl esters, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acids methyl esters or 8- aminocaprylic acid methyl esters.
According to currently preferred, specific preparation process is as follows：
4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyls Amine) -2- oxoethyls) benzamide (13a) preparation method, step is as follows：
(1) methyl (4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycinate (11a) preparation
Intermediate 4a 1.00g are added in anhydrous DMF, under ice bath, add the nitrogen of O- benzos three Azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add glycine Methyl ester hydrochloride 0.39g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and N, N- dimethyl are removed in washing Formamide, ethyl acetate layer are washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and is removed under reduced pressure Solvent, residue are dichloromethane with eluant, eluent:Methanol=30:1 volume ratio carries out column chromatography and purifies to obtain 0.87g product 11a, is White solid.
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (azanol) -2- oxoethyls) benzamide (13a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 11a 0.50g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.31g product 13a, For white solid.
N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) and benzamide (14a) preparation, step is as follows：
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycine (12a) preparation
11a 1.00g are added in 30mL methanol, 5mL 3M NaOH solutions is then added, stirs 4h at room temperature, are reacted After end, decompression boils off most of methanol, and residue adjusts pH to 5-6 with 1M HCl solutions.Filtering, filter cake are washed with frozen water, 0.81g product 12a are obtained after drying, are white solid, are directly thrown in next step.
(2) N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazoles -6- Base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a) preparation
Intermediate 12a 1g are added in the anhydrous DMFs of 100mL, under ice bath, add O- benzos three Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.86g and triethylamine 0.45g, after activating 30min, then add adjacent benzene Diamines 0.29g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and DMF is removed in washing, Ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and removal of solvent under reduced pressure is residual Slag dichloromethane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.47g product 14a, pale yellow colored solid Body.
(4) using p-nitrophenol as initiation material, nucleophilic substitution occurs with the bromine alkanoic acid methyl esters of different chain length and obtains Intermediate 16, intermediate 16 reduce to obtain intermediate 17 through Pd/C, and intermediate 17 occurs necleophilic reaction with compound 3 and obtains centre Body 18, ammonolysis reaction of the intermediate 18 through ester obtain end-product 19.
Reaction equation is as follows：
Wherein n is 1~7.
Reagent and condition in above-mentioned reaction：(a) different chain length bromine alkanoic acid methyl esters, potassium carbonate, acetone, flow back, overnight； (b) Pd/C, methanol, hydrogen, room temperature, overnight；(c) isopropanol, concentrated hydrochloric acid, flow back, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, Absolute methanol, room temperature, 2h.
The bromine alkanoic acid methyl esters of described different chain length is：2- methyl bromoacetates, 3- methyl bromide cs, 4- bromo butyric acid methyl esters, 5- bromo pentane acid A esters, 6- bromocaproic acids methyl esters, 7- bromines methyl heptanoate or 8- bromine methyl caprylates.
According to currently preferred, specific preparation process is as follows：
7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - The preparation of N- hydroxyls heptamide (19f), step are as follows：
(1) preparation of methyl 7- (4-nitrophenoxy) heptanoate (16f)
P-nitrophenol 1.00g, 7- bromine methyl heptanoate 1.93g and potassium carbonate 2.98g are added in 50mL acetone, heated up To backflow, reaction overnight, after reaction terminates, removes solvent under reduced pressure, 1.62g product 16f is obtained with re-crystallizing in ethyl acetate, for Huang Color solid.
(2) preparation of methyl 7- (4- amino-benzene oxygens) heptanoates (17f)
Intermediate 16f 1.00g are added in 50mL methanol, 10%Pd/C 0.1g is added, hydrogen is passed through under atmospheric agitation Gas, in room temperature reaction overnight, filtering, filter residue are washed with methanol, merging filtrate and washing lotion, remove solvent under reduced pressure, obtain 0.79g productions Thing 17f, it is light tan solid.
(3) methyl 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenoxy group)-heptanoate (18f) preparation
By the 0.5g of intermediate 3, intermediate 17f 0.52g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanols at room temperature In, backflow is warming up to, reaction is overnight.After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume The eluant, eluent of ratio carries out column chromatography and purifies to obtain 0.61g product 18f, is white solid.
(4) 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene oxygen Base)-N- hydroxyls heptamide (19f) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 18f 0.30g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.20g product 19f, For white solid.
(5) it is initiation material with intermediate 3, nucleophilic substitution, which occurs, with paranitroanilinum obtains intermediate 20, middle Body 20 is reduced to intermediate 21 through Pd/C, and the docosandioic acid mono-methyl generation of intermediate 21 and different chain length is amide condensed to obtain centre Body 22, the ammonolysis reaction that ester occurs for intermediate 22 obtain end-product 23.
Reaction equation is as follows：
Wherein n is 1~7.
The reagent and condition of above-mentioned reaction：(a) paranitroanilinum, isopropanol, concentrated hydrochloric acid, flow back, overnight；(b) Pd/C, first Alcohol, hydrogen, room temperature, overnight；(c) the docosandioic acid mono-methyl of different chain length, O- BTAs-N, N, N', N'- tetramethylurea four Fluoboric acid, triethylamine, N ' dinethylformamides, room temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, absolute methanol, room temperature, 2h。
The docosandioic acid mono-methyl of described different chain length is：Malonic acid monomethyl ester, monomethyl succinate, glutaric acid list first Ester, adipic acid monomethyl ester, pimelic acid mono-methyl, suberic acid mono-methyl or monomethyl azelate.
According to currently preferred, specific preparation process is as follows：
N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N8The preparation of-hydroxyl suberamide (23f), step are as follows：
(1)N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methyl-N2- (4- nitrobenzophenones) pyrimidine -2,4- diamines (20) preparation
By the 1.00g of intermediate 3, paranitroanilinum 0.58g and 0.5mL concentrated hydrochloric acid is added in 70mL isopropanols, heating To backflow, reaction overnight, after reaction terminates, is cooled to room temperature, filtered, and filter cake is washed with a small amount of isopropanol, dry cake, obtained 1.08g products 20, it is faint yellow solid.
(2)N2- (4- aminophenyls)-N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methylpyrimidine -2,4- diamines (21) preparation
The 1.00g of intermediate 20 is suspended in 70mL methanol, 0.1g 10%Pd/C is added, hydrogen is passed through under atmospheric agitation Gas, room temperature reaction overnight, after reaction terminates, remove solvent under reduced pressure, and residue with ethyl acetate is recrystallized to give 0.78g products 21, For light tan solid.
(3) methyl 8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino) -8- oxos monooctyl ester (22f) preparation
Suberic acid mono-methyl 0.33g is added in the anhydrous DMFs of 50mL, O- benzos are added under ice bath Triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.68g and triethylamine 0.36g, finish, 30min are activated under ice bath, activation After, the 0.76g of intermediate 21 is added, removes ice bath, room temperature reaction adds ethyl acetate dilution, water overnight, after the completion of reaction Remove DMF, ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, anhydrous sulphur Sour magnesium is dried, and removes solvent, residue dichloromethane under reduced pressure:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purified It is white solid to 0.37g products 22.
(4)N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N8The preparation of-hydroxyl suberamide (23f)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 22f 0.20g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.14g product 23f, For white solid.
(6) using p-fluoronitrobenzene as initiation material, nucleophilic substitution occurs with the aminoalkyl methyl esters of different chain length and obtains To intermediate 25, intermediate 25 reduces to obtain intermediate 26 through Pd/C, and intermediate 26 occurs nucleophilic substitution with intermediate 3 and obtained To intermediate 27, ammonolysis reaction of the intermediate 27 through ester obtains intermediate 28.
Reaction equation is as follows：
Wherein n is 1~7.
The reagent and condition of reaction：(a) the aminoalkyl methyl esters of different chain length, potassium carbonate, DMF, 50 DEG C, overnight；(b) Pd/C, hydrogen, methanol, overnight；(c) concentrated hydrochloric acid, isopropanol, flow back, overnight；(d) hydroxylamine hydrochloride, hydroxide Potassium, absolute methanol, room temperature, 2h.
The aminoalkyl methyl esters of described different chain length is：Glycine methyl ester, 3- aminopropanoates, 4-Aminobutanoicacid first Ester, 5- aminopentanoic acid methyl esters, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acids methyl esters or 8- aminocaprylic acid methyl esters.
According to currently preferred, specific preparation process is as follows：
6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyls amide (28e) preparation, step is as follows：
(1) preparation of methyl 6- ((4- nitrobenzophenones) amino) esters (25e)
P-fluoronitrobenzene 1.00g, 6-aminocaprolc acid methyl ester hydrochloride 1.54g and potassium carbonate 2.94g are added to 50mL N, In dinethylformamide, 50 DEG C are warming up to, overnight, after reaction terminates, room temperature is cooled to, reaction solution is poured into frozen water, analyse Go out yellow solid, filter, drying, residue petroleum ether：Ethyl acetate=4:The eluant, eluent of 1 volume ratio carries out column chromatography and obtained 1.32g product 25e, it is faint yellow solid.
(2) preparation of methyl 6- ((4- aminophenyls) amino) esters (26e)
Intermediate 25e 1.00g are suspended in 70mL methanol, add 10%Pd/C 0.1g, hydrogen is passed through under atmospheric agitation Gas, room temperature reaction overnight, after reaction terminates, remove solvent under reduced pressure, and residue with ethyl acetate is recrystallized to give 0.71g product 26e, For brown solid.
(3) methyl 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino)-own ester (27e) preparation
By the 0.50g of intermediate 3, intermediate 26e 0.49g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanols at room temperature In, backflow is warming up to, reaction is overnight.After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume The eluant, eluent of ratio carries out column chromatography and purifies to obtain 0.55g product 27e, is faint yellow solid.
(4) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino)-N- hydroxyls amide (28e) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 27e 0.20g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.13g product 28e, For light red solid.
The structural formula of target compound is as follows：
The specific preparation process of the compound will be described in detail in embodiment.
Those skilled in the art can optimize to improve yield to above-mentioned steps, and they can be according to the basic of this area Knowledge works out synthetic route, such as selects reactant, solvent and temperature, can avoid side reaction by using various blocking groups Occur so as to improve yield.These conventional guard methods can be found in T.Greene, Protecting Groups in Organic Synthesis。
Detailed description of the invention
Term and definition implication used herein is as follows：
ACHN cell behaviour renal cell adenocarcinoma cells, ags cell are human gastric adenocarcinoma, hel cell behaviour red white corpuscle Leukaemia, HeLa cells are human cervical carcinoma cell, and HT-1080 cells are human fibrosarcoma cell, and HT-29 cells, which are behaved, to be tied Colon-cancer cell, K562 cells are human chronic polymorpho nuclear leukemia cells, KG1 cell behaviour acute myeloid leukemia cells, MDA- MB-231 is human breast cancer cell, and MOLT-4 is people's acute lymphoblastic leukemia cell, and PC-3 cells are human prostata cancer Cell and HUVEC cell Human umbilical vein endothelial cells.
3rd, the application of the double target spot inhibitor of HDAC and VEGFR based on pazopanib structure
The double target spot inhibitor compounds of the HDAC also provided based on pazopanib structure and VEGFR of the invention are preparing prevention Or treatment and the application in tumor-related illness medicine.
Described tumor-related illness includes all kinds of blood tumors and all kinds of solid tumors.
Described all kinds of blood tumors include：Each quasi-leukemia, myelosis knurl.For example serious urgency of various types of leukaemia Property lymphocytic leukemia, acute myeloid leukaemia, acute megakaryocytic leukemia etc..It is white that myelosis knurl includes chronic Myelogenous Blood disease, polycythemia vera, primary thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic acidophilus Property granulocytic leukemia, systemic mastocytosis and other non-classified myelosis knurls.
Described solid tumor includes：Various forms of nasopharyngeal carcinoma, clear-cell carcinoma, soft tissue sarcoma, thyroid papillary carcinoma, Thymoma, liver cancer, breast cancer, melanoma, prostate cancer, retinoblastoma etc..
One kind prevention or treatment and tumor-related illness pharmaceutical composition, pazopanib knot is based on comprising of the present invention The double target spot inhibitor of the HDAC and VEGFR of structure or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers Or excipient.
Brief description of the drawings
Western Blot experimental results of Fig. 1 compound 6d and 13f after HeLa cells handle 4h；
Fig. 2 compounds 6d and 13f suppress HUVECs segment dislocation experimental results；
Fig. 3 compounds 6d and 13f suppresses rat chest aorta ring into blood vessel experimental result；
Fig. 4 nude mouse tumor photos；
Fig. 5 various dose compound 6d and 13f inhibition rate of tumor growth.
Embodiment
With reference to example, the present invention is described further, but not limited to this.
Embodiment 1：Compound 6a-6c synthesis, by taking 6a as an example.
(1) preparation of N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -6- amino -2H- indazoles (2)
2,3- dimethyl -6- amino -2H- indazoles 5.00g, 2,4- dichloro pyrimidine 13.9g and sodium acid carbonate 10.4g is molten In 100mL absolute ethyl alcohols, 79 DEG C are heated to, flows back after 4h, cools down to room temperature, is filtered, filter cake is fully washed with ethyl acetate Wash, collect filtrate, be concentrated under reduced pressure, remove solvent, pale solid is filtrated to get after being fully beaten with ethyl acetate, with methanol weight After crystallization 7.64g products 2, be white solid, yield：90.0%；Mp:215-216℃.1H NMR(300MHz,DMSO-d6)δ 9.99 (s, 1H), 8.15 (d, J=5.9Hz, 1H), 7.94 (s, 1H), 7.63 (dd, J=0.8,8.9Hz, 1H), 6.98 (dd, J =1.8,8.9Hz, 1H), 6.77 (d, J=5.9Hz, 1H), 4.01 (s, 3H), 2.58 (s, 3H).
(2) N- (2- chlorine pyrimidine-4-yl)-N, the preparation of 2,3- trimethyl -2H- indazole -6- amine (3)
The 1.00g of previous step product 2 and cesium carbonate 2.40g are added in 50mL DMFs, room temperature is anti- 20min is answered, iodomethane 0.78g is then slowly added into, finishes, 2h is reacted at room temperature, reaction solution is poured into frozen water, is separated out immediately big Faint yellow solid is measured, filtering, after drying, 1.06g products 3 is obtained with re-crystallizing in ethyl acetate, are light yellow crystal, yield： 80.0%；Mp:173-174℃.1H NMR(400MHz,DMSO-d6) δ 7.95 (d, J=6.1Hz, 1H), 7.80 (dd, J=0.8, 8.7Hz, 1H), 7.51 (dd, J=0.8,1.8Hz, 1H), 6.88 (dd, J=1.8,8.8Hz, 1H), 6.24 (d, J=6.1Hz, 1H),4.06(s,3H),3.42(s,3H),2.63(s,3H)。
(3) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoic acid The preparation of (4a)
The 0.50g of intermediate 3 and p-aminobenzoic acid 0.36g are scattered in 30mL isopropanols, 2 drop concentrated hydrochloric acids is added, adds Heat back flow reaction 4h, is cooled to room temperature to 85 DEG C, filters, washs filter cake with isopropanol and ethyl acetate, be dried to obtain 0.53g Product 4a, is white solid, yield：80%；Mp:>250℃.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),9.80 (s, 1H), 7.91 (d, J=6.3Hz, 1H), 7.79 (d, J=8.7Hz, 3H), 7.74 (d, J=8.6Hz, 2H), 7.49 (d, J= 1.7Hz, 1H), 6.91 (dd, J=1.8,8.8Hz, 1H), 5.94 (d, J=6.2Hz, 1H), 4.08 (s, 3H), 3.51 (s, 3H), 2.64(s,3H).ESI-MS m/z:387.5[M-H]-。
(4) methyl 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene first The preparation of acid esters (5a)
4a 0.50g are added in 50mL absolute methanols, 0.60g thionyl chlorides are then added dropwise at 0 DEG C, finish, After being incubated 30min, it is heated to flowing back after removing ice bath, after reacting 5h, solvent under reduced pressure is steamed, crude product recrystallisation from isopropanol 0.50g product 5a are obtained, are white solid, yield：96%；Mp:198-200℃.1H NMR(400MHz,DMSO-d6)δ9.63 (s, 1H), 7.92 (d, J=6.0Hz, 1H), 7.83 (d, J=8.6Hz, 2H), 7.78 (d, J=8.6Hz, 1H), 7.72 (d, J= 8.6Hz, 2H), 7.46 (dd, J=0.8,1.7Hz, 1H), 6.89 (dd, J=1.8,8.8Hz, 1H), 5.91 (d, J=6.0Hz, 1H),4.07(s,3H),3.80(s,3H),3.49(s,3H),2.64(s,3H).ESI-MS m/z:403.5[M+H]+。
(5) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyls The preparation of benzamide (6a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 5a 0.20g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of molten Agent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 80.6mg product 6a, be White solid, yield：40%；Mp:210-212℃.1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.49(s,1H), 8.85 (s, 1H), 7.89 (d, J=6.1Hz, 1H), 7.84-7.70 (m, 3H), 7.59 (d, J=8.3Hz, 2H), 7.46 (s, 1H), 6.90 (d, J=8.7Hz, 1H), 5.86 (d, J=6.2Hz, 1H), 4.07 (s, 3H), 3.49 (s, 3H), 2.64 (s, 3H) .HRMS(AP-ESI)m/z calcd for C21H21N7O2[M+H]+404.1757,found 404.1739.Embodiment 2:Chemical combination Thing 6d-6e synthesis, by taking 6d as an example
(1) N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2- Base) amino) benzamide (6d) preparation
Intermediate 4a 0.50g are added in the anhydrous DMFs of 50mL, under ice bath, add O- benzos three Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.49g and triethylamine 0.26g, after activating 30min, then add adjacent benzene Diamines 0.17g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and DMF is removed in washing, Ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and removal of solvent under reduced pressure is residual Slag dichloromethane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.40g product 6d, consolidates for canescence Body, yield：65%；Mp:138-140℃.1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.49(s,1H),7.91(d, J=6.0Hz, 1H), 7.87 (d, J=9.0Hz, 2H), 7.83 (d, J=8.8Hz, 2H), 7.80-7.76 (m, 1H), 7.47 (d, J =2.3Hz, 1H), 7.17 (dd, J=1.5,7.9Hz, 1H), 6.96 (td, J=1.6,7.6Hz, 1H), 6.91 (dd, J=1.8, 8.8Hz, 1H), 6.79 (dd, J=1.5,8.0Hz, 1H), 6.60 (td, J=1.5,7.5Hz, 1H), 5.87 (d, J=6.0Hz, 1H),4.89(s,2H),4.06(s,3H),3.51(s,3H),2.63(s,3H).HRMS(AP-ESI)m/z calcd for C21H21N7O2[M+H]+ 479.2230,found 479.2257。
Embodiment 3:Compound 10a-10b synthesis, by taking 10a as an example
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- methoxies The preparation of base-N-methyl-benzamide (7a)
Intermediate 4a 1.00g are added in anhydrous DMF, under ice bath, addition O- BTAs- N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add N, O- dimethyl Hydroxylamine hydrochloride 0.30g and triethylamine 0.31g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and washing is removed DMF, ethyl acetate layer are washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is done It is dry, removal of solvent under reduced pressure, residue dichloromethane:Methanol=35:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.78g product 7a, are white solid, yield 70%；Mp:216-218℃.1H NMR(400MHz,DMSO-d6)δ9.46(s, 1H), 7.90 (d, J=6.0Hz, 1H), 7.82-7.74 (m, 3H), 7.48 (d, J=8.6Hz, 2H), 7.46 (d, J=1.4Hz, 1H), 6.89 (dd, J=1.8,8.8Hz, 1H), 5.87 (d, J=6.0Hz, 1H), 4.06 (s, 3H), 3.55 (s, 3H), 3.48 (s,3H),3.23(s,3H),2.63(s,3H)。
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzaldehyde The preparation of (8a)
Compound 7a 1.00g are dissolved in 50mL anhydrous tetrahydro furans, and -40 DEG C are cooled in low-temp reaction instrument.To It is slowly added to tetrahydrochysene lithium aluminium 0.26g in batches, after maintaining this thermotonus 2h, reaction to terminate, is slowly carefully quenched with frozen water Reaction is to there is no bubble generation.Reaction solution is diluted with water, and is extracted with ethyl acetate, and merges organic layer, and saturation NaCl solution is washed Wash, anhydrous magnesium sulfate is dried, and be concentrated under reduced pressure solvent, residue dichloromethane:Methanol=40:The eluant, eluent of 1 volume ratio carries out post Chromatographic purifying obtains 0.61g product 8a, is white solid, yield：70%；Mp:242-244℃.1H NMR(400MHz,DMSO- d6) δ 9.77 (d, J=4.6Hz, 2H), 7.96-7.93 (m, 3H), 7.78 (d, J=8.7Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.47 (d, J=1.6Hz, 1H), 6.90 (dd, J=1.8,8.8Hz, 1H), 5.92 (d, J=6.0Hz, 1H), 4.07 (s, 3H),3.50(s,3H),2.64(s,3H)。
(3) ethyl (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl) acrylate (9a) preparation
Phosphonoacetate 0.32g is added into 50mL anhydrous tetrahydro furans, -5-0 DEG C is cooled to, is slowly added to NaH0.16g, finish, stir 20min, 8a 0.52g tetrahydrofuran solution is then added dropwise, overnight, reaction finishes for room temperature reaction Afterwards, the ammonium chloride solutions of 50mL 10% are added, stir stratification after 30min, after organic phase is dried, filtering, are concentrated to give thick Product.Residue dichloromethane:Methanol=40:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.48g product 9a, is white Color solid, yield：48%；Mp:195-197℃.1H NMR(400MHz,DMSO-d6) δ 9.50 (s, 1H), 7.89 (d, J= 6.0Hz, 1H), 7.83 (d, J=8.7Hz, 2H), 7.78 (dd, J=0.8,8.7Hz, 1H), 7.58-7.51 (m, 3H), 7.46 (dd, J=0.8,1.8Hz, 1H), 6.90 (dd, J=1.8,8.8Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 5.84 (d, J= 6.0Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 4.07 (s, 3H), 3.49 (s, 3H), 2.64 (s, 3H), 1.25 (t, J= 7.1Hz,3H).(4) (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl)-N- hydroxyacrylamides (10a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 9a 0.50g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of molten Agent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.29g product 10a, be White solid, yield：60%；Mp:194-196℃.1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),9.42(s,1H), 8.96 (s, 1H), 7.88 (d, J=5.9Hz, 1H), 7.81 (d, J=8.3Hz, 2H), 7.77 (d, J=8.8Hz, 1H), 7.46 (s, 1H), 7.43-7.32 (m, 3H), 6.95-6.83 (m, 1H), 6.28 (d, J=15.7Hz, 1H), 5.83 (d, J=6.1Hz, 1H),4.07(s,3H),3.49(s,3H),2.64(s,3H).HRMS(AP-ESI)m/z calcd for C23H23N7O2[M+H]+ 430.1991,found 430.1988。
Embodiment 4：Compound 13a-13i synthesis, by taking 13a as an example
(1) methyl (4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycinate (11a) preparation
Intermediate 4a 1.00g are added in the anhydrous DMFs of 100mL, under ice bath, add O- benzos three Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add sweet ammonia Acid methyl ester hydrochloride salt 0.39g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and N, N- diformazans are removed in washing Base formamide, ethyl acetate layer are washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and decompression removes Remove solvent, residue dichloromethane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.87g product 11a, For white solid, yield 74%；Mp:170-172℃.1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.72(t,J =5.9Hz, 1H), 7.90 (d, J=6.0Hz, 1H), 7.84 (d, J=8.6Hz, 2H), 7.77 (d, J=8.7Hz, 1H), 7.71 (d, J=8.5Hz, 2H), 7.46 (d, J=1.7Hz, 1H), 6.90 (dd, J=1.8,8.8Hz, 1H), 5.85 (d, J=6.1Hz, 1H), 4.07 (s, 3H), 3.98 (d, J=5.8Hz, 2H), 3.65 (s, 3H), 3.50 (s, 3H), 2.64 (s, 3H).
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (azanol) -2- oxoethyls) benzamide (13a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 11a (0.50g, 1.09mmol) is dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure Most of solvent is removed, residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, is produced Thing 13a, is white solid (0.31g, yield 61%), Mp:216-218℃.1H NMR(400MHz,DMSO-d6)δ10.53 (s, 1H), 9.46 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 7.89 (d, J=5.9Hz, 1H), 7.82 (d, J=8.5Hz, 2H), 7.77 (d, J=8.7Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.46 (d, J=1.8Hz, 1H), 6.90 (dd, J= 1.8,8.8Hz, 1H), 5.85 (d, J=6.0Hz, 1H), 4.07 (s, 3H), 3.76 (d, J=5.8Hz, 2H), 3.49 (s, 3H), 2.64(s,3H).HRMS(AP-ESI)m/z calcd for C23H24N8O3[M-H]-459.1971,found 459.1921。
Embodiment 5：Compound 14a-14g synthesis, by taking 14a as an example
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycine (12a) preparation
11a (1.00g, 2.18mmol) is added in 30mL methanol, then adds 5mL 3M NaOH solutions, at room temperature 4h is stirred, after reaction terminates, decompression boils off most of methanol, and residue adjusts pH to 5-6 with 1M HCl solutions.Filtering, filter cake Washed with frozen water, obtain product 12a after drying, be white solid (0.81g, yield：84%), Mp:>250 DEG C, directly cast one Walk1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),10.69(s,1H),8.79(s,1H),8.01–7.61(m,6H), 7.59 (d, J=1.7Hz, 1H), 6.95 (dd, J=1.8,8.8Hz, 1H), 6.03 (s, 1H), 4.09 (s, 3H), 3.92 (d, J= 5.8Hz,2H),3.57(s,3H),2.66(s,3H)。
(2) N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazoles -6- Base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a) preparation
Intermediate 12a (1g, 2.24mmol) is added in anhydrous DMF, under ice bath, adds O- benzene And triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid (0.86g, 2.69mmol) and triethylamine (0.45g, 4.48mmol), after activating 30min, o-phenylenediamine (0.29g, 2.69mmol) is then added, reaction at room temperature overnight, has been reacted Into rear addition ethyl acetate dilution, DMF is removed in washing, ethyl acetate layer saturated sodium bicarbonate solution and Saturation NaCl solution is washed, and anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, residue dichloromethane:Methanol=30:1 volume ratio Eluant, eluent carry out column chromatography purify to obtain product 14a, faint yellow solid (0.47g, yield 39%), Mp:178-180℃ .1H NMR(400MHz,DMSO-d6) δ 9.51 (s, 1H), 9.23 (s, 1H), 8.62 (t, J=5.8Hz, 1H), 7.90 (d, J= 6.1Hz, 1H), 7.83 (d, J=8.7Hz, 2H), 7.79-7.71 (m, 3H), 7.49-7.43 (m, 1H), 7.12 (d, J= 7.5Hz, 1H), 6.93-6.89 (m, 2H), 6.71 (dd, J=1.4,7.9Hz, 1H), 6.54 (t, J=7.5Hz, 1H), 5.86 (d, J=6.2Hz, 1H), 4.92 (s, 2H), 4.07 (s, 3H), 4.05-4.00 (m, 2H), 3.50 (s, 3H), 2.64 (s, 3H) .HRMS(AP-ESI)m/z calcd for C29H29N9O2[M+H]+536.2444,found 536.2498。
Embodiment 6：Compound 19a-19g synthesis, by taking 19f as an example
(1) preparation of methyl 7- (4-nitrophenoxy) heptanoate (16f)
P-nitrophenol 1.00g, 7- bromine methyl heptanoate 1.93g and potassium carbonate 2.98g are added in 50mL acetone, heated up To backflow, reaction overnight, after reaction terminates, removes solvent under reduced pressure, 1.62g product 16f is obtained with re-crystallizing in ethyl acetate, for Huang Color solid, yield:80%；ESI-MS m/z:282.3[M+H]+。
(2) preparation of methyl 7- (4- amino-benzene oxygens) heptanoates (17f)
Intermediate 16f 1.00g are added in 50mL methanol, 10%Pd/C 0.1g is added, hydrogen is passed through under atmospheric agitation Gas, in room temperature reaction overnight, filtering, filter residue are washed with methanol, merging filtrate and washing lotion, remove solvent under reduced pressure, obtain 0.79g productions Thing 17f, is light tan solid, yield：88%；ESI-MS m/z:251.4[M+H]+, direct plunge into next step.
(3) methyl 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenoxy group)-heptanoate (18f) preparation
By the 0.5g of intermediate 3, intermediate 17f 0.52g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanols at room temperature In, backflow is warming up to, reaction is overnight.After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume The eluant, eluent of ratio carries out column chromatography purifying, obtains 0.61g product 18f, is white solid, yield：70%；ESI-MS m/z: 503.6[M+H]+。
(4) 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene oxygen Base)-N- hydroxyls heptamide (19f) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 18f 0.30g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.20g product 19f, For white solid, yield：65%；1H NMR(400MHz,DMSO-d6) δ 10.33 (s, 1H), 8.93 (s, 1H), 8.65 (d, J= 1.8Hz, 1H), 7.80 (d, J=6.0Hz, 1H), 7.75 (dd, J=0.8,8.7Hz, 1H), 7.60 (d, J=8.9Hz, 2H), 7.42 (dd, J=0.8,1.8Hz, 1H), 6.87 (dd, J=1.8,8.8Hz, 1H), 6.75 (d, J=8.9Hz, 2H), 5.73 (d, J=5.9Hz, 1H), 4.06 (s, 3H), 3.88 (t, J=6.5Hz, 2H), 3.45 (s, 3H), 2.63 (s, 3H), 2.02-1.90 (m, 2H), 1.67 (p, J=6.8Hz, 2H), 1.51 (p, J=7.4Hz, 2H), 1.39 (p, J=7.2Hz, 2H), 1.34-1.21 (m,2H).ESI-MS m/z:504.7[M+H]+。
Embodiment 7：Compound 23a-23g synthesis, by taking compound 23f as an example
(1)N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methyl-N2- (4- nitrobenzophenones) pyrimidine -2,4- diamines (20) preparation
The 1.00g of intermediate 3, paranitroanilinum 0.58g and 0.5mL concentrated hydrochloric acid are added in 70mL isopropanols, heated up To backflow, reaction overnight, after reaction terminates, is cooled to room temperature, filtered, and filter cake is washed with a small amount of isopropanol, dry cake, obtained 1.08g products 20, are faint yellow solid, yield：80%；1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.08(s, 2H), 7.99 (d, J=7.0Hz, 1H), 7.87 (d, J=8.8Hz, 1H), 7.83 (s, 2H), 7.59 (d, J=1.8Hz, 1H), 6.95 (dd, J=1.8,8.7Hz, 1H), 6.17 (s, 1H), 4.10 (s, 3H), 3.58 (s, 3H), 2.67 (s, 3H).
(2)N2- (4- aminophenyls)-N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methylpyrimidine -2,4- diamines (21) preparation
The 1.00g of intermediate 20 is suspended in 70mL methanol, 10%Pd/C 0.1g is added, hydrogen is passed through under atmospheric agitation Gas, room temperature reaction overnight, after reaction terminates, remove solvent under reduced pressure, and residue with ethyl acetate is recrystallized to give 0.78g products 21, For light tan solid, yield：84%；ESI-MS m/z:360.4[M+H]+。
(3) methyl 8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino) -8- oxos monooctyl ester (22f) preparation
Suberic acid mono-methyl 0.33g is added in the anhydrous DMFs of 50mL, O- benzos are added under ice bath Triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.68g and 0.36g triethylamine, finishes, 30min is activated under ice bath, activation After, the 0.76g of intermediate 21 is added, removes ice bath, room temperature reaction adds ethyl acetate dilution, water overnight, after the completion of reaction Remove DMF, ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, anhydrous sulphur Sour magnesium is dried, and removes solvent, residue dichloromethane under reduced pressure：Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purified It is white solid to 0.37g product 22f, yield：40%；ESI-MS m/z:530.5[M+H]+。
(4)N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N8The preparation of-hydroxyl suberamide (23f)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 22f 0.20g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.14g product 23f, For white solid, yield：70%；1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.68(s,1H),9.04(s,1H), 8.65 (s, 1H), 7.82 (d, J=5.9Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.64-7.56 (m, 2H), 7.43 (d, J= 1.7Hz, 1H), 7.37 (d, J=8.9Hz, 2H), 6.88 (dd, J=1.8,8.8Hz, 1H), 5.76 (d, J=6.0Hz, 1H), 4.06 (s, 3H), 3.46 (s, 3H), 2.63 (s, 3H), 2.25 (t, J=7.4Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.64-1.40(m,4H),1.34-1.21(m,4H).ESI-MS m/z:531.6[M+H]+。
Embodiment 8：Compound 28a-28g synthesis, by taking compound 28e as an example
(1) preparation of methyl 6- ((4- nitrobenzophenones) amino) esters (25e)
P-fluoronitrobenzene 1.00g, 6-aminocaprolc acid methyl ester hydrochloride 1.54g and potassium carbonate 2.94g are added to 50mL N, In dinethylformamide, 50 DEG C are warming up to, overnight, after reaction terminates, room temperature is cooled to, reaction solution is poured into frozen water, analyse Go out yellow solid, filter, drying, residue petroleum ether：Ethyl acetate=4:The eluant, eluent of 1 volume ratio carries out column chromatography and obtained 1.32g product 25e, are faint yellow solid, yield:70%；ESI-MS m/z:267.3[M+H]+。
(2) preparation of methyl 6- ((4- aminophenyls) amino) esters (26e)
Intermediate 25e 1.00g are suspended in 70mL methanol, 10%Pd/C 0.1g is added, hydrogen is passed through under atmospheric agitation Gas, room temperature reaction overnight, after reaction terminates, remove solvent under reduced pressure, and residue with ethyl acetate is recrystallized to give 0.71g product 26e, For brown solid, yield：80%；ESI-MS m/z:237.4[M+H]+。
(3) methyl 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino)-own ester (27e) preparation
By the 0.5g of intermediate 3, intermediate 26e 0.49g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanols at room temperature In, backflow is warming up to, reaction is overnight.After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume The eluant, eluent of ratio carries out column chromatography and purifies to obtain product 27e, is 0.55g faint yellow solids, yield：65%；ESI-MS m/z: 488.6[M+H]+。
(4) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino)-N- hydroxyls amide (28e) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is azanol potassium Methanol solution.Compound 27e 0.20g are dissolved in 30mL azanol potassium solutions, and after 2h is stirred at room temperature, the removing that is concentrated under reduced pressure is most of Solvent, residual residue adjust pH to 5-6 with 1M HCl, separate out white solid, filtering, dry cake, obtain 0.13g product 28e, For light red solid, yield：66%.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.78(s,1H),8.68(s, 1H), 7.76-7.73 (m, 2H), 7.43 (d, J=1.6Hz, 1H), 7.37 (d, J=8.4Hz, 2H), 6.87 (dd, J=1.8, 8.8Hz, 1H), 6.45 (d, J=8.4Hz, 2H), 5.68 (d, J=6.0Hz, 1H), 4.06 (s, 3H), 3.49 (s, 1H), 3.44 (s, 3H), 2.93 (t, J=7.0Hz, 2H), 1.96 (t, J=7.3Hz, 2H), 1.61-1.10 (m, 6H) .ESI-MS m/z: 489.3[M+H]+。
Embodiment 9：The external HDAC inhibitory activity test experiments of compound
The HeLa nuclear extracts (mainly containing HDAC1 and HDAC2) that we are easy to get first by convenience are used as HDAC enzymes source, The external HDACs inhibitory activity of target compound is determined.
The external HDAC inhibitory activity of the compound of table 1
Experiment conclusion：Majority of compounds has certain inhibitory action to HDACs, in hydroxamic acid compound 13e and 13f's is active best, hence it is evident that better than positive control drug SAHA.Preferably, it lives 6d and 14e activity in o-phenylenediamine class compound Property is suitable with positive control drug MS275.
Embodiment 10：The external HDAC subtype-selectives experiment of representative compound
The external HDAC subtype-selectives of the representative compound of table 2
aUndetermined
Experiment conclusion：Hydroxamic acid representative compound 10a is similar with positive control drug SAHA with 13f, is wide spectrum Hdac inhibitor, but compound 13f is better than SAHA to HDAC6 inhibitory activity.O-phenylenediamine class representative compound 6d and 14g is similar with positive control drug MS275, is Class I selectivity hdac inhibitors.
Embodiment 11：The external VEGFR-2 inhibitory activity determination experiment of compound
All target compounds are determined first under 0.2 μM of concentration to VEGFR-2 percent inhibition, and then further Determine the IC of the external anti-VEGFR-2 of 4 representative compounds (10a, 13f, 6d, 14g)50Value.
The external VEGFR-2 inhibitory activity of the compound of table 3
aUndetermined
Experiment conclusion：Majority of compounds shows stronger VEGFR-2 inhibitory activity (inhibiting rates in 200nM> 90%), representative compound 10a, 13f, 6d and 14g show suitable external of positive control drug Pazapanib VEGFR-2 inhibitory activity.
Embodiment 12：The immunoblot experiment of representative compound
It is real We conducted Western Blot in order to further study compound in the cell to HDAC inhibitory action Test, determine representative compound 6d and 13f to acetylated H4 (Class I HDAC substrate) and The influence of acetylated tubulin (HDAC6 substrate) expression.Wherein SAHA, TubA and MS275 are positive Comparison medicine, β-Actin are internal standards.Experimental result is referring to Fig. 1.
Experiment conclusion：Compound 6d can significantly improve acetylated histones H4 (Ac-HH4) level at 1 μM, its activity with MS275 is suitable, but compound 6d can not raise acetylation tubulin (Ac-tubulin) level, and it is one to show compound 6d Individual Class I HDAC selective depressants.Compound 13f can significantly improve acetylation tubulin (Ac- in 100nM Tubulin level), its activity are better than TubA and SAHA；13f can also improve acetylated histones H4 (Ac-HH4) water simultaneously Flat, it is wide spectrum hdac inhibitor to show compound 13f.
Embodiment 13：The extracorporeal anti-tumor cell-proliferation activity experiment of representative compound
We employ the extracorporeal anti-tumor cell-proliferation activity that more commonly used MTT methods determine test-compound.
The extracorporeal anti-tumor cell-proliferation activity of the representative compound of table 4
aUndetermined
Experiment conclusion：Most compound shows certain anti-increasing to a variety of blood tumors and solid tumor cell system Effect is grown, compound 10a and 13f activity is optimal wherein in hydroxamic acid compound, shows and positive control drug SAHA Suitable anti-tumour cell proliferative activity.Compound 6d activity is optimal in o-phenylenediamine class compound, and it is right with the positive to show According to the suitable anti-tumour cell proliferative activities of medicine MS275.
The representative compound of embodiment 14 suppresses Human umbilical vein endothelial cells and tested into lumen of vessels
We have selected representative compound 6d and 13f, determine compound under 1 μM of concentration to HUVECs segment dislocations Influence, and select Pazopanib as positive control drug.Experimental result is referring to Fig. 2.
Experiment conclusion：Representative compound 6d and 13f is shown and positive control drug Pazopanib under 1 μM of concentration Suitable external anti-HUVECs is active into lumen of vessels.
The rat chest aorta of the representative compound of embodiment 15 is into vascular study activity experiment
We have further carried out rat chest aorta and the external anti-angiogenic life for further assessing compound are tested into blood vessel It is Viability, influences of the representative compound 6d and 13f to rat chest aorta into blood vessel under 5 μM of concentration is determined, it is positive right It is Pazopanib according to medicine.Experimental result is referring to Fig. 3.
Experiment conclusion：It is micro- that compound 6d, 13f and Pazopanib can almost completely inhibit arterial ring under 5 μM of concentration The formation of blood vessel.
Antitumor activity is tested inside the representative compound of embodiment 16
Based on compound 6d and 13f extracorporeal anti-tumor cell-proliferation activities excellent in HT-29 cell lines, we establish Nude mice by subcutaneous HT-29 lotus knurl models, positive control is used as using SAHA and Pazopanib.6d and 13f are with 50mg/ for compound Two dosages of kg/day and 100mg/kg/day, SAHA is with 100mg/kg/day and Pazopanib with 50mg/ Kg/day is administered orally.Administration puts to death animal after 21 days and terminates to test, and calculates the tumour life of test-compound and positive control drug Long inhibiting rate (TGI), the antitumor activity of compound is assessed in terms of the volume and weight two of tumor.Experimental result referring to, figure 4th, Fig. 5.
Experiment conclusion：Compound 6d and 13f show anti-cancer activity in vivo, and wherein 6d activity is preferably.In 100mg/kg/ During day dosage, 6d activity be better than listing hdac inhibitor class medicine SAHA, in 50mg/kg/day dosage, 6d it is active with it is upper VEGFR inhibitor class medicine pazopanibs in city are suitable, have very high follow-up study Development volue.

Claims (10)

1. the double target spot inhibitor of HDAC and VEGFR based on pazopanib structure, its pharmaceutically acceptable salt, solvate or Prodrug, it is characterised in that with the structure shown in below formula I, II or III：
Wherein
X is
N is 0~9；
Y is
2. the double target spot inhibitor of HDAC and VEGFR as claimed in claim 1 based on pazopanib structure, it is characterised in that
X is in contraposition or the meta of phenyl ring in Y and II in formula I
X is
N is 0-7；
Y is
3. the double target spot inhibitor of HDAC and VEGFR as claimed in claim 1 or 2 based on pazopanib structure, its feature exist In compound is one of following：
4. the preparation method of the double target spot inhibitor of HDAC and VEGFR as claimed in claim 1 based on pazopanib structure, is One of following method：
(1) with 2,3- dimethyl -6- amino -2H- indazoles for initiation material, under sodium acid carbonate alkalescence condition with 2,4- dichloros Pyrimidine occurs nucleophilic substitution and obtains intermediate 2, and intermediate 2 obtains intermediate under cesium carbonate catalysis with iodomethane reaction 3, intermediate 3 occurs nucleophilic substitution from different substituted aniline under concentrated hydrochloric acid catalysis and obtains the intermediate of key intermediate 4. 4 protect to obtain intermediate 5 through methyl esters, and ammonolysis reaction of the intermediate 5 through ester obtains end-product 6a-6c；In addition intermediate 4a-4b with O-phenylenediamine obtains end-product 6d-6e through amide condensed；
Reaction equation is as follows：
Wherein 4a, 5a, 6a, 6d phenyl ring are contraposition substitutions, and 4b, 5b, 6b, 6e phenyl ring are meta substitutions；
Reagent and condition in above-mentioned reaction equation：(a) 2,4- dichloro pyrimidines, sodium acid carbonate, absolute ethyl alcohol, backflow, 4h；(b) carbon Sour caesium, iodomethane, DMF, room temperature, 2h；(c) isopropanol, concentrated hydrochloric acid, backflow, 4h；(d) nitrogen of O- benzos three Azoles-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, triethylamine, o-phenylenediamine, DMF, 0 DEG C-room temperature, overnight (e) absolute methanol, thionyl chloride, flow back, overnight；(f) hydroxylamine hydrochloride, potassium hydroxide, absolute methanol, room temperature, 2h；
The aniline of described different substitutions is：P-aminobenzoic acid, gavaculine or 5- amino-2-methyl benzoic acid；
(2) it is initiation material with intermediate 4, with N, the generation of O- dimethyl hydroxylamine hydrochloride is amide condensed to obtain intermediate 7, centre Body 7 is reduced to aldehyde intermediate 8 through tetrahydrochysene lithium aluminium, intermediate 8 and phosphonoacetate occur Huo Naer-Wordsworth- Ai Mengsi reaction responses obtain intermediate 9, and ammonolysis of the intermediate 9 through ester obtains end-product 10；
Reaction equation is as follows：
Wherein 4a, 7a, 8a, 9a, 10a phenyl ring substitute for contraposition, 4b, 7b, 8b, 9b, and 10b phenyl ring substitutes for meta；
Reagent and condition in above-mentioned reaction equation：(a) N, O- dimethyl hydroxylamine hydrochloride, O- BTAs-N, N, N ', N '-four MU tetrafluoro boric acid, triethylamine, DMF, room temperature, overnight；(b) tetrahydrochysene lithium aluminium, tetrahydrofuran, -20 DEG C, 4h；(c) phosphonoacetate, sodium hydride, tetrahydrofuran, 0 DEG C-normal temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, nothing Water methanol, room temperature, 2h；
(3) it is initiation material with intermediate 4, intermediate 4 and the amino-alkane methyl esters of different chain length obtain through amide condensed reaction Intermediate 11, ammonolysis reaction of the intermediate 11 through ester obtain end-product 13；Intermediate 11 hydrolyzes under the conditions of Sodium Hydroxide Alkaline For intermediate 12, intermediate 12 obtains end-product 14 with o-phenylenediamine through amide condensed reaction；
Reaction equation is as follows：
Wherein 4a, 11a-11g, 12a-12g, 13a-13g, 14a-14g phenyl ring substitute for contraposition, 4b, 11h, and 13h phenyl ring is Meta substitutes, and n is 1~7；
Reagent and condition in above-mentioned reaction equation：(a) the amino-alkane methyl esters of different chain length, O- BTAs-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, triethylamine, DMF, room temperature, overnight；(b) hydroxylamine hydrochloride, potassium hydroxide, nothing Water methanol, room temperature, 2h；(c) 3M NaOH, methanol, room temperature, 2h；(d) o-phenylenediamine, O- BTAs-N, N, N ', N '-four MU tetrafluoro boric acid, triethylamine, DMF, room temperature, overnight；
The amino-alkane methyl esters of described different chain length is：Glycine methyl ester, 3- aminopropanoates, 4-Aminobutanoicacid methyl esters, 5- aminopentanoic acid methyl esters, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acids methyl esters or 8- aminocaprylic acid methyl esters；
(4) using p-nitrophenol as initiation material, nucleophilic substitution occurs with the bromine alkanoic acid methyl esters of different chain length and obtains centre Body 16, intermediate 16 reduce to obtain intermediate 17 through Pd/C, and intermediate 17 and 3 occurs necleophilic reaction and obtains intermediate 18, middle Ammonolysis reaction of the body 18 through ester obtains end-product 19；
Reaction equation is as follows：
Wherein n is 1~7；
Reagent and condition in above-mentioned reaction equation：(a) different chain length bromine alkanoic acid methyl esters, potassium carbonate, acetone, flow back, overnight；(b) Pd/C, methanol, hydrogen, room temperature, overnight；(c) isopropanol, concentrated hydrochloric acid, flow back, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide are anhydrous Methanol, room temperature, 2h；
The bromine alkanoic acid methyl esters of described different chain length is：2- methyl bromoacetates, 3- methyl bromide cs, 4- bromo butyric acid methyl esters, 5- bromines Methyl valerate, 6- bromocaproic acids methyl esters, 7- bromines methyl heptanoate or 8- bromine methyl caprylates；
(5) it is initiation material with intermediate 3, nucleophilic substitution, which occurs, with paranitroanilinum obtains intermediate 20, intermediate 20 Intermediate 21 is reduced to through Pd/C, the docosandioic acid mono-methyl generation of intermediate 21 and different chain length is amide condensed to obtain intermediate 22, the ammonolysis reaction that ester occurs for intermediate 22 obtains end-product 23；
Reaction equation is as follows：
Wherein n is 1~7；
Reagent and condition in above-mentioned reaction equation：(a) paranitroanilinum, isopropanol, concentrated hydrochloric acid, flow back, overnight；(b) Pd/C, first Alcohol, hydrogen, room temperature, overnight；(c) the docosandioic acid mono-methyl of different chain length, O- BTAs-N, N, N ', N '-tetramethylurea four Fluoboric acid, triethylamine, N ' dinethylformamides, room temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, absolute methanol, room temperature, 2h；
The docosandioic acid mono-methyl of described different chain length is：Malonic acid monomethyl ester, monomethyl succinate, monomethyl glutarate, oneself Acid monoethyl ester, pimelic acid mono-methyl, suberic acid mono-methyl or monomethyl azelate；
(6) using p-fluoronitrobenzene as initiation material, in being obtained with the aminoalkyl methyl esters generation nucleophilic substitution of different chain length Mesosome 25, intermediate 25 reduces to obtain intermediate 26 through Pd/C, during intermediate 26 obtains with the generation nucleophilic substitution of intermediate 3 Mesosome 27, ammonolysis reaction of the intermediate 27 through ester obtain intermediate 28；
Reaction equation is as follows：
Wherein n is 1~7；
Reagent and condition in above-mentioned reaction equation：(a) the aminoalkyl methyl esters of different chain length, potassium carbonate, N, N- dimethyl formyls Amine, 50 DEG C, overnight；(b) Pd/C, hydrogen, methanol, overnight；(c) concentrated hydrochloric acid, isopropanol, flow back, overnight；(d) hydroxylamine hydrochloride, hydrogen Potassium oxide, absolute methanol, room temperature, 2h；
The amino-alkane methyl esters of described different chain length is：Glycine methyl ester, 3- aminopropanoates, 4-Aminobutanoicacid methyl esters, 5- aminopentanoic acid methyl esters, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acids methyl esters or 8- aminocaprylic acid methyl esters.
5. the preparation method of the double target spot inhibitor of HDAC and VEGFR as claimed in claim 4 based on pazopanib structure, is One of following method：
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first The preparation method of acid amides (6a), step are as follows：
(1) preparation of N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -6- amino -2H- indazoles (2)
By 2,3- dimethyl -6- amino -2H- indazoles 5.00g, 2,4- dichloro pyrimidines 13.9g and sodium acid carbonate 10.4g, it is dissolved in In 100mL absolute ethyl alcohols, 79 DEG C are heated to, flows back after 4h, cools down to room temperature, is filtered, filter cake is fully washed with ethyl acetate, Filtrate is collected, is concentrated under reduced pressure, solvent is removed, is filtrated to get pale solid after being fully beaten with ethyl acetate, is tied again with methanol 7.64g products 2 are obtained after crystalline substance, are white solid；
(2) N- (2- chlorine pyrimidine-4-yl)-N, the preparation of 2,3- trimethyl -2H- indazole -6- amine (3)
The 1.00g of previous step product 2 and cesium carbonate 2.40g are added in 50mL DMFs, reacted at room temperature 20min, iodomethane 0.78g is then slowly added into, is finished, reacted at room temperature 2h, reaction solution is poured into frozen water, separated out immediately a large amount of Faint yellow solid, filtering, after drying, 1.06g products 3 are obtained with re-crystallizing in ethyl acetate, are light yellow crystal；
(3) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoic acid (4a) Prepare
The 0.50g of intermediate 3 and p-aminobenzoic acid 0.36g are scattered in 30mL isopropanols, 2 drop concentrated hydrochloric acids is added, is heated to 85 DEG C, back flow reaction 4h, room temperature is cooled to, filters, wash filter cake with isopropanol and ethyl acetate, be dried to obtain 0.53g products 4a, it is white solid；
(4) methyl 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoic ether The preparation of (5a)
4a 0.50g are added in 50mL absolute methanols, thionyl chloride 0.60g is then added dropwise at 0 DEG C, finishes, are incubated After 30min, it is heated to flowing back after removing ice bath, after reacting 5h, solvent under reduced pressure is steamed, crude product is obtained with recrystallisation from isopropanol 0.50g product 5a, it is white solid；
(5) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first The preparation of acid amides (6a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 5a 0.20g are dissolved in 30mL azanol potassium solutions, after 1h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 80.6mg product 6a, be white Color solid；
N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) The preparation method of benzamide (6d), step are as follows：
(1) N- (2- aminophenyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) ammonia Base) benzamide (6d) preparation
Intermediate 4a 0.50g are added in anhydrous DMF, under ice bath, add O- BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid 0.49g and triethylamine 0.26g, after activating 30min, o-phenylenediamine 0.17g is then added, Reaction adds ethyl acetate dilution overnight, after the completion of reaction at room temperature, and DMF, ethyl acetate layer are removed in washing Washed with saturated sodium bicarbonate solution and saturation NaCl solution, anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, residue dichloromethane Alkane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.40g product 6d, is pale solid；
(2) (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamides (10a) preparation
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- methoxyl groups-N- The preparation of methyl benzamide (7a)
Intermediate 4a 1.00g are added in anhydrous DMF, under ice bath, add O- BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add N, O- dimethyl hydrochloric acid Azanol 0.30g and triethylamine 0.31g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and N, N- are removed in washing Dimethylformamide, ethyl acetate layer are washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, and is subtracted Pressure removes solvent, residue dichloromethane:Methanol=35:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.78g products 7a, it is white solid；
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzaldehyde (8a) Prepare
Compound 7a 1.00g are dissolved in 50mL anhydrous tetrahydro furans, and -40 DEG C are cooled in low-temp reaction instrument；Xiang Qifen Criticize and be slowly added to tetrahydrochysene lithium aluminium 0.26g, after maintaining this thermotonus 2h, reaction to terminate, reaction carefully slowly is quenched with frozen water To there is no bubble generation；Reaction solution is diluted with water, and is extracted with ethyl acetate, and merges organic layer, the washing of saturation NaCl solution, nothing Water magnesium sulfate is dried, and be concentrated under reduced pressure solvent, residue dichloromethane:Methanol=40:It is pure that the eluant, eluent of 1 volume ratio carries out column chromatography Change obtains 0.61g product 8a, is white solid；
(3) ethyl (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) Phenyl) acrylate
The preparation of (9a)
Phosphonoacetate 0.32g is added into 50mL anhydrous tetrahydro furans, -5-0 DEG C is cooled to, is slowly added to NaH0.16g, finish, stir 20min, 8a 0.52g tetrahydrofuran solution is then added dropwise, overnight, reaction finishes for room temperature reaction Afterwards, the ammonium chloride solutions of 50mL 10% are added, stir stratification after 30min, after organic phase is dried, filtering, are concentrated to give thick Product；Residue dichloromethane:Methanol=40:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.48g product 9a, is white Color solid；
(4) (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxy acyls
The preparation of amine (10a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 9a 0.50g are dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 0.29g product 10a, be white Color solid；
(3) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyls Amine) -2- oxoethyls) benzamide (13a) preparation method, step is as follows：
(1) methyl (4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl) it is sweet The preparation of propylhomoserin ester (11a)
Intermediate 4a 1.00g are added in anhydrous DMF, under ice bath, add O- BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g, after activating 30min, then add glycine methyl ester hydrochloric acid Salt 0.39g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and DMF, second are removed in washing Ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, residue Use dichloromethane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.87g product 11a, is white solid；
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyls Amine) -2- oxoethyls) benzamide (13a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 11a 0.50g are dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 0.31g product 13a, be white Color solid；
N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (first Base) amino) pyrimidine -2-base) amino) benzamide (14a) preparation, step is as follows：
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzoyl) it is sweet The preparation of propylhomoserin (12a)
11a 1.00g are added in 30mL methanol, 5mL 3M NaOH solutions is then added, stirs 4h at room temperature, reaction terminates Afterwards, decompression boils off most of methanol, and residue adjusts pH to 5-6 with 1M HCl solutions；Filtering, filter cake are washed with frozen water, are dried After obtain 0.81g product 12a, be white solid, directly throw in next step；
(2) N- (2- ((2- aminophenyls) amino) -2- oxoethyls) -4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) and benzamide (14a) preparation
Intermediate 12a 1.00g are added in anhydrous DMF, under ice bath, add O- BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid 0.86g and triethylamine 0.45g, after activating 30min, then add o-phenylenediamine 0.29g, at room temperature reaction add ethyl acetate dilution overnight, after the completion of reaction, and DMF, acetic acid are removed in washing Methacrylate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, and anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, and residue is used Dichloromethane:Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.47g product 14a, faint yellow solid；
(4) 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - The preparation of N- hydroxyls heptamide (19f), step are as follows：
(1) preparation of methyl 7- (4-nitrophenoxy) heptanoate (16f)
P-nitrophenol 1.00g, 7- methyl bromoacetates 1.93g and potassium carbonate 2.98g are added in 50mL acetone, are warming up to back Stream, reaction overnight, after reaction terminates, remove solvent under reduced pressure, obtain 1.62g product 16f with re-crystallizing in ethyl acetate, consolidate for yellow Body；
(2) preparation of methyl 7- (4- amino-benzene oxygens) heptanoates (17f)
Intermediate 16f 1.00g are added in 50mL methanol, 10%Pd/C 0.1g is added, hydrogen is passed through under atmospheric agitation, in Overnight, filtering, filter residue is washed with methanol, merging filtrate and washing lotion, removes solvent under reduced pressure, obtain product 0.79g for room temperature reaction 17f, it is light tan solid；
(3) methyl 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene oxygen Base)-heptanoate (18f) preparation
By the 0.50g of intermediate 3, intermediate 17f 0.52g and 0.5mL concentrated hydrochloric acid is added in 50mL isopropanols at room temperature, is risen Temperature is to flowing back, and reaction is overnight；After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume ratio is washed De- agent carries out column chromatography and purifies to obtain 0.61g product 18f, is white solid；
(4) 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - The preparation of N- hydroxyls heptamide (19f)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 18f 0.30g are dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 0.20g product 19f, be white Color solid；
(5) N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N8The preparation of-hydroxyl suberamide (23f), step are as follows：
(1)N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methyl-N2- (4- nitrobenzophenones) pyrimidine -2,4- diamines (20) Prepare
By the 1.00g of intermediate 3, paranitroanilinum 0.58g and 0.5mL concentrated hydrochloric acid is added in 70mL isopropanols, is warming up to back Stream, reaction overnight, after reaction terminates, are cooled to room temperature, filtered, and filter cake is washed with a small amount of isopropanol, dry cake, obtains 1.08g Product 20, it is faint yellow solid；
(2)N2- (4- aminophenyls)-N4- (2,3- dimethyl -2H- indazole -6- bases)-N4- methylpyrimidine -2,4- diamines (21) Prepare
The 1.00g of intermediate 20 is suspended in 70mL methanol, adds 10%Pd/C 0.1g, hydrogen, room are passed through under atmospheric agitation Temperature reaction overnight, after reaction terminates, removes solvent under reduced pressure, residue with ethyl acetate is recrystallized to give 0.78g products 21, is shallow palm fibre Color solid；
(3) methyl 8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino) -8- oxos monooctyl ester (22f) preparation
Suberic acid mono-methyl 0.33g is added in the anhydrous DMFs of 50mL, the nitrogen of O- benzos three is added under ice bath Azoles-N, N, N ', N '-tetramethylurea tetrafluoro boric acid 0.68g and triethylamine 0.36g, finish, 30min is activated under ice bath, activation finishes Afterwards, the 0.76g of intermediate 21 is added, removes ice bath, room temperature reaction adds ethyl acetate dilution overnight, after the completion of reaction, and washing removes Fall DMF, ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturation NaCl solution, anhydrous magnesium sulfate Dry, remove solvent, residue dichloromethane under reduced pressure：Methanol=30:The eluant, eluent of 1 volume ratio carries out column chromatography and purifies to obtain 0.37g product 22f, it is white solid；
(4)N1- (4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl)-N8- The preparation of hydroxyl suberamide (23f)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 22f 0.20g are dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 0.14g product 23f, be white Color solid；
(6) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyls amide (28e) preparation, step is as follows：
(1) preparation of methyl 6- ((4- nitrobenzophenones) amino) esters (25e)
P-fluoronitrobenzene 1.00g, 6-aminocaprolc acid methyl ester hydrochloride 1.54g and potassium carbonate 2.94g are added to 50mL N, N- bis- In NMF, 50 DEG C are warming up to, overnight, after reaction terminates, room temperature is cooled to, reaction solution is poured into frozen water, is separated out yellow Color solid, filter, drying, residue petroleum ether:Ethyl acetate=4:The eluant, eluent of 1 volume ratio carries out column chromatography and obtains 1.32g Product 25e, it is faint yellow solid；
(2) preparation of methyl 6- ((4- aminophenyls) amino) esters (26e)
Intermediate 25e 1.00g are suspended in 70mL methanol, 10%Pd/C 0.1g is added, hydrogen, room is passed through under atmospheric agitation Temperature reaction overnight, after reaction terminates, removes solvent under reduced pressure, and residue with ethyl acetate is recrystallized to give 0.71g product 26e, for palm fibre Color solid；
(3) methyl 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino)-own ester (27e) preparation
By the 0.5g of intermediate 3, intermediate 26e 0.49g and 0.5mL concentrated hydrochloric acid is added in 50mL isopropanols at room temperature, is risen Temperature is to flowing back, and reaction is overnight；After reaction terminates, solvent, residue dichloromethane are removed under reduced pressure:Methanol=40:1 volume ratio is washed De- agent carries out column chromatography and purifies to obtain 0.55g product 27e, is faint yellow solid；
(4) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyls amide (28e) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in 70mL and 120mL absolute methanols respectively, obtain solution A and solution B； Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitation, obtained filtrate is the methanol of azanol potassium Solution；Compound 27e 0.20g are dissolved in 30mL azanol potassium solutions, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed most of solvent, Residual residue adjusts pH to 5-6 with 1M HCl, separates out white solid, filtering, dry cake, obtains 0.13g product 28e, is light Red solid.
6. compound the answering in the medicine of prevention or treatment with tumor-related illness is prepared as described in claim 1,2 or 3 With.
7. application as claimed in claim 6, it is characterised in that described to be with tumor-related illness：Various blood tumors are each Kind solid tumor.
8. application as claimed in claim 7, it is characterised in that described all kinds of blood tumors are：Each quasi-leukemia, myelosis Knurl；Described each quasi-leukemia is：Serious ALL, acute myeloid leukaemia, acute megakaryoblastic are white Blood disease；Described myelosis knurl is：Chronic myelogenous leukemia, polycythemia vera, primary thrombocytosis, bone Marrow fibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and other not The myelosis knurl of classification.
9. application as claimed in claim 7, it is characterised in that described solid tumor is：Various forms of nasopharyngeal carcinoma, nephrocyte Cancer, soft tissue sarcoma, thyroid papillary carcinoma, thymoma, liver cancer, breast cancer, melanoma, prostate cancer or retina are female thin Born of the same parents' knurl.
10. a kind of be suitable to pharmaceutical composition administered orally or parenterally, comprising the compound described in claim 1,2 or 3 and One or more pharmaceutically acceptable carriers or excipient.
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CN102060848A (en) * 2010-12-09 2011-05-18 天津药物研究院 Preparation and application of aromatic amine substituted pyrimidine derivatives
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