CN107619407B - Bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure and its preparation method and application - Google Patents

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

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CN107619407B
CN107619407B CN201710677980.2A CN201710677980A CN107619407B CN 107619407 B CN107619407 B CN 107619407B CN 201710677980 A CN201710677980 A CN 201710677980A CN 107619407 B CN107619407 B CN 107619407B
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amino
methyl
base
room temperature
acid
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CN107619407A (en
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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 HDAC and bis- target spot inhibitor of VEGFR and its preparation method and application based on pazopanib structure.The compound has structure shown in general formula I, II or III.The present invention also provides the preparation method of such compound and in preparation prevention or treatment and the application in tumor-related illness drug.

Description

The bis- target spot inhibitor of HDAC and VEGFR and its preparation side based on pazopanib structure 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 Bis- target spot inhibitor of HDAC and VEGFR and its preparation method and application.
Background technique
Pazopanib Pazopanib is a Mutiple Targets receptor tyrosine kinase inhibitor, to vascular endothelial growth factor Three hypotypes (VEGFR-1, VEGFR-2, VEGFR-3) of receptor VEGFR 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 In October, 2009 ratifies listing for there is the advanced stage kidney of the past chemotherapy experience patient thin by U.S. Food and Drug Administration FDA 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 advanced stage soft tissue sarcoma by FDA approval listing again opinion in oncology,2013,25,373).However 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 multiple target point drug be enhance tumour to drug susceptibility and reduce drug resistance of tumor a strategy.
Histon deacetylase (HDAC) HDACs is one group of enzyme of internal regulation acetylation of histone level, the acetyl of histone Change level has important influence to the transcriptional regulatory of chromatinic structure and gene, HDACs mutation and unconventionality expression usually with The generation of tumour is closely related.HDACs inhibitor has been shown to have antitumor action, at present existing 5 small molecule HDAC suppression 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 relationship, pazopanib and hdac inhibitor use in conjunction Cause the interest of researcher.The study found that the combination of pazopanib and hdac inhibitor (VPA, SAHA) are in soft tissue sarcoma In show the inside and outside antitumor action of 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 work of the killing to the drug resistant melanoma of dabrafenib/Trimetinib is shown in the combination of pazopanib experiment in vivo and in vitro With, synergistic effect with activate a plurality of signal path related (Booth L.etc., Oncotarget, 2017,8,16367). Researches show that be mutated when pazopanib and hdac inhibitor SAHA drug combination to TP53 for one clinical I phase of report in 2015 Especially the tumour patient of metastatic sarcoma and metastatic colorectal carcinoma shows apparent curative effect, wherein position Progression free survival Phase and middle position Overall survival are obviously prolonged (Fu S.etc., Annals of Oncology, 2015,26,1012).2017 most Researches show that hdac inhibitor abexinost and pazopanib combination to have good tolerance for the clinical I phase newly reported Property, and can effectively overcome pazopanib drug resistance (Aggarwal, Rahul, etc., Journal of Clinical Oncology, 2017,35,1231)。
Clinically, the anti-tumor drug use in conjunction of different role mechanism has been considered as avoiding the standard side of drug resistance Case, but drug combination there is a problem of it is following: (1) drug combination pharmacokinetics is complicated, and drug-drug interactions are bad Reaction it is difficult to predict；(2) compatibility of different pharmaceutical and dosage setting clinically have difficulties.Multiple target point drug refers to while making For the single medicine molecule of multiple target spots, multiple target point drug not only has the advantages of drug combination, but also overcomes joint and use Some defects of medicine.Multiple target point drug pharmacokinetics are simple, avoid drug-drug interaction, safer, improve The compliance of patient becomes a popular direction of current antineoplastic drug design.Currently, based on pazopanib structure The bis- target spot inhibitor of HDAC and VEGFR have no relevant report in the prior art.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides based on pazopanib structure HDAC and VEGFR bis- target spots suppression Preparation, the present invention also provides the preparation method of above compound and purposes.
The technical solution of the present invention is as follows:
One, the bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure
The present invention contains the bis- target spot inhibitor of the HDAC/VEGFR based on pazopanib structure, pharmaceutically acceptable Salt, solvate or prodrug have structure shown in following general formula I, II or III:
Wherein:
X is
N is 0~9；
Y is
It is preferred according to the present invention,
X is in contraposition or meta position in Y and II in general formula I；
X is
N is 0~7；
Y is
It is further preferred that above compound is one of following:
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first Amide (6a),
3- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first Amide (6b),
5- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyl -2- Methyl benzamide (6c),
N- (2- aminophenyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6d),
N- (2- aminophenyl) -3- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6e),
(E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamide (10a),
(E) -3- (3- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamide (10b),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyl Amine) -2- oxoethyl) benzamide (13a),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (3- (hydroxyl Amine) -3- oxopropyl) benzamide (13b),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (4- (hydroxyl Amine) -4- oxo butyl) benzamide (13c),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (5- (hydroxyl Amine) -5- oxopentyl) benzamide (13d),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyl Amine) -6- oxo-hexyl) benzamide (13e),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (7- (hydroxyl Amine) -7- oxo heptyl) benzamide (13f),
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (8- (hydroxyl Amine) -8- oxo octyl) benzamide (13g),
3- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyl Amine) -6- oxo-hexyl) benzamide (13h),
5- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (6- (hydroxyl Amine) -6- oxo-hexyl) -2- methyl benzamide (13i),
N- (2- ((2- aminophenyl) amino) -2- oxoethyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a),
N- (3- ((2- aminophenyl) amino) -3- oxopropyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14b),
N- (4- ((2- aminophenyl) amino) -4- oxo butyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14c),
N- (5- ((2- aminophenyl) amino) -5- oxopentyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14d),
N- (6- ((2- aminophenyl) amino) -6- oxo-hexyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14e),
N- (7- ((2- aminophenyl) amino) -7- oxo heptyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14f),
N- (8- ((2- aminophenyl) amino) -8- oxo octyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14g),
2- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyl acetamide (19a),
3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxypropanamide (19b),
4- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxybutyrate amide (19c),
5- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyvaleramide (19d),
6- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyl hexanamide (19e),
7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxyl heptamide (19f),
8- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - N- hydroxy capryloyl amine (19g),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N3Hydroxyl malonamide (23a),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N4Hydroxy-succinamide (23b),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N5Hydroxyl glutaramide (23c),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N6Hydroxyl adipamide (23d),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N7Hydroxyl heptanedioyl amine (23e),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N8Hydroxyl suberamide (23f),
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N9Hydroxyl nonanedioyl amine (23g),
2- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyl acetamide (28a)
3- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxypropanamide (28b)
4- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxybutyrate amide (28c)
5- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyvaleramide (28d)
6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyl amide (28e)
7- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyl heptamide (28f) or
8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxy capryloyl amine (28g).
Two, the preparation method of the bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure
The present invention contains the preparation method of HDAC and the bis- target spot inhibitor of VEGFR based on pazopanib structure, is following One of method:
(1) with 2,3- dimethyl -6- amino -2H- indazole for starting material, with 2,4- under sodium bicarbonate alkaline condition Dichloro pyrimidine occurs nucleophilic substitution and obtains intermediate 2, during intermediate 2 obtains under cesium carbonate catalysis, 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 intermediate 5 obtains final product 6a-6c through the ammonolysis reaction of ester；Furthermore intermediate 4a- 4b and o-phenylenediamine obtain final product 6d-6e through amide condensed.
Reaction equation is as follows:
The phenyl ring of wherein 4a, 5a, 6a, 6d are that contraposition replaces, 4b, 5b, and the phenyl ring of 6b, 6e are that meta position replaces.
Reagent and condition in above-mentioned reaction equation: (a) 2,4- dichloro pyrimidine, sodium bicarbonate, dehydrated alcohol, reflux, 4h； (b) cesium carbonate, iodomethane, n,N-Dimethylformamide, room temperature, 2h；(c) isopropanol, concentrated hydrochloric acid, reflux, 4h；(d) O- benzo Triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, o-phenylenediamine, n,N-Dimethylformamide, 0 DEG C-room temperature, Overnight；(e) anhydrous methanol, thionyl chloride flow back, overnight；(f) hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2h.
The different aniline replaced are as follows: p-aminobenzoic acid, gavaculine or 5- amino-2-methyl benzene first Acid.
Preferred according to the present invention, specific preparation process is as follows:
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxy benzenes first The preparation method of amide (6a), steps are as follows:
(1) preparation of N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -6- amino -2H- indazole (2)
By 2,3- dimethyl -6- amino -2H- indazole 5.00g, 2,4- dichloro pyrimidine 13.9g, and sodium bicarbonate 10.4g, It is dissolved in 100mL dehydrated alcohol, is heated to 79 DEG C, flow back after 4h, cool down to room temperature, filter, filter cake ethyl acetate is abundant Filtrate is collected in washing, is concentrated under reduced pressure, and removes solvent, pale solid is obtained by filtration after being sufficiently beaten with ethyl acetate, uses methanol 7.64g product 2 is obtained after recrystallization, is white solid.
(2) N- (2- chlorine pyrimidine-4-yl)-N, the preparation of 2,3- trimethyl -2H- indazole -6- amine (3)
Previous step product 2 1.00g and cesium carbonate 2.40g are added in 50mL n,N-Dimethylformamide, 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 ice water, is precipitated immediately big Faint yellow solid is measured, filtering after drying, obtains 1.06g product 3 with re-crystallizing in ethyl acetate, is light yellow crystal.
(3) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzoic acid The preparation of (4a)
It disperses intermediate 3 0.50g and p-aminobenzoic acid 0.36g in 30mL isopropanol, 2 drop concentrated hydrochloric acids is added, add To 85 DEG C, back flow reaction 4h is cooled to room temperature heat, and filtering washs filter cake with isopropanol and ethyl acetate, is dried to obtain 0.53g Product 4a is white solid.
(4) methyl 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene first The preparation of acid esters (5a)
4a 0.50g is added in 50mL anhydrous methanol, thionyl chloride 0.60g is then added dropwise at 0 DEG C, finishes, It after keeping the temperature 30min, is heated to flowing back after removing ice bath, after reacting 5h, solvent under reduced pressure be steamed, crude product recrystallisation from isopropanol 0.50g product 5a is obtained, is white solid.
(5) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyl The preparation of benzamide (6a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 5a 0.20g is dissolved in 30mL azanol potassium solution, and after 1h is stirred at room temperature, it is most of molten that removing is concentrated under reduced pressure Agent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 80.6mg product 6a, is White solid.
N- (2- aminophenyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) Amino) benzamide (6d) preparation method, steps are as follows:
(1) N- (2- aminophenyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2- Base) amino) benzamide (6d) preparation
Intermediate 4a 0.50g is added in the anhydrous n,N-Dimethylformamide of 50mL, under ice bath, O- benzo three is added After activating 30min, adjacent benzene is then added in nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.49g and triethylamine 0.26g Diamines 0.17g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and n,N-Dimethylformamide is removed in washing, Ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry, and solvent is removed under reduced pressure, residual Slag is purified to obtain 0.40g product 6d with silica gel column chromatography, is pale solid.
It (two) is starting 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 Huo Naer-Wo Ziwo occurs for intermediate 8 and phosphonoacetate Si-Ai Mengsi reacts to obtain intermediate 9, and intermediate 9 obtains final product 10 through the ammonolysis of ester.
Reaction equation is as follows:
The phenyl ring of wherein 4a, 7a, 8a, 9a, 10a are that contraposition replaces, 4b, 7b, 8b, 9b, and the phenyl ring of 10b is meta position substitution.
Reagent and condition in above-mentioned reaction equation: (a) N, O- dimethyl hydroxylamine hydrochloride, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, 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, anhydrous methanol, room temperature, 2h.
Preferred according to the present invention, specific preparation process is as follows:
(E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene Base)-N- hydroxyacrylamide (10a) preparation:
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- methoxy The preparation of base-N-methyl-benzamide (7a)
It is added to intermediate 4a 1.00g in anhydrous n,N-Dimethylformamide, under ice bath, three nitrogen of O- benzo is added Then N, O- bis- is added after activating 30min in azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g Methyl hydroxylamine hydrochloride 0.30g and triethylamine 0.31g, overnight, ethyl acetate dilution, washing is added in reaction after the reaction was completed at room temperature N,N-Dimethylformamide is removed, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, anhydrous slufuric acid Magnesium is dry, and solvent is removed under reduced pressure, residue methylene chloride: methanol=35:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 0.78g product 7a is white solid.
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzaldehyde The preparation of (8a)
Compound 7a 1.00g is dissolved in 50mL anhydrous tetrahydro furan, and is cooled to -40 DEG C in low-temp reaction instrument.To It is slowly added to tetrahydrochysene lithium aluminium 0.26g in batches, this thermotonus 2h is maintained slowly carefully to be quenched after reaction with ice water Reaction is to there is no bubble generations.Reaction solution is diluted with water, and is extracted with ethyl acetate, and merges organic layer, and saturation NaCl solution is washed It washs, anhydrous magnesium sulfate is dry, solvent is concentrated under reduced pressure, residue methylene chloride: methanol=40:1 volume ratio eluant, eluent carries out column Chromatographic purifying obtains 0.61g product 8a, is white solid.
(3) ethyl (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl) acrylate (9a) preparation
Phosphonoacetate 0.32g is added into 50mL anhydrous tetrahydro furan, is cooled to -5-0 DEG C, is slowly added to NaH 0.16g, finishes, and stirs 20min, and the tetrahydrofuran solution of 8a 0.52g is then added dropwise, and room temperature reaction is stayed overnight, end of reaction Afterwards, 10% ammonium chloride solution of 50mL is added, stirs stratification after 30min, after organic phase is dry, filtering is concentrated to get thick Product.Residue methylene chloride: methanol=40:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 0.48g product 9a, is white Color solid.
(4) (E) -3- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) Phenyl)-N- hydroxyacrylamide (10a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 9a 0.50g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.29g product 10a, For white solid.
It (three) is starting material with intermediate 4, intermediate 4 is reacted with the amino-alkane methyl esters of different chain length through amide condensed Intermediate 11 is obtained, intermediate 11 obtains final product 13 through the ammonolysis reaction of ester；Intermediate 11 is under the conditions of Sodium Hydroxide Alkaline It is hydrolyzed to intermediate 12, intermediate 12 reacts to obtain final product 14 with o-phenylenediamine through amide condensed.
Reaction equation is as follows:
The phenyl ring of wherein 4a, 11a-11g, 12a-12g, 13a-13g, 14a-14g are that contraposition replaces, 4b, 11h, the benzene of 13h Ring is meta position substitution, and n is 1~7.
Reagent and condition in above-mentioned reaction equation: (a) the amino-alkane methyl esters of different chain length, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, room temperature, overnight；(b) hydroxylamine hydrochloride, hydroxide Potassium, anhydrous methanol, room temperature, 2h；(c) 3M NaOH, methanol, room temperature, 2h；(d) o-phenylenediamine, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, room temperature, overnight.
The amino-alkane methyl esters of the different chain length is: glycine methyl ester, 3- aminopropanoate, 4-Aminobutanoicacid first Ester, 5- aminopentanoic acid methyl ester, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acid methyl esters or 8- aminocaprylic acid methyl esters.
Preferred according to the present invention, specific preparation process is as follows:
4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (hydroxyl Amine) -2- oxoethyl) benzamide (13a) preparation method, steps are as follows:
(1) methyl (4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycinate (11a) preparation
It is added to intermediate 4a 1.00g in anhydrous n,N-Dimethylformamide, under ice bath, three nitrogen of O- benzo is added Then glycine is added after activating 30min in azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g Methyl ester hydrochloride 0.39g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and N, N- dimethyl are removed in washing Formamide, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry, is removed under reduced pressure Solvent, residue are methylene chloride with eluant, eluent: methanol=30:1 volume ratio carries out column chromatographic purifying and obtains 0.87g product 11a, is White solid.
(2) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (azanol) -2- oxoethyl) benzamide (13a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 11a 0.50g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.31g product 13a, For white solid.
N- (2- ((2- aminophenyl) amino) -2- oxoethyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) and benzamide (14a) preparation, steps are as follows:
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycine (12a) preparation
11a 1.00g is added in 30mL methanol, 5mL 3M NaOH solution is then added, stirs 4h at room temperature, is reacted After, decompression boils off most of methanol, and residue adjusts pH to 5-6 with 1M HCl solution.Filtering, filter cake are washed with ice water, 0.81g product 12a is obtained after drying, is white solid, is directly thrown in next step.
(2) N- (2- ((2- aminophenyl) amino) -2- oxoethyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- Base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a) preparation
It is added to intermediate 12a 1g in the anhydrous n,N-Dimethylformamide of 100mL, under ice bath, O- benzo three is added After activating 30min, adjacent benzene is then added in nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.86g and triethylamine 0.45g Diamines 0.29g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and n,N-Dimethylformamide is removed in washing, Ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry, and solvent is removed under reduced pressure, residual Slag methylene chloride: methanol=30:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 0.47g product 14a, pale yellow colored solid Body.
(4) using p-nitrophenol as starting material, nucleophilic substitution occurs with the bromine alkanoic acid methyl esters of different chain length and obtains Intermediate 16, intermediate 16 restore to obtain intermediate 17 through Pd/C, and intermediate 17 and compound 3 occur necleophilic reaction and obtain centre Body 18, intermediate 18 obtain final product 19 through the ammonolysis reaction of ester.
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, Anhydrous methanol, room temperature, 2h.
The bromine alkanoic acid methyl esters of the different chain length is: 2- methyl bromoacetate, 3- methyl bromide c, 4- bromo butyric acid methyl ester, 5- bromo pentane acid A ester, 6- bromocaproic acid methyl esters, 7- bromine methyl heptanoate or 8- bromine methyl caprylate.
Preferred according to the present invention, specific preparation process is as follows:
7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenoxy group) - The preparation of N- hydroxyl heptamide (19f), steps 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 reflux, overnight, after reaction, evaporating solvent under reduced pressure obtains 1.62g product 16f with re-crystallizing in ethyl acetate for reaction, for Huang Color solid.
(2) preparation of methyl 7- (4- amino-benzene oxygen) heptanoate (17f)
Intermediate 16f 1.00g is added in 50mL methanol, 10%Pd/C 0.1g is added, is passed through hydrogen under atmospheric agitation Gas, overnight in room temperature reaction, filtering, filter residue are washed with methanol, merging filtrate and washing lotion, evaporating solvent under reduced pressure, obtain 0.79g production Object 17f is light tan solid.
(3) methyl 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) Phenoxy group)-heptanoate (18f) preparation
By 3 0.5g of intermediate, intermediate 17f 0.52g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanol at room temperature In, it is warming up to reflux, reaction is overnight.After reaction, evaporating solvent under reduced pressure, residue methylene chloride: methanol=40:1 volume The eluant, eluent of ratio carries out column chromatographic purifying and obtains 0.61g product 18f, is white solid.
(4) 7- (4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene oxygen Base)-N- hydroxyl heptamide (19f) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 18f 0.30g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.20g product 19f, For white solid.
(5) it is starting material with intermediate 3, nucleophilic substitution occurs with paranitroanilinum and obtains intermediate 20, it is intermediate 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 final 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- benzotriazole-N, N, N', N'- tetramethylurea four Fluoboric acid, triethylamine, N ' dinethylformamide, room temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2h。
The docosandioic acid mono-methyl of the 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.
Preferred according to the present invention, specific preparation process is as follows:
N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) - N8The preparation of hydroxyl suberamide (23f), steps are as follows:
(1)N4(2,3- dimethyl -2H- indazole -6- base)-N4Methyl-N2(4- nitrobenzophenone) pyrimidine -2,4- diamines (20) preparation
By 3 1.00g of intermediate, paranitroanilinum 0.58g and 0.5mL concentrated hydrochloric acid is added in 70mL isopropanol, heating To reflux, reaction overnight, after reaction, is cooled to room temperature, and is filtered, and filter cake is washed with a small amount of isopropanol, and dry cake obtains 1.08g product 20 is faint yellow solid.
(2)N2(4- aminophenyl)-N4(2,3- dimethyl -2H- indazole -6- base)-N4Methylpyrimidine -2,4- diamines (21) preparation
20 1.00g of intermediate is suspended in 70mL methanol, 0.1g 10%Pd/C is added, is passed through hydrogen under atmospheric agitation Gas, overnight, after reaction, evaporating solvent under reduced pressure, residue with ethyl acetate is recrystallized to give 0.78g product 21 for room temperature reaction, For light tan solid.
(3) methyl 8- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino) -8- oxo monooctyl ester (22f) preparation
Suberic acid mono-methyl 0.33g is added in the anhydrous n,N-Dimethylformamide of 50mL, O- benzo is 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, 21 0.76g of intermediate is added, removes ice bath, overnight, ethyl acetate dilution, water is added in room temperature reaction after the reaction was completed Remove n,N-Dimethylformamide, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, anhydrous sulphur Sour magnesium is dry, and evaporating solvent under reduced pressure, residue methylene chloride: methanol=30:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains It is white solid to 0.37g product 22.
(4)N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (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 respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 22f 0.20g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.14g product 23f, For white solid.
(6) using p-fluoronitrobenzene as starting material, nucleophilic substitution occurs with the aminoalkyl methyl esters of different chain length and obtains To intermediate 25, intermediate 25 restores to obtain intermediate 26 through Pd/C, and intermediate 26 occurs nucleophilic substitution with intermediate 3 and obtains To intermediate 27, intermediate 27 obtains intermediate 28 through the ammonolysis reaction of ester.
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, n,N-Dimethylformamide, 50 DEG C, overnight；(b) Pd/C, hydrogen, methanol, overnight；(c) concentrated hydrochloric acid, isopropanol flow back, overnight；(d) hydroxylamine hydrochloride, hydroxide Potassium, anhydrous methanol, room temperature, 2h.
The aminoalkyl methyl esters of the different chain length is: glycine methyl ester, 3- aminopropanoate, 4-Aminobutanoicacid first Ester, 5- aminopentanoic acid methyl ester, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acid methyl esters or 8- aminocaprylic acid methyl esters.
Preferred according to the present invention, specific preparation process is as follows:
6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) phenyl) ammonia Base)-N- hydroxyl amide (28e) preparation, steps are as follows:
(1) preparation of methyl 6- ((4- nitrobenzophenone) amino) ester (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, is cooled to room temperature, reaction solution is poured into ice water, is analysed Yellow solid out filters, and drying, residue petroleum ether: ethyl acetate=4:1 volume ratio eluant, eluent carries out column and chromatographs to obtain 1.32g product 25e is faint yellow solid.
(2) preparation of methyl 6- ((4- aminophenyl) amino) ester (26e)
It is suspended in intermediate 25e 1.00g in 70mL methanol, 10%Pd/C 0.1g is added, is passed through hydrogen under atmospheric agitation Gas, overnight, after reaction, evaporating solvent under reduced pressure, residue with ethyl acetate is recrystallized to give 0.71g product 26e for room temperature reaction, For brown solid.
(3) methyl 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino)-own ester (27e) preparation
By 3 0.50g of intermediate, intermediate 26e 0.49g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanol at room temperature In, it is warming up to reflux, reaction is overnight.After reaction, evaporating solvent under reduced pressure, residue methylene chloride: methanol=40:1 volume The eluant, eluent of ratio carries out column chromatographic purifying and obtains 0.55g product 27e, is faint yellow solid.
(4) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino)-N- hydroxyl amide (28e) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 27e 0.20g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.13g product 28e, For light red solid.
The structural formula of target compound is as follows:
The specific preparation step of the compound will be described in detail in embodiment.
Those skilled in the art can optimize above-mentioned steps to improve yield, they can be according to the basic of this field Knowledge works out synthetic route, such as selects reactant, solvent and temperature, can be by using various blocking groups to avoid side reaction Occur 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 meaning used herein is as follows:
ACHN cell is people's renal cell adenocarcinoma cell, and ags cell is human gastric adenocarcinoma, and hel cell is people's red white corpuscle Leukaemia cell, HeLa cell are human cervical carcinoma cell, and HT-1080 cell is human fibrosarcoma cell, and HT-29 cell, which is behaved, to be tied Colon-cancer cell, K562 cell are human chronic polymorpho nuclear leukemia cells, and KG1 cell is people's acute myeloid leukemia cell, MDA- MB-231 is human breast cancer cell, and MOLT-4 is people's acute lymphoblastic leukemia cell, and PC-3 cell is human prostata cancer Cell and HUVEC cell Human umbilical vein endothelial cells.
Three, the application of the bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure
The present invention also provides based on pazopanib structure HDAC and the bis- target spot inhibitor compounds of VEGFR preparation prevent Or the application in treatment and tumor-related illness drug.
The tumor-related illness includes all kinds of blood tumors and all kinds of solid tumors.
All kinds of blood tumors include: each quasi-leukemia, myelosis tumor.For example serious urgency of various types of leukaemia Property lymphocytic leukemia, acute myeloid leukaemia, acute megakaryocytic leukemia etc..Myelosis tumor includes that chronic Myelogenous is white Blood disease, polycythemia vera, primary thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic acidophilus Property granulocytic leukemia, systemic mastocytosis and other non-classified myelosis tumors.
The solid tumor include: various forms of nasopharyngeal carcinoma, clear-cell carcinoma, soft tissue sarcoma, thyroid papillary carcinoma, Thymoma, liver cancer, breast cancer, melanoma, prostate cancer, retinoblastoma etc..
It is a kind of prevention or treatment with tumor-related illness pharmaceutical composition, comprising it is of the present invention be based on pazopanib knot The bis- target spot inhibitor of the HDAC and VEGFR of structure or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers Or excipient.
Detailed description of the invention
Western Blot experimental result of Fig. 1 compound 6d and 13f after HeLa cell handles 4h；
Fig. 2 compound 6d and 13f inhibit HUVECs segment dislocation experimental result；
Fig. 3 compound 6d and 13f inhibit rat chest aorta ring at blood vessel experimental result；
Fig. 4 nude mouse tumor photo；
Fig. 5 various dose compound 6d and 13f inhibition rate of tumor growth.
Specific embodiment
Below with reference to example, the present invention is described further, but not limited to this.
Embodiment 1: the synthesis of compound 6a-6c, by taking 6a as an example.
(1) preparation of N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -6- amino -2H- indazole (2)
2,3- dimethyl -6- amino -2H- indazole 5.00g, 2,4- dichloro pyrimidine 13.9g and sodium bicarbonate 10.4g is molten In 100mL dehydrated alcohol, 79 DEG C are heated to, flows back after 4h, cools down to room temperature, is filtered, filter cake is sufficiently washed with ethyl acetate It washs, collects filtrate, be concentrated under reduced pressure, remove solvent, pale solid is obtained by filtration after being sufficiently beaten with ethyl acetate, with methanol weight 7.64g product 2 is obtained after crystallization, is 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)
Previous step product 2 1.00g and cesium carbonate 2.40g are added in 50mL n,N-Dimethylformamide, 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 ice water, is precipitated immediately big Measure faint yellow solid, filtering, after drying, obtain 1.06g product 3 with re-crystallizing in ethyl acetate, be 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- base) (methyl) amino) pyrimidine -2-base) amino) benzoic acid The preparation of (4a)
It disperses intermediate 3 0.50g and p-aminobenzoic acid 0.36g in 30mL isopropanol, 2 drop concentrated hydrochloric acids is added, add To 85 DEG C, back flow reaction 4h is cooled to room temperature heat, and filtering washs filter cake with isopropanol and ethyl acetate, is 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- base) (methyl) amino) pyrimidine -2-base) amino) benzene first The preparation of acid esters (5a)
4a 0.50g is added in 50mL anhydrous methanol, 0.60g thionyl chloride is then added dropwise at 0 DEG C, finishes, It after keeping the temperature 30min, is heated to flowing back after removing ice bath, after reacting 5h, solvent under reduced pressure be steamed, crude product recrystallisation from isopropanol 0.50g product 5a is obtained, is 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- base) (methyl) amino) pyrimidine -2-base) amino)-N- hydroxyl The preparation of benzamide (6a)
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 5a 0.20g is dissolved in 30mL azanol potassium solution, and after 2h is stirred at room temperature, it is most of molten that removing is concentrated under reduced pressure Agent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 80.6mg product 6a, is 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 The synthesis of object 6d-6e, by taking 6d as an example
(1) N- (2- aminophenyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2- Base) amino) benzamide (6d) preparation
Intermediate 4a 0.50g is added in the anhydrous n,N-Dimethylformamide of 50mL, under ice bath, O- benzo three is added After activating 30min, adjacent benzene is then added in nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.49g and triethylamine 0.26g Diamines 0.17g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and n,N-Dimethylformamide is removed in washing, Ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry, and solvent is removed under reduced pressure, residual Slag methylene chloride: methanol=30:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 0.40g product 6d, solid 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: the synthesis of compound 10a-10b, by taking 10a as an example
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino)-N- methoxy The preparation of base-N-methyl-benzamide (7a)
Intermediate 4a 1.00g is added in anhydrous n,N-Dimethylformamide, under ice bath, O- benzotriazole-is added Then N, O- dimethyl is added after activating 30min in N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g Hydroxylamine hydrochloride 0.30g and triethylamine 0.31g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and washing is removed N,N-Dimethylformamide, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry Dry, solvent is removed under reduced pressure, residue methylene chloride: methanol=35:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 0.78g product 7a is 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- base) (methyl) amino) pyrimidine -2-base) amino) benzaldehyde The preparation of (8a)
Compound 7a 1.00g is dissolved in 50mL anhydrous tetrahydro furan, and is cooled to -40 DEG C in low-temp reaction instrument.To It is slowly added to tetrahydrochysene lithium aluminium 0.26g in batches, this thermotonus 2h is maintained slowly carefully to be quenched after reaction with ice water Reaction is to there is no bubble generations.Reaction solution is diluted with water, and is extracted with ethyl acetate, and merges organic layer, and saturation NaCl solution is washed It washs, anhydrous magnesium sulfate is dry, solvent is concentrated under reduced pressure, residue methylene chloride: methanol=40:1 volume ratio eluant, eluent carries out column 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- base) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl) acrylate (9a) preparation
Phosphonoacetate 0.32g is added into 50mL anhydrous tetrahydro furan, is cooled to -5-0 DEG C, is slowly added to NaH0.16g is finished, and stirs 20min, and the tetrahydrofuran solution of 8a 0.52g is then added dropwise, and room temperature reaction is stayed overnight, end of reaction Afterwards, 10% ammonium chloride solution of 50mL is added, stirs stratification after 30min, after organic phase is dry, filtering is concentrated to get thick Product.Residue methylene chloride: methanol=40:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 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- base) (methyl) amino) pyrimidine -2-base) ammonia Base) phenyl)-N- hydroxyacrylamide (10a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 9a 0.50g is dissolved in 30mL azanol potassium solution, and after 2h is stirred at room temperature, it is most of molten that removing is concentrated under reduced pressure Agent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 0.29g product 10a, is 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: the synthesis of compound 13a-13i, by taking 13a as an example
(1) methyl (4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycinate (11a) preparation
Intermediate 4a 1.00g is added in the anhydrous n,N-Dimethylformamide of 100mL, under ice bath, O- benzo three is added Then sweet ammonia is added after activating 30min in nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid 0.98g and triethylamine 0.52g Acid methyl ester hydrochloride salt 0.39g, overnight, ethyl acetate dilution is added in reaction after the reaction was completed at room temperature, and N, N- diformazan are removed in washing Base formamide, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, and anhydrous magnesium sulfate is dry, and decompression removes Remove solvent, residue methylene chloride: methanol=30:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains 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- base) (methyl) amino) pyrimidine -2-base) amino)-N- (2- (azanol) -2- oxoethyl) benzamide (13a) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 11a (0.50g, 1.09mmol) is dissolved in 30mL azanol potassium solution, 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, and white solid, filtering is precipitated, and dry cake is produced Object 13a, for white solid (0.31g, yield 61%), Mp:216-218 DEG C of1H 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: the synthesis of compound 14a-14g, by taking 14a as an example
(1) 4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzoyl Base) glycine (12a) preparation
11a (1.00g, 2.18mmol) is added in 30mL methanol, 5mL 3M NaOH solution is then added, at room temperature 4h is stirred, after reaction, decompression boils off most of methanol, and residue adjusts pH to 5-6 with 1M HCl solution.Filtering, filter cake It is washed with ice water, obtains product 12a after dry, be that (yield: 84%) 0.81g, Mp: > 250 DEG C, directly casts one to white solid 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- aminophenyl) amino) -2- oxoethyl) -4- ((4- ((2,3- dimethyl -2H- indazole -6- Base) (methyl) amino) pyrimidine -2-base) amino) benzamide (14a) preparation
Intermediate 12a (1g, 2.24mmol) is added in anhydrous n,N-Dimethylformamide, under ice bath, O- benzene is added 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) then is added, reaction overnight, has been reacted at room temperature Diluted at rear addition ethyl acetate, n,N-Dimethylformamide is removed in washing, ethyl acetate layer saturated sodium bicarbonate solution and It is saturated NaCl solution washing, anhydrous magnesium sulfate is dry, solvent is removed under reduced pressure, residue methylene chloride: methanol=30:1 volume ratio Eluant, eluent carry out column chromatographic purifying and obtain product 14a, faint yellow solid (0.47g, yield 39%), Mp:178-180 DEG C .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: the synthesis of compound 19a-19g, 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 reflux, overnight, after reaction, evaporating solvent under reduced pressure obtains 1.62g product 16f with re-crystallizing in ethyl acetate for reaction, for Huang Color solid, yield: 80%；ESI-MS m/z:282.3[M+H]+。
(2) preparation of methyl 7- (4- amino-benzene oxygen) heptanoate (17f)
Intermediate 16f 1.00g is added in 50mL methanol, 10%Pd/C 0.1g is added, is passed through hydrogen under atmospheric agitation Gas, overnight in room temperature reaction, filtering, filter residue are washed with methanol, merging filtrate and washing lotion, evaporating solvent under reduced pressure, obtain 0.79g production Object 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- base) (methyl) amino) pyrimidine -2-base) amino) Phenoxy group)-heptanoate (18f) preparation
By 3 0.5g of intermediate, intermediate 17f 0.52g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanol at room temperature In, it is warming up to reflux, reaction is overnight.After reaction, evaporating solvent under reduced pressure, residue methylene chloride: methanol=40:1 volume The eluant, eluent of ratio carries out column chromatographic 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- base) (methyl) amino) pyrimidine -2-base) amino) benzene oxygen Base)-N- hydroxyl heptamide (19f) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 18f 0.30g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 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: the synthesis of compound 23a-23g, by taking compound 23f as an example
(1)N4(2,3- dimethyl -2H- indazole -6- base)-N4Methyl-N2(4- nitrobenzophenone) pyrimidine -2,4- diamines (20) preparation
3 1.00g of intermediate, paranitroanilinum 0.58g and 0.5mL concentrated hydrochloric acid are added in 70mL isopropanol, heated up To reflux, reaction overnight, after reaction, is cooled to room temperature, and is filtered, and filter cake is washed with a small amount of isopropanol, and dry cake obtains 1.08g product 20 is 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- aminophenyl)-N4(2,3- dimethyl -2H- indazole -6- base)-N4Methylpyrimidine -2,4- diamines (21) preparation
20 1.00g of intermediate is suspended in 70mL methanol, 10%Pd/C 0.1g is added, is passed through hydrogen under atmospheric agitation Gas, overnight, after reaction, evaporating solvent under reduced pressure, residue with ethyl acetate is recrystallized to give 0.78g product 21 for room temperature reaction, 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- base) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino) -8- oxo monooctyl ester (22f) preparation
Suberic acid mono-methyl 0.33g is added in the anhydrous n,N-Dimethylformamide of 50mL, O- benzo is 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, 21 0.76g of intermediate is added, removes ice bath, overnight, ethyl acetate dilution, water is added in room temperature reaction after the reaction was completed Remove n,N-Dimethylformamide, ethyl acetate layer saturated sodium bicarbonate solution and saturation NaCl solution are washed, anhydrous sulphur Sour magnesium is dry, and evaporating solvent under reduced pressure, residue methylene chloride: methanol=30:1 volume ratio eluant, eluent carries out column chromatographic purifying and obtains It is white solid, yield: 40% to 0.37g product 22f；ESI-MS m/z:530.5[M+H]+。
(4)N1(4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (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 respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 22f 0.20g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 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: the synthesis of compound 28a-28g, by taking compound 28e as an example
(1) preparation of methyl 6- ((4- nitrobenzophenone) amino) ester (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, is cooled to room temperature, reaction solution is poured into ice water, is analysed Yellow solid out filters, and drying, residue petroleum ether: ethyl acetate=4:1 volume ratio eluant, eluent carries out column and chromatographs to obtain 1.32g product 25e is faint yellow solid, yield: 70%；ESI-MS m/z:267.3[M+H]+。
(2) preparation of methyl 6- ((4- aminophenyl) amino) ester (26e)
Intermediate 25e 1.00g is suspended in 70mL methanol, 10%Pd/C 0.1g is added, is passed through hydrogen under atmospheric agitation Gas, overnight, after reaction, evaporating solvent under reduced pressure, residue with ethyl acetate is recrystallized to give 0.71g product 26e for room temperature reaction, For brown solid, yield: 80%；ESI-MS m/z:237.4[M+H]+。
(3) methyl 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) Phenyl) amino)-own ester (27e) preparation
By 3 0.5g of intermediate, intermediate 26e 0.49g and 0.5mL concentrated hydrochloric acid is added to 50mL isopropanol at room temperature In, it is warming up to reflux, reaction is overnight.After reaction, evaporating solvent under reduced pressure, residue methylene chloride: methanol=40:1 volume The eluant, eluent of ratio carries out column chromatographic purifying and obtains product 27e, is 0.55g faint yellow solid, yield: 65%；ESI-MS m/z: 488.6[M+H]+。
(4) 6- ((4- ((4- ((2,3- dimethyl -2H- indazole -6- base) (methyl) amino) pyrimidine -2-base) amino) benzene Base) amino)-N- hydroxyl amide (28e) preparation
KOH 28.0g and hydroxylamine hydrochloride 23.53g are dissolved in respectively in 70mL and 120mL anhydrous methanol, obtain solution A and molten Liquid B.Under ice bath, solution A is added dropwise in solution B, after stirring 2h, filters out precipitating, obtained filtrate is azanol potassium Methanol solution.Compound 27e 0.20g is dissolved in 30mL azanol potassium solution, after 2h is stirred at room temperature, is concentrated under reduced pressure and is removed major part Solvent, residual residue adjust pH to 5-6 with 1M HCl, and white solid, filtering is precipitated, and dry cake obtains 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
HeLa nuclear extract that we have used convenience to be easy to get first (mainly containing HDAC1 and HDAC2) as HDAC enzyme source, The external HDACs inhibitory activity of target compound is determined.
The external HDAC inhibitory activity of 1 compound of table
Experiment conclusion: majority of compounds has certain inhibiting effect to HDACs, in hydroxamic acid compound 13e and The activity of 13f is best, hence it is evident that is better than positive control drug SAHA.The activity of 6d and 14e preferably, is lived in o-phenylenediamine class compound Property is suitable with positive control drug MS275.
Embodiment 10: the external HDAC subtype-selective experiment of representative compound
The external HDAC subtype-selective of 2 representative compound of table
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 the inhibitory activity of HDAC6.O-phenylenediamine class representative compound 6d and 14g is similar with positive control drug MS275, is Class I selectivity hdac inhibitor.
Embodiment 11: the external VEGFR-2 inhibitory activity measurement experiment of compound
All target compounds are determined first under 0.2 μM of concentration to the percent inhibition of VEGFR-2, 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 3 compound of table
aUndetermined
Experiment conclusion: majority of compounds 200nM show stronger VEGFR-2 inhibitory activity (inhibiting rate > 90%) it is comparable external that, representative compound 10a, 13f, 6d and 14g show positive control drug Pazapanib VEGFR-2 inhibitory activity.
Embodiment 12: the immunoblot experiment of representative compound
In order to further study compound in the cell to the inhibiting effect of HDAC, it is real that We conducted Western Blot 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 the level of acetylated histones H4 (Ac-HH4) at 1 μM, activity with MS275 is suitable, but compound 6d cannot increase the level of acetylation tubulin (Ac-tubulin), shows that compound 6d is one A Class I HDAC selective depressant.Compound 13f can significantly improve acetylation tubulin (Ac- in 100nM Tubulin level), activity are better than TubA and SAHA；13f can also improve the water of acetylated histones H4 (Ac-HH4) simultaneously It is flat, show that compound 13f is wide spectrum hdac inhibitor.
Embodiment 13: the extracorporeal anti-tumor cell-proliferation activity experiment of representative compound
We use the extracorporeal anti-tumor cell-proliferation activity that more commonly used MTT method determines test-compound.
The extracorporeal anti-tumor cell-proliferation activity of 4 representative compound of table
aUndetermined
Experiment conclusion: most compound shows certain anti-increasing to a variety of blood tumors and solid tumor cell system Effect is grown, wherein compound 10a and 13f activity is optimal in hydroxamic acid compound, shows and positive control drug SAHA Comparable 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 comparable anti-tumour cell proliferative activity of medicine MS275.
14 representative compound of embodiment inhibits Human umbilical vein endothelial cells to test at lumen of vessels
We have selected representative compound 6d and 13f, determine compound under 1 μM of concentration to HUVECs segment dislocation 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 Comparable external anti-HUVECs is at lumen of vessels activity.
The rat chest aorta of 15 representative compound of embodiment is at vascular study activity experiment
Our further progresss rat chest aorta tests the external anti-angiogenic life of further assessment compound at blood vessel It is Viability, influence of the representative compound 6d and 13f under 5 μM of concentration to rat chest aorta at blood vessel 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.
The internal anti-tumor activity of 16 representative compound of embodiment is tested
Based on compound 6d and 13f extracorporeal anti-tumor cell-proliferation activity excellent in HT-29 cell line, we are established Nude mice by subcutaneous HT-29 lotus knurl model, uses SAHA and Pazopanib as positive control.Compound 6d and 13f are with 50mg/ Two dosages of kg/day and 100mg/kg/day, SAHA is with 100mg/kg/day and Pazopanib with 50mg/ Kg/day oral administration.Putting to death animal after administration 21 days terminates to test, and the tumour for calculating test-compound and positive control drug is raw Long inhibiting rate (TGI) assesses the antitumor activity of compound in terms of volume and weight two of tumor.Experimental result referring to, figure 4, Fig. 5.
Experiment conclusion: compound 6d and 13f show anti-cancer activity in vivo, and wherein 6d activity is preferable.In 100mg/kg/ When day dosage, 6d activity be better than listing hdac inhibitor class drug SAHA, in 50mg/kg/day dosage, 6d activity with it is upper VEGFR inhibitor class drug pazopanib in city is suitable, has very high follow-up study Development volue.

Claims (9)

1. the bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure, pharmaceutically acceptable salt, feature exist In with structure shown in following general formula I, II or III:
Wherein
X is
N is 0~9；
Y is
2. the bis- target spot inhibitor of HDAC and VEGFR as described in claim 1 based on pazopanib structure, which is characterized in that
X is in the contraposition or meta position of phenyl ring in Y and II in general formula I；
X is
N is 0-7；
Y is
3. the bis- target spot inhibitor of HDAC and VEGFR as claimed in claim 1 or 2 based on pazopanib structure, feature exist In compound is one of following:
4. the preparation method of the bis- target spot inhibitor of HDAC and VEGFR as described in claim 1 based on pazopanib structure, is One of following method:
(1) with 2,3- dimethyl -6- amino -2H- indazole be starting material, under sodium bicarbonate alkaline condition with 2,4- dichloro Pyrimidine occurs nucleophilic substitution and obtains intermediate 2, and intermediate 2 obtains intermediate with iodomethane reaction under cesium carbonate catalysis 3, intermediate 3 occurs nucleophilic substitution from different substituted aniline under concentrated hydrochloric acid catalysis and obtains intermediate 4a-4c, intermediate 4a-4c protects to obtain intermediate 5a-5c through methyl esters, and intermediate 5a-5c obtains final product 6a-6c through the ammonolysis reaction of ester；Furthermore Intermediate 4a-4b and o-phenylenediamine obtain final product 6d-6e through amide condensed；
Reaction equation is as follows:
The phenyl ring of wherein 4a, 5a, 6a, 6d are that contraposition replaces, 4b, 5b, and the phenyl ring of 6b, 6e are that meta position replaces；
Reagent and condition in above-mentioned reaction equation: (a) 2,4- dichloro pyrimidine, sodium bicarbonate, dehydrated alcohol, reflux, 4h；(b) carbon Sour caesium, iodomethane, n,N-Dimethylformamide, room temperature, 2h；(c) isopropanol, concentrated hydrochloric acid, reflux, 4h；(d) three nitrogen of O- benzo Azoles-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, triethylamine, o-phenylenediamine, n,N-Dimethylformamide, 0 DEG C-room temperature, overnight (e) anhydrous methanol, thionyl chloride flow back, overnight；(f) hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2h；
The different aniline replaced are as follows: p-aminobenzoic acid, gavaculine or 5- amino-2-methyl benzoic acid；
(2) using intermediate 4a-4b as starting material, with N, the generation of O- dimethyl hydroxylamine hydrochloride is amide condensed to obtain intermediate 7a- 7b, intermediate 7a-7b are reduced to aldehyde intermediate 8a-8b through tetrahydrochysene lithium aluminium, and intermediate 8a-8b and phosphonoacetate occur Huo Naer-Wordsworth-Ai Mengsi reaction response obtains intermediate 9a-9b, and intermediate 9a-9b obtains whole production through the ammonolysis of ester Object 10a-10b；
Reaction equation is as follows:
The phenyl ring of wherein 4a, 7a, 8a, 9a, 10a are that contraposition replaces, 4b, 7b, 8b, 9b, and the phenyl ring of 10b is meta position substitution；
Reagent and condition in above-mentioned reaction equation: (a) N, O- dimethyl hydroxylamine hydrochloride, O- benzotriazole-N, N, N ', N '-four Methylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, room temperature, overnight；(b) tetrahydrochysene lithium aluminium, tetrahydrofuran, -20 DEG C, 4h；(c) phosphonoacetate, sodium hydride, tetrahydrofuran, 0 DEG C-room temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, nothing Water methanol, room temperature, 2h；
(3) using intermediate 4a-4c as starting material, the amino-alkane methyl esters of intermediate 4a-4c and different chain length is through amide condensed Reaction obtains intermediate 11a-11i, and intermediate 11a-11i obtains final product 13a-13i through the ammonolysis reaction of ester；Intermediate 11a- 11h is hydrolyzed to intermediate 12a-12g under the conditions of Sodium Hydroxide Alkaline, and intermediate 12a-12g and o-phenylenediamine are through amide condensed Reaction obtains final product 14a-14g；
Reaction equation is as follows:
The phenyl ring of wherein 4a, 11a-11g, 12a-12g, 13a-13g, 14a-14g are that contraposition replaces, and the phenyl ring of 4b, 11h, 13h are Meta position replaces, and n is 1~7；
Reagent and condition in above-mentioned reaction equation: (a) the amino-alkane methyl esters of different chain length, O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, 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- benzotriazole-N, N, N ', N '-four Methylurea tetrafluoro boric acid, triethylamine, n,N-Dimethylformamide, room temperature, overnight；
The amino-alkane methyl esters of the different chain length is: glycine methyl ester, 3- aminopropanoate, 4-Aminobutanoicacid methyl esters, 5- aminopentanoic acid methyl ester, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acid methyl esters or 8- aminocaprylic acid methyl esters；
(4) using p-nitrophenol as starting material, nucleophilic substitution occurs with the bromine alkanoic acid methyl esters of different chain length and obtains centre Body 16a-16g, intermediate 16a-16g restore to obtain intermediate 17a-17g through Pd/C, and intermediate 17a-17g and 3 generation nucleophilics are anti- Intermediate 18a-18g should be obtained, intermediate 18a-18g obtains final product 19a-19g through the ammonolysis reaction of ester；
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 the different chain length is: 2- methyl bromoacetate, 3- methyl bromide c, 4- bromo butyric acid methyl ester, 5- bromine Methyl valerate, 6- bromocaproic acid methyl esters, 7- bromine methyl heptanoate or 8- bromine methyl caprylate；
(5) it is starting material with intermediate 3, nucleophilic substitution occurs with paranitroanilinum and obtains intermediate 20, intermediate 20 It is reduced to intermediate 21 through Pd/C, the docosandioic acid mono-methyl generation of intermediate 21 and different chain length is amide condensed to obtain intermediate The ammonolysis reaction that ester occurs for 22a-22g, intermediate 22a-22g obtains final product 23a-23g；
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- benzotriazole-N, N, N ', N '-tetramethylurea four Fluoboric acid, triethylamine, N ' dinethylformamide, room temperature, overnight；(d) hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2h；
The docosandioic acid mono-methyl of the 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 starting material, occur during nucleophilic substitution obtains with the aminoalkyl methyl esters of different chain length Mesosome 25a-25g, intermediate 25a-25g restore to obtain intermediate 26a-26g through Pd/C, and intermediate 26a-26g and intermediate 3 are sent out Raw nucleophilic substitution obtains intermediate 27a-27g, and intermediate 27a-27g obtains intermediate 28a-28g through the ammonolysis reaction of ester；
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 formyl 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, anhydrous methanol, room temperature, 2h；
The amino-alkane methyl esters of the different chain length is: glycine methyl ester, 3- aminopropanoate, 4-Aminobutanoicacid methyl esters, 5- aminopentanoic acid methyl ester, 6-aminocaprolc acid methyl esters, 7- aminoheptylic acid methyl esters or 8- aminocaprylic acid methyl esters.
5. compound as claimed in claim 1,2 or 3 prevents or treats answering in the drug with tumor-related illness in preparation With.
6. application as claimed in claim 5, which is characterized in that described and tumor-related illness are as follows: various blood tumors are each Kind solid tumor.
7. application as claimed in claim 6, which is characterized in that all kinds of blood tumors are as follows: each quasi-leukemia, myelosis Tumor；Each quasi-leukemia are as follows: serious acute lymphoblastic leukemia, acute myeloid leukaemia, acute megakaryoblastic are white Blood disease；The myelosis tumor are as follows: chronic myelogenous leukemia, polycythemia vera, primary thrombocytosis, bone Marrow fibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and other not The myelosis tumor of classification.
8. application as claimed in claim 6, which is characterized in that the solid tumor are as follows: 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' tumor.
9. it is a kind of suitable for pharmaceutical composition administered orally or parenterally, it include compound described in claim 1,2 or 3 and one Kind or a variety of pharmaceutically acceptable carriers or excipient.
CN201710677980.2A 2017-08-10 2017-08-10 Bis- target spot inhibitor of HDAC and VEGFR based on pazopanib structure and its preparation method and application Expired - Fee Related CN107619407B (en)

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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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