CN104817553B - The pyrimidinediamine class compound and its derivative and its medical usage of a kind of aromatic radical-heterocyclic substituted - Google Patents
The pyrimidinediamine class compound and its derivative and its medical usage of a kind of aromatic radical-heterocyclic substituted Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of pyrimidinediamine micromolecular organic compound of a kind of novel aromatic base-heterocyclic substituted indicated by structure formula (I) and the like or its pharmaceutically acceptable salts, and the pharmaceutical composition containing such compound, and its application that is used to prepare in the drug for the relevant disease for treating various malignant tumours and metastases.
Description
Technical field
The present invention relates to pyrimidinediamine class compound of a kind of novel aromatic base-heterocyclic substituted and the like, synthesis sides
Method and its medical usage.Such compound or the use of pharmaceutical composition in the preparation of antitumor drugs containing such compound
On the way, various malignant tumours are used for, the treatment of the relevant diseases such as all kinds of metastases and recurrence is included.The invention further relates to such changes
Close the preparation method of object.
Technical background
Disubstituted diaminopyrimidine compounds play an important role in the treatment of tumour.Listing in 2006 reaches sand
The chronic myelocytic leukemia of imatinib-resistant is treated by targeting BCR-Abl fusion proteins for Buddhist nun (Dasatinib)；2009
The pazopanib (Pazopanib) of year listing, which passes through, targets VEGFR treatment advanced renal cell carcinomas；The Ceritinib of listing in 2014
(Ceritinib) gram azoles is treated for the drug resistant non-small cell lung cancer of Buddhist nun by targeting EML4-ALK fusion proteins；It obtains within 2014
The CO-1686 that FDA breaks through sex therapy qualification is drug resistant non-small thin by targeting EGFR T790M treatment Gefitinibs and Erlotinib
Born of the same parents' lung cancer, these small-molecule drugs are all containing the dominance structure in di-amino-pyrimidine this pharmaceutical chemistry meaning.
It finds that these small molecules mainly play antitumor action by targeting tyrosine kinases by analysis, and passes through
Literature search is it has also been found that more and more clinical tyrosine kinase inhibitors for neutralizing preclinical study all contain di-amino-pyrimidine
This dominance structure.For example, NVP-BGJ398 is used for the tumour that medical needle expands FGFR by targeting FGFR
(NCT02160041)；AZD1480 is used for treating advanced solid tumor (NCT01219543), PF-00562271 by targeting JAK
It is used for treating cancer of pancreas, head and neck cancer and prostate cancer (NCT00666926) by targeting FAK；R460 is used for by targeting Syk
Treat chronic lymphocytic leukemia (Quiroga MP, et al.Blood, 2009,114 (5), 1029-1037).Certainly also have
More be in preclinical diaminopyrimidine compounds by target tyrosine kinases be used for treating the generation of tumour, development,
Transfer, recurrence and drug resistance.
Diaminopyrimidine derivatives serve not only as tyrosine kinase inhibitor obtain in the preparation of antitumor drugs it is great at
Work(, and more and more diaminopyrimidine derivatives are also targeting preparation research of other target spots for new type antineoplastic medicine
In have made great progress.For example, BKM120 is used for treating metastatic or Locally advanced cervical carcinoma by targeting PI3K
(NCT01613677)；BX-912 can significantly inhibit the growth of kinds of tumor cells and apoptosis-induced by targeting PDK-1
(Feldman RI,et al.J Biol Chem.2005,280(20),19867-19874)；NSC23766 is by targeting Rac energy
The proliferation and Anchorage Independent for enough inhibiting lung carcinoma cell PC-9 cells grow (Gao Y, et al.Proc Natl Acad Sci
U S A,2004,101(20), 7618-7623)；Aurora A Inhibitor I effectively inhibit colon by targeting Aurora
Cancer cell HCT116 cell Proliferations (Aliagas-Martin I, et al.J Med Chem, 2009,52 (10), 3300-
3307)。
, it was also found that aromatic radical thiazole compound and the like also has in the research of this part application researcher early period
There are good antitumor activity, the present invention creatively to be designed and synthesized a kind of new by combining two-part dominance structure
The diaminopyrimidines and the like of type aromatic radical-heterocyclic substituted pass through this that compound structure is transformed
The more special disubstituted pyrimidinediamine class compound of class formation, it is excellent that bioassay results also indicate that such compound has
Antitumor activity, including all there is excellent neoplasm growth activity in vivo and in vitro, while there is excellent antitumor cell to move
Move activity.In addition, such compound also has good physicochemical property, these can increase in the improvement of drug effect and physicochemical property
Add the druggability of such compound.Compared with inhibiting normal cell activity, the compounds of this invention to inhibiting tumour cells activity more
Add specifically, this novel chemical constitution is expected to develop into the drug candidate of a kind of oncotherapy in the future.
Invention content
The purpose of the present invention is to provide the pyrimidinediamine class compounds and associated class of a kind of novel aromatic base-heterocyclic substituted
Antitumor candidate compound is can be used as like object, including salt and ester etc. can be used in it.
Another object of the present invention is to provide the pyrimidinediamine class compound of such aromatic radical-heterocyclic substituted and associated class
Pharmaceutical composition like object and pharmaceutically acceptable salt or containing above compound is preparing the various malignant tumours for the treatment of, especially
Be lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma, carcinoma of urinary bladder, kidney with
And the application in the drug in the diseases such as carcinoma of mouth and relevant cancer metastasis and relapsing course.
The present invention also provides the pyrimidinamine compounds or pharmaceutically acceptable salt of a kind of substitution of aromatic radical thiazole, under
State the expression of structure formula (I)：
Wherein：
X is CH or N；
Y is O or S；
R1And R2One in following groups：Hydrogen, C1-C5Alkyl, phenyl, benzyl or furfuryl；In addition, R1With
R2It is asynchronously hydrogen；
R3One in following groups：Hydrogen, benzyloxy, benzene ethyoxyl, phenylpropyl alcohol oxygroup, halogen or benzyl amino；
R4For hydrogen or methyl.
The present invention also provides a kind of pyrimidinamine compound or pharmaceutically acceptable salts, are the pyrimidinamine compounds
The acid-addition salts formed with acid；Wherein, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, lemon
Acid, methanesulfonic acid, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, maleic acid or succinic acid.
The present invention also provides the pyrimidinamine compounds or pharmaceutically acceptable salt of a kind of substitution of aromatic radical thiazole, are institutes
Pyrimidinamine compound is stated to be combined to form marker with radioactive group, fluorophor or biotin.
The present invention provides pyrimidinamine compound or pharmaceutically acceptable salt, including：
N2Isobutyl group-N4((2- (3- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (2- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((4- methyl -2- (4- (benzene ethyoxyl) phenyl) -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- (benzyl amino) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- (3- phenylpropyl alcohols oxygroup) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- fluorophenyls) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (2- chlorphenyls) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- chlorphenyls) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2,N2Dipropyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2,N2Diethyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2((2- furyls) methyl)-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl) -2,4- pyrimidinediamines,
N2Normal-butyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2N-pentyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2Benzyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2Phenyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl -5- oxazolyls) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((5- (4- (benzyloxy) phenyl) -2- furyls) methyl) -2,4- pyrimidinediamines,
N2Normal-butyl-N4((5- (4- (benzyloxy) phenyl) -2- furyls) methyl) -2,4- pyrimidinediamines,
N2Isobutyl group-N4((5- (4- (benzyloxy) phenyl) -2- thienyls) methyl) -2,4- pyrimidinediamines and
N2Normal-butyl-N4((5- (4- (benzyloxy) phenyl) -2- thienyls) methyl) -2,4- pyrimidinediamines.
The present invention provides a kind of pharmaceutical composition, wherein containing pyrimidinediamine class compound of the present invention and associated class
Like object or pharmaceutically acceptable salt and pharmaceutically acceptable carrier.Pharmaceutical composition of the present invention is formulated into can
Injecting fluid, aerosol, emulsifiable paste, gelling agent, pill, capsule, syrup, transdermal patch or excipient.
The present invention also provides the pyrimidinamine compounds and related analogs object or pharmaceutically acceptable salt to make
Application in standby antitumor drug.The present invention propose the pyrimidinamine compound, its hydrate or its can pharmaceutically connect
The salt received is inhibiting applying for tumor cell proliferation, growth, migration and infiltration；Wherein, the tumour cell include lung carcinoma cell,
Breast cancer cell, colon cancer cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, pancreatic cancer cell, leukaemia cell,
Ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity.
It is pernicious in preparation treatment that the invention also provides the pyrimidinamine compound or its pharmaceutically acceptable salts
Application in the drug of tumour；Wherein, the malignant tumour includes lung carcinoma cell, breast cancer cell, colon cancer cell, prostate
Cancer cell, liver cancer cells, skin cancer cell, pancreatic cancer cell, leukaemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney are thin
Born of the same parents and cancer cell of oral cavity.
The invention also provides the pyrimidinamine compounds or its hydrate or pharmaceutically acceptable salt to prepare
Treat the application in Malignant tumor of bonal metastasis and the drug of recurrence；Wherein, the malignant tumour includes that lung carcinoma cell, breast cancer are thin
Born of the same parents, colon cancer cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, pancreatic cancer cell, leukaemia cell, oophoroma are thin
Born of the same parents, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity.
In the present invention, pyrimidinamine compound or its pharmaceutically acceptable salt can be used alone or join with other drugs
It closes and uses.
Description of the drawings
It is thin to variety classes breast cancer cell or normal breast epithelial under various concentration that Fig. 1 show the compounds of this invention
The design sketch of born of the same parents' Proliferation Ability.
Fig. 2 inhibits Colon Cancer Cells effect statistical chart, wherein Fig. 2 (a) with showing the compounds of this invention concentration dependent
It is the effect statistical chart that the compounds of this invention inhibits HT29 to inhibit the effect statistical chart of HCT116, Fig. 2 (b) for the compounds of this invention.
Fig. 3 inhibits proliferation of lung cancer cells effect statistical chart, wherein Fig. 3 with showing the compounds of this invention concentration dependent
(a) the effect statistical chart for being the compounds of this invention inhibition A549, Fig. 3 (b) are the effect statistical chart that the compounds of this invention inhibits PC-9.
Fig. 4 show the compounds of this invention and taxol under various concentration to people source or mouse source breast cancer cell and
Normal mammary epithelial Inhibit proliferaton inhibition statistical chart.Wherein Fig. 4 (a) is that the compounds of this invention and taxol inhibit people
The breast cancer cell MDA-MB-231 cultivation effect statistical charts in source, Fig. 4 (b) are that the compounds of this invention and taxol inhibit people source
Breast cancer cell MCF7 cultivation effect statistical chart, Fig. 4 (c) are the breast cancer cell that the compounds of this invention and taxol inhibit category source
4T1 cultivation effect statistical charts, Fig. 4 (d) are the effect that chemical combination of the present invention and taxol object inhibit normal mammary epithelial MCF10A
Fruit statistical chart.
Fig. 5 show the compounds of this invention under various concentration to human breast cancer cell (MCF7 and T47D) and mouse source mammary gland
The design sketch that cancer cell (4T1) clonality influences.
Fig. 6 show the compounds of this invention to people source breast cancer cell (MDA-MB-231) and mouse source breast cancer cell 4T1
The influence diagram of lateral transfer inhibiting rate.Wherein, Fig. 6 (a) is the compounds of this invention to people source breast cancer cell MDA-MB-231's
Migration effect aspect graph, Fig. 6 (b) are to be moved to people source breast cancer cell MDA-MB-231 under the compounds of this invention various concentration
Move effect statistical chart.Fig. 6 (c) is the compounds of this invention to the migration effect aspect graph of mouse source breast cancer cell 4T1, Fig. 6 (d)
For under the compounds of this invention various concentration to the migration effect statistical chart of mouse source breast cancer cell 4T1, with control group (drug concentration
When being zero) migrating cell number be 100%, remaining each group compared with the control group, determines its relative mobility.
Fig. 7 show the compounds of this invention to people source breast cancer cell (MDA-MB-231) and mouse source breast cancer cell 4T1
Invade the influence diagram of inhibiting rate.Wherein, Fig. 7 (a) is invasion of the compounds of this invention to people source breast cancer cell MDA-MB-231
Effect aspect graph, Fig. 7 (b) are the invasion effect to people source breast cancer cell MDA-MB-231 under the compounds of this invention various concentration
Statistical chart.Fig. 7 (c) is invasion effect aspect graph of the compounds of this invention to mouse source breast cancer cell 4T1, and Fig. 7 (d) is this hair
To the invasion effect statistical chart of mouse source breast cancer cell 4T1 under bright compound various concentration, with control group (drug concentration zero
When) invasion cell number is 100%, remaining each group compared with the control group, determines its with respect to invasion rates.
Fig. 8 show the growth result figure that the compounds of this invention inhibits 4T1 in situ tumors.Wherein, Fig. 8 (a) is the present invention
It is to give the compounds of this invention difference that compound, which inhibits the mouse entity tumor size situation removed after growth of breast cancers, Fig. 8 (b),
Mouse tumor volume change statistical results chart after number of days, Fig. 8 (c) are that mouse weight becomes after giving the compounds of this invention different number of days
Change figure.
Fig. 9 show growth and the transfer result figure that the compounds of this invention inhibits 4T1 in situ tumors.Wherein, Fig. 9 (a) is
The compounds of this invention inhibits the IVIS living imaging systems of growth of breast cancers to take pictures result figure, and shade shows that tumour cell is poly-
Collection number；Fig. 9 (b) is to give tumour lung transfer figure after the compounds of this invention, and Fig. 9 (c) is after giving the compounds of this invention
Tumour pulmonary nodule number statistical results chart, Fig. 9 (d) are to give tumour lung rate of transform statistical form after the compounds of this invention.
Figure 10 show the compounds of this invention and inhibits MDA-MB-231 in situ tumor growth result figures.Wherein, Figure 10 (a)
For the compounds of this invention inhibit growth of breast cancers mouse tumor volume change figure, Figure 10 (b) be give the compounds of this invention or
Statistical chart of the mouse tumor weight relative to control after person's taxol 25 days.
Figure 11 show the experimental transfer knot that the compounds of this invention inhibits breast cancer tail vein (MDA-MB-231 tumours)
Fruit is schemed.Wherein, Figure 11 (a) is that the compounds of this invention inhibits the IVIS living imaging systems of breast cancer Lung metastases to take pictures as a result, face
The bright tumour cell aggregation of color depth superficial number.Figure 11 (b) is that IVIS living imaging systems are taken pictures the statistical chart of result.
Figure 12 show the compounds of this invention and inhibits the transfer of tumour in the disease animal model spontaneously shifted and answer
Send out result figure.Figure 12 (a) is that IVIS living imaging systems are taken pictures figure, and Figure 12 (b) and 12 (c) are respectively mouse recurrence and remote in situ
Hold transfer and relapse situation statistical chart.
Specific implementation mode
In conjunction with following specific examples and attached drawing, the present invention is described in further detail, protection content of the invention
It is not limited to following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that change
Change and advantage is all included in the present invention, and using appended claims as protection domain.
1H-NMR is measured with Varian MercuryAMX300 type instrument；MS is measured with VG ZAB-HS or VG-7070 type instrument,
It is the sources EI (70ev) in addition to indicating；All solvents using preceding by re-distillation, used anhydrous solvent be by
Standard method, which is dried, to be obtained；In addition to explanation, all reactions are to carry out and tracked with TLC under protection of argon gas, are post-processed
Shi Junjing saturated common salts are washed and anhydrous magnesium sulfate drying process；The purifying of product uses silica gel (200-300 in addition to explanation
Mesh) column chromatography；Used silica gel, including 200-300 mesh and GF254 are that Haiyang Chemical Plant, Qingdao or Yantai edge win silica gel
Company produces.
Embodiment one：The preparation of each compound
Embodiment 1-01, compound N2Isobutyl group-N4((2- (3- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) first
Base) -2,4- pyrimidinediamines preparation (ZH001)
By 3- (benzyloxy) thiobenzamides according to bibliography (Sierra
M.L.et.al.J.Med.Chem.2007,685-695. 2- (3- (benzyloxy) phenyl) -5- (bromoethyl) -4- methyl) is prepared
Thiazole；Then 2- (3- (benzyloxy) phenyl) -5- (bromoethyl) -4- methylthiazols are pressed into bibliography (Wurdak
H.et.al.Proc.Natl.Acad.Sci.USA 2010,16542-16547.) prepare compound (2- (3- (benzyloxy) benzene
Base) -4- methyl-5-thiazoles base) methyl amine；By (2- (3- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl amine
(190mg, 0.61mmol) and compound 2,4- dichloro pyrimidines (296mg, 2mmol) are dissolved in 10ml ethanol solutions, are heated to 40
Degree Celsius stirring 10 hours, mixture after reaction removes ethyl alcohol through vacuum distillation, is extracted twice with dichloromethane and water, organic
It is mutually dried with anhydrous magnesium sulfate through saturated common salt water washing, vacuum distillation obtains crude product, and chemical combination is purified to obtain through silica gel column chromatography
Object N- ((2- (3- (benzyloxy) phenyl -4- methyl-5-thiazoles base) methyl) -2- chlorine pyrimidine -4- amine；By N- ((2- (3- (benzyloxies
Base) phenyl -4- methyl-5-thiazoles base) methyl) -2- chlorine pyrimidine -4- amine mixes with isobutyl amine (1ml), it is dissolved in 10ml isobutyls
Alcohol is heated to 120 degrees Celsius of reflux and obtained mixture is boiled off isobutanol, with two after reaction carries out 10 hours
Chloromethanes and water are extracted twice, and organic phase is dried after saturated common salt water washing with anhydrous magnesium sulfate, and vacuum distillation is slightly produced
Object purifies to obtain compound N through silica gel column chromatography2Isobutyl group-N4((2- (3- (benzyloxy) phenyl) -4- methyl-5-thiazoles
Base) methyl) -2,4- pyrimidinediamines.1H NMR(300MHz,CDCl3)δ:8.34-8.31(m,1H),7.55-7.27(m,8H),
7.03-7.00 (m, 1H), 5.73 (d, J=6.0Hz, 1H), 5.13 (s, 2H), 4.69 (d, J=5.4Hz, 2H), 3.25 (t, J
=6.3Hz, 2H), 2.49 (s, 3H), 1.94-1.85 (m, 1H), 0.98 (d, J=6.6Hz, 6H).
Embodiment 1-01 to 1-23, table 1 show the preparation method of compound ZH001 to ZH023
Embodiment two：Inhibition test of the compounds of this invention to growth of tumour cell
Embodiment 2-1, MTS method measures cell Proliferation
Influence of the object of the present invention to variety classes tumor cell proliferation is measured using MTS methods.Method is as follows：By cell with 5
×103A/hole density is connected in 96 orifice plates (Corning), after routine culture makes cell adherent for 24 hours, sequentially adds various concentration
The compounds of this invention makes its final concentration be respectively 1.0nM, 100nM, 500nM, 1.0 μM, 5.0 μM, 10.0 μM, 20.0 μM,
50.0 μM, the DMSO of equivalent is added in control group (every group sets 3 multiple holes).After continuing routine culture 48h, it is even that tetramethyl is added per hole
Nitrogen azoles salting liquid 20 μ L, 37 DEG C of 5%CO2It is incubated 2 hours or so in incubator.96 orifice plates are placed in microplate reader (SPECTRA
MAX 190) in, its OD value is measured under 490nm wavelength.Influence of the statistical analysis drug for cell survival rate.As a result as schemed
Shown in 1-4, wherein：
(A) design sketch that the compounds of this invention inhibits a variety of Cells Proliferation of Human Breast Cancer under various concentration, is shown in Fig. 1, can
Inhibit people source Cells Proliferation of Human Breast Cancer with seeing the compounds of this invention concentration dependent and to normal mammary epithelial proliferation without aobvious
Writing influences.Compared with the control group, after the compounds of this invention ZH001-023 of various concentration is added, breast cancer cell (MDA-MB-
231, MCF7, BT549, Bcap37 and T47D) proliferative capacity is significantly inhibited, effectively inhibits to the half of breast cancer cell
Concentration (IC50) respectively at 1-5 μM or so, and be in apparent dose-dependence.Moreover, the compounds of this invention is to normal breast
The toxic effect of glandular epithelium MCF10A is smaller, and half effective inhibition concentration is more than 20 μM or more, illustrates the compounds of this invention
Also there is preferable selectivity between breast cancer cell and normal breast epithelium cell.
(B) the compounds of this invention has strong inhibition under various concentration to colon cancer cell, as shown in Fig. 2,
It can be seen that the compounds of this invention concentration dependent inhibit Colon Cancer Cells.Tested colon cancer cell (HCT116 and
HT29 etc.) on, the compounds of this invention ZH001-023 dose-dependently inhibits the proliferation of these cancer cells, illustrates the present invention
Compound also significantly inhibits colon cancer cell.
(C) the compounds of this invention has strong inhibition under various concentration to lung carcinoma cell, as shown in figure 3, can
Inhibit proliferation of lung cancer cells with seeing the compounds of this invention concentration dependent.In the lung carcinoma cell (A549 and PC-9 etc.) tested
On, the compounds of this invention ZH001-023 dose-dependently inhibits the proliferation of these cancer cells, illustrates the compounds of this invention pair
Lung carcinoma cell equally significantly inhibits.
(D) the compounds of this invention and taxol under various concentration to breast cancer cell and normal cell proliferation inhibition
Statistics, is shown in Fig. 4.The compounds of this invention at low concentrations (<At 5 μM), three plants of breast cancer cells of taxol pair (MDA-MB-231,
MCF7 and 4T1) proliferation inhibition activity be better than the compounds of this invention, but when the compounds of this invention concentration be more than 5 μM when, the present invention
Compound is better than the inhibitory activity of this three plants of breast cancer cells the taxol inhibitory activity with concentration.What is more important, this
Invention compound is significantly less than taxol to the toxicity of normal mammary epithelial.These results tentatively illustrate the compounds of this invention
More optionally inhibit the proliferation of tumour cell.
In addition, by the compounds of this invention to prostate gland cancer cell, liver cancer cells, skin cancer cell, pancreatic cancer cell, white blood
The kinds of tumor cells such as sick cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity carry out Proliferation Ability
Effect experiment achieves and similar significantly inhibits effect.
The inhibition that embodiment 2-2, the compounds of this invention form tumor cell clone.
Solid tumor is formed by proliferation by tumour cell.Clone forming method (colony formation) detects tumour
Cells in vitro forms the proliferation and one-tenth knurl ability of clone.It, can be according to the clonality of tumour cell when testing in vitro
To reflect that it generates the power of solid tumor ability in vivo.Therefore colony formation can be utilized to test chemical combination of the present invention in vitro
Influence of the object to the clonality of tumour cell, to evaluate the anticancer effect of compound.
Method is as follows：By breast cancer cell MCF7, T47D and 4T1 with 3 × 103The density of a/ware is inoculated in six orifice plates,
Culture is grouped afterwards for 24 hours, if secondary orifices 4, is separately added into the untested compound ZH001-023 of various concentration, its final concentration is made to distinguish
For 1.0 μM and 2.5 μM, the DMSO of equivalent is added in control group.Continue to cultivate, replaces a subculture and respective concentration within every two days
Close object.After 7 days, culture medium is discarded, PBS is washed 3 times, and 4% paraformaldehyde room temperature fixes 10min, 2 ‰ violet staining 5min, from
Water is rinsed.It takes pictures under microscope, calculates cell clonal formation quantity.Experimental result is as shown in Figure 5, it is seen that the compounds of this invention
There is obvious inhibiting effect to breast cancer cell Clone formation.Compound is in the case where 1.0 μM of concentration are acted on to this two plants of lung carcinoma cells
Cloning capacity have apparent inhibition, the Clone formation of this three plants of breast cancer cells is completely inhibited under 2.5 μM of concentration, from addition
One angle illustrates that such compound has the function of very strong inhibition tumour growth.
In addition, by the compounds of this invention to lung carcinoma cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, cancer of pancreas
The kinds of tumor cells such as cell, leukaemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity into
Row Clone formation inhibition is tested, and is achieved and similar is significantly inhibited effect.
Embodiment three：Inhibition test of the compounds of this invention to tumor cell migration
Embodiment 3-1, the compounds of this invention are to the inhibition of tumour cell lateral transfer
The inhibition to tumor cell migration ability is detected by scarification (wound healing)
It can be moved along the flat less place of Cell-oriented is cultivated when cell is cultivated in vitro.Therefore, cell can covered with
Culture dish in artificial " drawing " go out one " scar ", then the cell at left and right sides of " scar " can be to " scar " regional movement, finally
Again it migrates to the region, i.e., it is so-called " scar healing ".According to the cell quantity for moving to " scar " region and " scar is cured
Close " degree, you can judge the locomitivity of cell.
Method is as follows：By a certain number of tumor cell inoculations to 6 orifice plates, cell is cultivated in 37 DEG C of 5%CO2 incubators
For 24 hours, until cell is grown to 80% or so.In the hole for covering with cell, bore dia longitudinal scratch are cultivated with the edges sterilizing tip of 10 μ L,
It is washed twice with PBS after cut, the cell scratched is cleaned, 2mL is then added into cell culture well respectively containing various concentration
Culture plate is put into incubator, continues routine culture 12h or so by the culture medium of the compounds of this invention ZH001-023, until control
The group cut head of district expires cell.The case where microscopically observation cell is moved to dashed part, takes pictures.Statistical analysis various dose medicine
Object group migrates into the cell quantity of scribe area, determines influence of the drug to cell migration ability.At the same time, with MTS methods
The corresponding cell of detection (as mentioned before) respective concentration drug effect 12h proliferative conditions, to determine wound healing
Whether experiment is influenced by cell Proliferation.
The results are shown in Figure 6, it is seen that the compounds of this invention dose-dependently inhibits people source breast cancer cell MDA-MB-
The migration of 231 and mouse source breast cancer cell 4T1.Wherein, Fig. 6 (a) is the compounds of this invention to breast cancer cell MDA-MB-231
The design sketch of inhibition of metastasis, Fig. 6 (c) are the compounds of this invention to breast cancer cell 4T1 inhibition of metastasis design sketch, Fig. 6 (b),
(d) it is respectively Fig. 6 (a), (c) statistical result.Compared with the control group, in the cell of breast cancer cancer cell MDA-MB-231 and 4T1
Cut migrates in experimental model, and the compounds of this invention ZH001-023 is effective to the half of the inhibition of metastasis of MDA-MB-231 and 4T1
Inhibition concentration IC50Between 1~2.5 μM and 0.1~0.5 μM, mammary gland is inhibited with illustrating the compounds of this invention concentration dependent
The lateral transfer of cancer cell.
In addition, by the compounds of this invention to lung carcinoma cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, cancer of pancreas
The kinds of tumor cells such as cell, leukaemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity into
Row lateral transfer inhibition is tested, and is achieved and similar is significantly inhibited effect.
Embodiment 3-2, Transwell method detects influence of the object of the present invention to cellular infiltration
Transwell migration experiments detect cellular infiltration situation using the cells Boyden.The cells Transwell bottom is spread
Permeable polycarbonate film on have the micropores of 8 μm of a large amount of diameters.When experiment, the cells Transwell are put into 24 orifice plates, are gathered
Entire hole is divided into upper and lower two Room by carbonic ester film, and the small interiors Transwell deserve to be called room, and lower room, upper interior Sheng are claimed in culture plate
There are culture supernatants, lower interior to fill lower layer's culture solution, levels culture solution is separated by with polycarbonate membrane, the cells Transwell
Upper chamber spreads one layer of collagen stroma Matrigel in advance, then by cell inoculation in upper interior, since polycarbonate membrane has permeability, under
Serum in layer culture solution can be induced to indoor cell and migrate downward into so that be moved to lower room from the upper chamber face of film
Face.But tumour cell must first dissolve collagen stroma to move to lower room, then be moved by dissolving the cavity, this mistake
Journey, it is similar to the impregnation process of tumour cell in vivo, it can be used for reflecting the invasiveness ability of tumour cell.
Method is as follows：The tumour cell of logarithmic growth phase is with 5 × 104A/hole is seeded to is covered with 10% in advance
In the upper chamber of the cells Matrigel (BD) Transwell, dosing group is separately added into 0.1 μM as indicated above, 0.5 μM, 1.0 μM,
2.5 μM, 5 μM, 10.0 μM, 20 μM of the compounds of this invention ZH001-023, the DMSO of equivalent is added in control group.In lower room respectively
It is each that 800 μ L complete mediums are added.12h or for 24 hours is cultivated in routine culture incubator.The cells transwell are taken out, cotton swab is used
The upper chamber one side for dipping in the cells wiping transwell, the cell for not wearing film is wiped.By Transwell in 4% paraformaldehyde room
Temperature fixes 10min, 2 ‰ violet staining 5min, and tap water rinses.Take pictures under microscope, count per in hole up and down in 5
Theca cell number/visual field is worn in the cell number in a visual field, acquisition.Every group averagely sets 3 secondary orifices.Statistics various dose medicine group wears film
The quantity of cell determines influence of the drug to cell migration ability.
The results are shown in Figure 7, in the Transwell Soaking experiment models of breast cancer cell MDA-MB-231, these changes
Close the half effective inhibition concentration IC that object inhibits MDA-MB-231 infiltrations50Between 1-2.5 μM；Breast cancer 4T1's
In Transwell Soaking experiment models, IC of the compounds of this invention to infiltration inhibition50Between 0.1-0.5 μM, illustrate the present invention
Compound equally shows the ability of significant anti-breast cancer cellular infiltration in liquid wetting property.The experimental results showed that the present invention
Compound dose-dependently inhibits the invasion of people source breast cancer cell MDA-MB-231 and mouse source breast cancer cell 4T1.
In addition, by the compounds of this invention to lung carcinoma cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, cancer of pancreas
The kinds of tumor cells such as cell, leukaemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity into
Row infiltration inhibition experiment, achieves and similar significantly inhibits effect.
Example IV：Inhibiting effect of the compounds of this invention to tumour growth and transfer in Mice Body
Embodiment 4-1 the compounds of this invention is to inhibiting mammary gland of mouse carcinoma in situ
6-8 weeks Bal b/c female mice, breast pad in-situ injection 7 × 104A mouse mastopathy cell 4T1.6 after lotus knurl
It, primary tumor grows to diameter about 3-5mm, 2 groups are equally divided by mouse primary tumor size, every group 8, administration group is pressed respectively
According to corresponding dosage intraperitoneal injection of drugs 5.0mg/kg/day, control group injects equivalent solvent (DMSO).Injection compound daily
Preceding measurement tumor size simultaneously weighs mouse weight.It is administered continuously to 21 days, stripping measurement of tumor is taken pictures.The experimental results showed that this
Invention compound has inhibition to mouse source breast cancer cell growth, and is had not significant impact to mouse weight.Such as Fig. 8 results
It has been shown that, relative to control group, tumor size is 1477 ± 319mm3, which, which has tumor size, significantly presses down
It makes and uses, tumor size is 329 ± 174mm3, volume reduces 77%, sees Fig. 8 (a) design sketch and 8 (b) statistical result.It is noting
During penetrating, mouse weight is compared with the control group without occurring particularly apparent difference, such as Fig. 8 (c).
In addition, by the compounds of this invention to lung cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma,
The Several Kinds of Malignancy such as carcinoma of urinary bladder, kidney and carcinoma of mouth carry out the experiment of carcinoma in situ lotus knurl model inhibition, achieve phase
As significantly inhibit effect.
Embodiment 4-2. the compounds of this invention inhibits mouse breast cancer Lung metastases
The experimental simulation clinically morbidity of breast cancer Lung metastases and therapeutic process.In the Bal b/c females of 6-8 week old
7 × 10 are inoculated at mouse mammary pad4A/mouse mastopathy cell 4T1 for having of label only.After 7 days, it can measure
To the primary tumor that diameter is about 3-5mm at inoculation.Mouse is divided into 2 groups by mouse bioluminescence imaging technology (IVIS), respectively
Start the compound that 5.0mg/kg/day is injected intraperitoneally, control group only injection solvent DMSO observes the compound for breast with this
The influence of gland cancer lung transfer.After administration 21 days, Nasopharyngeal neoplasms situation is tracked using bioluminescence imaging technology IVIS.By mouse
After execution, stripping tumour extremely organ (lung, bone, liver, the heart, kidney etc.) is taken pictures, and dissection calculates the quantity of lung's transfer stove and is subject to
Statistics.Under the dosage of 5.0mg/kg/day, the distribution of mouse metastatic lesion reduces 95%, illustrates such compound to this kind of
The transfer of tumour also significantly inhibits.Fig. 9 shows that the compounds of this invention shifts growth of breast cancers and shift lung knot
Joint number has inhibition.The case where taking pictures after Fig. 9 (a) display IVIS living imagings and stripping organ.Fig. 9 (b) show lung
Portion's picture and metastases node design sketch.The statistical chart of lung's metastatic nodules shown in Fig. 9 (c).Fig. 9 (d) shows this compound
Inhibit the phenomenon that Metastasis in Breast Cancer rate.
In addition, by the compounds of this invention to lung cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma,
The Several Kinds of Malignancy such as carcinoma of urinary bladder, kidney and carcinoma of mouth carry out metastasis models inhibition experiment, achieve similar
Significantly inhibit effect.
Inhibition of the embodiment 4-3. the compounds of this invention to people source growth of breast cancers and spontaneous metastasis
In-situ injection 1 × 10 was padded to 6-8 weeks Female nude mice breast6A human breast cancer cell MDA-MB-231-
luciferase.After lotus knurl 6 days, mouse is uniformly divided into 4 groups according to the result of the tumor size of IVIS reflections, it is respectively negative
Control group, 2.5 mg/kg dosage administration groups, 5.0mg/kg dosage the compounds of this invention administration group, 5.0mg/kg taxols are positive
Control group.According to corresponding dosage, intraperitoneal injection of drugs, negative control group inject equivalent solvent (DMSO) to administration group every other day respectively,
Positive controls inject taxol according to dosage.Mouse weight is weighed before injection compound daily, is administered continuously to 35 days, uses
Mouse bioluminescence imaging technology (IVIS), observes the growing state of tumour cell.After mouse is put to death, its organ is dissected, is utilized
IVIS observes the fluorescing matter of the important transfer organ such as lung.
Medication that the results are shown in Figure 10 counted the therapeutic effect gross tumor volume and weight of mouse breast cancer growth after 35 days
Figure.Figure 10 shows the compounds of this invention compared with the control group, this compound of 2.5mg/kg and 5mg/kg dosage then significantly inhibits
The growth of mammary gland primary tumor.And Figure 10 (a) is the statistical result obtained by living animal imaging system software for calculation, Figure 10
(b) it is the mouse weight statistical result being stripped out after testing, as a result shows that the compounds of this invention can inhibit well
The taxanes of the growth of primary tumor, effect and same dose are seemingly.
In addition, by the compounds of this invention to lung cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma,
The Several Kinds of Malignancy such as carcinoma of urinary bladder, kidney and carcinoma of mouth carry out the experiment of tumour spontaneous metastasis model inhibition, achieve
It is similar to significantly inhibit effect.
Embodiment 4-4. the compounds of this invention imitates the inhibition of mouse tumor transfer in breast cancer experimental metastases model
Fruit
In 6-8 weeks BALB/c Female nude mices tail vein injection 1 × 106A mouse mastopathy cell MDA-MB231-luc, greatly
Substrate is injected after about spending 12 hours to take pictures, and mouse stochastic averagina is then divided into 4 groups, it is ensured that every group of injected survival of mouse
Cell number is much the same, and respectively negative control group, 2.5mg/kg dosage administration group, 5.0mg/kg dosage the compounds of this invention are given
Medicine group and 5.0mg/kg dosage taxol positive controls.On the day of injection tumour cell, administration group is respectively according to corresponding
Dosage intraperitoneal injection of drugs injects drug every other day, and negative control group injects equivalent solvent (DMSO), and positive controls are according to dosage
Inject taxol.Mouse weight is weighed before every 2 days injection compounds, is administered continuously to 22 days, using mouse bioluminescence imaging technology
(IVIS), the transfer case of tumour cell is observed.Such as Figure 11.
The compounds of this invention inhibits the experimental result of Metastasis in Breast Cancer recurrence as shown in figure 11, and Figure 11 (a) is administration the 0th day
With the 22nd day after therapeutic effect figure that mouse breast cancer is experimentally shifted.Figure 11 (b) is antitumous effect statistical chart.As a result it shows
Show that then significantly inhibiting breast cancer in the compound of 2.5mg/kg dosage and 5.0mg/kg dosage experimentally shifts, and has dose-dependant
Effect.The result shows that and compared with positive control Taxol, under same dose, the compounds of this invention inhibits breast cancer experiment
Property transfer effect be better than taxol.
In addition, by the compounds of this invention to lung cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma,
The Several Kinds of Malignancy such as carcinoma of urinary bladder, kidney and carcinoma of mouth carry out the experiment of tumor experiment metastasis model inhibition, obtain
It is similar to significantly inhibit effect.
Embodiment five：The compounds of this invention inhibits the effect of the recurrence and far-end transfer in situ of tumour
Usual patient with breast cancer can take it is in situ cut off this expectant treatment means, but after cutting off, there is very big probability meeting
Tumorigenic recurrence and far-end transfer.4T1 mouse source breast cancer lotus knurl model can the spontaneous high metastatic tumour of generation, can be transferred to
The organs such as lung, liver, bone, kidney, lymph node and brain, while re-forming stove in situ in the primary position of breast cancer.Due to 4T1 cells
It is mouse source breast cancer cell, the growth in BAL b/c mouse and transfer characteristic and the growth of breast cancers transfer process in human body
It is close.It is usually used in human milk simulating gland cancer occurrence and development process, especially late period VI primary breast cancers.So this animal can be utilized
Model simulates the therapy of the tumor resection in clinically expectant treatment well.
6-8 weeks female BAL b/c mouse, by 7 × 104A mouse mastopathy cell 4T1-luciferase is inoculated into mouse
Mammary fat pad, 5 days or so the primary tumors for just forming 5mm or so.After 12 days, mouse is put down by bioluminescence imaging technology (IVIS)
Be divided into 4 groups, respectively negative control group, 2.5mg/kg/day dosage administration group, 5.0mg/kg/day dosage administration group and
5.0mg/kg/day dosage taxol positive controls.13rd day, the primary tumor of mouse is cut off, is sewed up a wound.Start within 15th day
Give the compounds of this invention.After administration 14 days, using mouse bioluminescence imaging technology (IVIS), observation the compounds of this invention is to mouse
Recurrence and the influence of far-end transfer in situ.
For experimental result as shown in 12, Figure 12 (a) is after medication 14 days to mouse breast cancer recurrence and far-end transfer in situ
Therapeutic effect figure, right half part are respectively recurrence rate 12 (b) in situ and distal end recurrence rate statistical chart 12 (c).Compared with the control group,
In situ tumor recurrence rate can be reduced to 50% and 12.5% or so by the compounds of this invention of various dose from 80% or so；Distally
Metastases occurrence probability is reduced to 12.5% and 12.5% or so from 40% or so, and can only be by original position with the taxol of dosage
Tumor recurrence probability and distal tumor transfer occurrence probability are reduced to 37.5% and 25% respectively, and obvious the compounds of this invention is to swollen
The protective effect of tumor mouse is substantially better than taxol.
In addition, by the compounds of this invention to lung cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma,
The Several Kinds of Malignancy such as carcinoma of urinary bladder, kidney and carcinoma of mouth carry out neoplasm in situ recurrence and far-end transfer model inhibition is real
It tests, achieves and similar significantly inhibit effect.
Following example 1-02 provides the preparation method and product detection knot of the compounds of this invention ZH002-023 to 1-23
Fruit.Embodiment 1-02, compound N2Isobutyl group N4((2- (2- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methyl) -2,
The preparation of 4- pyrimidinediamines (ZH002)
3- (benzyloxy) thiobenzamide is replaced as 2- (benzyloxy) thiobenzamide, by prepare compound
The method prepare compound ZH002 of ZH001.1H NMR(300MHz,CDCl3)δ:8.35-8.32 (m, 1H), 7.78 (d, J=
5.4Hz, 1H), 7.47-7.29 (m, 6H), 7.08-7.01 (m, 2H), 5.69 (d, J=6.0Hz, 1H), 5.28 (s, 2H),
4.65 (d, J=4.5Hz, 2H), 3.20 (t, J=6.0Hz, 2H), 2.48 (s, 3H), 1.90-1.83 (m, 1H), 0.94 (d, J
=6.6Hz, 6H).
Embodiment 1-03, compound N2Isobutyl group-N4((4- methyl -2- (4- (benzene ethyoxyl) phenyl) -5- thiazolyls)
Methyl) -2,4- pyrimidinediamines (ZH003) preparation
3- (benzyloxy) thiobenzamide is replaced as 4- (benzene ethyoxyl) thiobenzamide, by prepare compound
The method prepare compound ZH003 of ZH001.1H NMR(300MHz,CDCl3)δ:7.78 (d, J=8.7Hz, 3H), 7.35-7.27
(m, 5H), 6.91 (d, J=8.7Hz, 2H), 5.71 (d, J=6.0Hz, 1H), 4.66 (d, J=5.4Hz, 2H), 4.21 (t, J
=6.9 Hz, 2H), 3.24 (t, J=6.3Hz, 2H), 3.11 (t, J=6.9Hz, 2H), 2.46 (s, 3H), 1.93-1.84 (m,
1H), 0.97 (d, J=6.6Hz, 6H).
Embodiment 1-04, compound N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) first
Base) -2,4- pyrimidinediamines (ZH004) preparation
3- (benzyloxy) thiobenzamide is replaced as 4- (benzyloxy) thiobenzamide, by prepare compound
The method prepare compound ZH004 of ZH001.1H NMR(300MHz,CDCl3)δ:7.82-7.78(m,3H),7.46-7.35(m,
5H), 7.00 (d, J=9.0Hz, 2H), 5.72 (d, J=6.0Hz, 1H), 5.11 (s, 2H), 4.70-4.66 (m, 2H), 3.25
(t, J=8.1Hz, 2H), 2.46 (s, 3H), 2.09-2.01 (m, 1H), 0.98 (d, J=6.6Hz, 6H).
Embodiment 1-05, compound N2Isobutyl group-N4((2- (4- (benzyl amino) phenyl) -4- methyl-5-thiazoles base) first
Base) -2,4- pyrimidinediamines (ZH005) preparation
3- (benzyloxy) thiobenzamide is changed into 4- (benzamido group) thiobenzamide, by prepare compound ZH001
Method prepare compound ZH005.1H NMR(300MHz,CDCl3)δ:7.80 (d, J=7.8Hz, 2H), 7.29-7.16 (m,
6H), 7.05-7.03 (m, 2H), 5.97-5.94 (m, 1H), 4.90 (s, 2H), 4.76 (d, J=3.6Hz, 2H), 3.30 (t, J
=5.7Hz, 2H), 2.49 (s, 3H), 1.95-1.88 (m, 1H), 0.99 (d, J=6.6Hz, 6H).
Embodiment 1-06, compound N2Isobutyl group-N4((2- (4- (3- phenylpropyl alcohols oxygroup) phenyl) -4- methyl-5-thiazoles
Base) methyl) -2,4- pyrimidinediamines (ZH006) preparation
3- (benzyloxy) thiobenzamide is replaced as 4- (phenylpropyl alcohol oxygroup) thiobenzamide, by prepare compound
The method prepare compound ZH006 of ZH001.1H NMR(300MHz,CDCl3)δ:7.80-7.73(m,3H),7.31-7.20(m,
5H), 6.90 (d, J=8.7Hz, 2H), 5.71 (d, J=5.7Hz, 1H), 4.78 (d, J=4.2Hz, 2H), 4.70 (s, 2H),
3.99 (t, J=6.3Hz, 2H), 3.65 (q, J=7.2Hz, 2H), 3.26 (t, J=6.0Hz, 2H), 2.81 (t, J=7.5Hz,
2H), 2.16-2.07 (m, 2H), 1.95-1.86 (m, 1H), 0.98 (d, J=6.6Hz, 6H).
Embodiment 1-07, compound N2Isobutyl group-N4((2- (4- fluorophenyls) -4- methyl-5-thiazoles base) methyl) -2,
The preparation of 4- pyrimidinediamines (ZH007)
3- (benzyloxy) thiobenzamide is replaced as 4- fluoro thio benzamides, by the side of prepare compound ZH001
Method prepare compound ZH007.1H NMR(300MHz,CDCl3)δ:7.85-7.80(m,2H),7.40-7.38(m,2H),7.11-
7.06 (m, 1H), 5.93 (d, J=5.4Hz, 1H), 4.73 (s, 2H), 3.27 (t, J=5.4Hz, 3H), 2.48 (s, 3H),
1.95-1.85 (m, 1H), 0.97 (d, J=6.0Hz, 6H).
Embodiment 1-08, compound N2Isobutyl group-N4((2- (2- chlorphenyls) -4- methyl-5-thiazoles base) methyl) -2,
The preparation of 4- pyrimidinediamines (ZH008)
3- (benzyloxy) thiobenzamide is replaced as 2- chlorine thiobenzamides, by the side of prepare compound ZH001
Method prepare compound ZH008.1H NMR(300MHz,CDCl3)δ:8.16-8.12 (m, 1H), 7.85 (d, J=5.7Hz, 1H),
7.48-7.45 (m, 1H), 7.37-7.32 (m, 2H), 5.72 (d, J=5.7Hz, 1H), 4.72 (d, J=5.4Hz, 2H), 3.24
(t, J=6.3Hz, 2H), 2.52 (s, 3H), 1.93-1.84 (m, 1H), 0.97 (d, J=6.6Hz, 6H).
Embodiment 1-09, compound N2Isobutyl group-N4((2- (4- chlorphenyls) -4- methyl-5-thiazoles base) methyl) -2,
The preparation of 4- pyrimidinediamines (ZH009)
3- (benzyloxy) thiobenzamide is replaced as 4- chlorine thiobenzamides, by the side of prepare compound ZH001
Method prepare compound ZH009.1H NMR(300MHz,CDCl3)δ:7.82 (d, J=8.7Hz, 3H), 7.40 (d, J=8.7Hz,
2H), 5.73 (d, J=6.0Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 3.26 (t, J=6.3Hz, 2H), 2.50 (s, 3H),
1.95-1.86 (m, 1H), 0.99 (d, J=6.6Hz, 6H).
Embodiment 1-10, compound N2Isobutyl group-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidines
The preparation of diamines (ZH010)
3- (benzyloxy) thiobenzamide is replaced as thiobenzamide, by the method system of prepare compound ZH001
Standby compound ZH010.1H NMR(300MHz,CDCl3)δ:7.98-7.93(m,3H),7.48-7.45(m,3H),7.13(s,
1H), 5.82 (d, J=5.7Hz, 1H), 4.72 (d, J=6.0Hz, 2H), 3.77 (s, 8H).
Embodiment 1-11, compound N2,N2Dipropyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- is phonetic
The preparation of pyridine diamines (ZH011)
Isobutyl amine is replaced as dipropylamine, by the method prepare compound ZH011 of prepare compound ZH010.1H NMR
(300 MHz,CDCl3)δ:7.90-7.85 (m, 3H), 7.41-7.38 (m, 3H), 5.65 (d, J=5.7Hz, 1H), 4.69 (d, J
=5.4Hz, 2H), 3.50 (t, J=7.5Hz, 4H), 2.47 (s, 3H), 1.70-1.51 (m, 4H), 0.91 (t, J=7.5Hz,
6H)。
Embodiment 1-12, compound N2,N2Diethyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- is phonetic
The preparation of pyridine diamines (ZH012)
Isobutyl amine is replaced as diethylamide, by the method prepare compound ZH012 of prepare compound ZH010.1H NMR
(300 MHz,CDCl3)δ:7.92-7.85 (m, 3H), 7.41-7.38 (m, 3H), 5.66 (d, J=5.7Hz, 1H), 4.70 (d, J
=5.4Hz, 2H), 3.61 (q, J=7.2Hz, 4H), 2.48 (s, 3H), 1.18 (t, J=6.9Hz, 6H).
Embodiment 1-13, compound N2((2- furyls) methyl)-N4((4- methyl -2- phenyl -5- thiazolyls) first
Base) -2,4- pyrimidinediamines (ZH013) preparation
Isobutyl amine is replaced as chaff amine, by the method prepare compound ZH013 of prepare compound ZH010.1H NMR
(300MHz, CDCl3)δ:7.88-7.84(m,3H),7.41-7.39(m,3H),7.35-7.34(m,1H),6.31-6.29(m,
1H), 6.23-6.22 (m, 1H), 5.77 (d, J=5.7Hz, 1H), 4.68 (d, J=5.4Hz, 2H), 4.63 (d, J=5.7Hz,
2H),2.47(s,3H).Embodiment 1-14, compound N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl -5- thiophenes
Oxazolyl) methyl) -2,4- pyrimidinediamines (ZH014) preparation
3- (benzyloxy) thiobenzamide is replaced as 4- (benzyloxy) thiobenzamide, by prepare compound
The method prepare compound ZH014 of ZH001.1H NMR(300MHz,CDCl3)δ:7.90-7.85(m,2H),7.81-7.79(m,
1H), 7.42-7.39 (m, 3H), 5.73 (d, J=6.0Hz, 1H), 4.96 (d, J=6.0Hz, 2H), 3.38 (q, J=6.3Hz,
2H), 2.49 (s, 3H), 1.67-1.60 (m, 2H), 0.98 (t, J=7.2Hz, 3H).
Embodiment 1-15, compound N2Normal-butyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidines
The preparation of diamines (ZH015)
Isobutyl amine is replaced as n-butylamine, by the method prepare compound ZH015 of prepare compound ZH010.1H NMR
(300 MHz,CDCl3)δ:7.89-7.82 (m, 3H), 7.41-7.39 (m, 3H), 5.72 (d, J=5.7Hz, 1H), 4.68 (d, J
=5.4Hz, 2H), 3.41 (q, J=6.0Hz, 2H), 2.48 (s, 3H), 1.64-1.54 (m, 2H), 1.48-1.36 (m, 2H),
0.94 (t, J=7.5 Hz, 3H).
Embodiment 1-16, compound N2N-pentyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidines
The preparation of diamines (ZH016)
Isobutyl amine is replaced as 1- aminopentanes, by the method prepare compound ZH016 of prepare compound ZH010.1H
NMR (300MHz,CDCl3)δ:7.88-7.82 (m, 3H), 7.41-7.39 (m, 3H), 5.72 (d, J=5.7Hz, 1H), 4.68
(d, J=5.7Hz, 2H), 3.39 (q, J=6.6Hz, 2H), 2.48 (s, 3H), 1.63-1.58 (m, 2H), 1.36-1.34 (m,
2H), 0.90 (t, J=6.9Hz, 3H).
Embodiment 1-17, compound N2Benzyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidines two
The preparation of amine (ZH017)
Isobutyl amine is replaced as benzylamine, by the method prepare compound ZH017 of prepare compound ZH010.1H NMR
(300MHz, CDCl3)δ:7.86-7.82 (m, 3H), 7.44-7.24 (m, 9H), 5.76 (d, J=6.0Hz, 1H), 4.66 (d, J
=5.7Hz, 4H), 2.45 (s, 3H).
Embodiment 1-18, compound N2Phenyl-N4((4- methyl -2- phenyl -5- thiazolyls) methyl) -2,4- pyrimidines two
The preparation of amine (ZH018)
Isobutyl amine is replaced as aniline, by the method prepare compound ZH018 of prepare compound ZH010.1H NMR
(300MHz, CDCl3)δ:7.97-7.94 (m, 1H), 7.90-7.85 (m, 2H), 7.60 (d, J=8.7Hz, 2H), 7.41-
7.39 (m, 3H), 7.34-7.31 (m, 1H), 7.04-6.99 (m, 1H), 5.90 (d, J=5.7Hz, 1H), 4.74 (d, J=
5.1Hz,2H),2.49(s, 3H)。
Embodiment 1-19, compound N2Isobutyl group-N4((2- (4- (benzyloxy) phenyl) -4- methyl -5- oxazolyls) first
Base) -2,4- pyrimidinediamines (ZH019) preparation
By 4- benzyloxies yl benzoic acid, EDC.HCl and HOBt are dissolved in DMF, are stirred after five minutes, are added under condition of ice bath
Enter DL-Alanine ester hydrochloride, to the reaction was complete, extraction, drying obtain product methyl 2- through column chromatographic isolation and purification for stirring
(4- (benzyloxy) benzamido) methyl propionate；Compound 2- (4- (benzyloxy) benzamido) methyl propionate is dissolved in
In methanol, the aqueous solution of 4.0 equivalent lithium hydroxides is added dropwise under condition of ice bath, stirring removes methanol to the reaction was complete, adjusts pH
It extracted after=1, be evaporated and obtain product methyl 2- (4- (benzyloxy) benzamido) propionic acid through column chromatographic isolation and purification；By 2-
(4- (benzyloxy) benzamido) propionic acid dissolves in 10ml benzene, and oxalyl chloride is added at 0 DEG C, then under room temperature overnight, decompression
Extra solvent is removed in distillation, is cooled to that residue is dissolved in the MeOH of 30ml at 0 DEG C 1ml triethylamines are slowly added dropwise, room temperature
Reaction 3 hours, is evaporated extra solvent and is extracted with ethyl acetate twice, organic phase is after saturated common salt water washing with anhydrous sulphur
Sour magnesium drying, is concentrated under reduced pressure to give crude product, and compound 2- (4- (benzyloxy-phenyl)) -4- methyl is obtained after purification by column chromatography
Oxazole -5- methyl formates；2- (4- (benzyloxy-phenyl)) -4- Jia Ji oxazole -5- methyl formates are dissolved in 30ml anhydrous ethers,
Reaction system is cooled to 0 DEG C, LiAlH is then added portionwise4, water inactivation on the rocks, filters to take filtrate after reacting 1 hour at 0 DEG C
It is extracted twice with ethyl acetate extraction and water, is dried, be concentrated under reduced pressure to give with anhydrous magnesium sulfate after organic phase saturated common salt water washing
Crude product obtains compound 2- (4- (benzyloxy-phenyl)) -4- Jia Ji oxazole -5- methanol after purification by column chromatography；With 2- (4-
(benzyloxy-phenyl)) -4- methyl oxazole -5- methanol replace (2- (3- (benzyloxy) phenyl) -4- methyl-5-thiazoles base) methanol after
The synthesis step of ZH001 and method is taken to obtain N2- isobutyl groups-N4- ((2- (4- (benzyloxy) phenyl) -4- methyl -5- oxazoles
Base) methyl) -2,4- pyrimidinediamines (ZH019).1H NMR (300MHz,CDCl3)δ:7.73 (d, J=5.4Hz, 1H), 7.37-
7.19 (m, 7H), 6.87 (d, J=8.7Hz, 2H), 5.61 (d, J=6.0Hz, 1H), 4.99 (s, 2H), 4.54 (d, J=
4.8Hz, 2H), 3.42 (s, 3H), 3.12 (t, J=6.3Hz, 2H), 1.83-1.67 (m, 1H), 0.88 (d, J=6.6Hz,
6H)。
Embodiment 1-20, compound N2Isobutyl group-N4((5- (4- (benzyloxy) phenyl) -2- furyls) methyl) -2,4-
The preparation of pyrimidinediamine (ZH020)
4- bromothiophene -2- formaldehyde is replaced as 5- (4- (benzyloxy) phenyl) furans -2- formaldehyde, by prepare compound
The method prepare compound ZH020 of ZH001.1H NMR(300MHz,CDCl3)δ:7.82-7.80 (m, 1H), 7.57 (d, J=
8.7Hz, 2H), 7.46-7.34 (m, 5H), 6.99 (d, J=8.7Hz, 2H), 6.44 (d, J=3.3Hz, 1H), 6.29 (d, J=
3.3Hz, 1H), 5.76 (d, J=6.0Hz, 1H), 5.09 (s, 3H), 4.56 (d, J=4.5Hz, 2H), 4.13 (q, J=
7.2Hz, 1H), 3.22 (t, J=6.3 Hz, 2H), 1.95-1.81 (m, 1H), 0.96 (d, J=6.6Hz, 6H).
Embodiment 1-21, compound N2Normal-butyl-N4((5- (4- (benzyloxy) phenyl) -2- furyls) methyl) -2,4-
The preparation of pyrimidinediamine (ZH021)
Isobutyl amine is replaced as n-butylamine, by the method prepare compound ZH021 of prepare compound ZH020.1H NMR
(300 MHz,CDCl3)δ:7.82-7.81 (m, 1H), 7.56 (d, J=8.7Hz, 2H), 7.45-7.33 (m, 5H), 6.98 (d, J
=8.1Hz, 2H), 6.44 (d, J=3.3Hz, 1H), 6.28 (d, J=3.3Hz, 1H), 5.76 (d, J=6.0Hz, 1H), 5.09
(s, 3H), 4.55 (d, J=4.2Hz, 2H), 3.38 (q, J=6.3Hz, 2H), 1.62-1.53 (m, 2H), 1.44-1.36 (m,
2H), 0.93 (t, J=7.2 Hz, 3H).
Embodiment 1-22, compound N2Isobutyl group-N4((5- (4- (benzyloxy) phenyl) -2- thienyls) methyl) -2,4-
The preparation of pyrimidinediamine (ZH022)
5- (4- (benzyloxy) phenyl) furans -2- formaldehyde is replaced as 5- (4- (benzyloxy) phenyl) thiophene -2-formaldehyde, is pressed
The method prepare compound ZH022 of prepare compound ZH020.1H NMR(300MHz,CDCl3)δ:7.84-7.83(m,1H),
7.49-7.27 (m, 7H), 7.04-6.92 (m, 4H), 5.73 (d, J=6.0Hz, 1H), 5.09 (s, 2H), 4.68 (d, J=
6.0Hz, 2H), 3.24 (t, J=6.0Hz, 2H), 1.95-1.82 (m, 1H), 0.97 (d, J=6.6Hz, 6H).
Embodiment 1-23, compound N2Normal-butyl-N4((5- (4- (benzyloxy) phenyl) -2- thienyls) methyl) -2,4-
The preparation of pyrimidinediamine (ZH023)
Isobutyl amine is replaced as n-butylamine, by the method prepare compound ZH023 of prepare compound ZH022.1H NMR
(300 MHz,CDCl3)δ:7.82-7.80 (m, 1H), 7.49-7.34 (m, 7H), 7.04-6.92 (m, 4H), 5.74 (d, J=
6.0Hz, 1H), 5.09 (s, 3H), 4.69 (d, J=5.4Hz, 2H), 3.40 (q, J=6.6Hz, 2H), 1.64-1.54 (m,
2H), 1.45-1.38 (m, 2H), 0.94 (t, J=7.2Hz, 3H).
Claims (8)
1. the pyrimidinediamine micromolecular organic compound or its pharmaceutically acceptable salt of a kind of aromatic radical-heterocyclic substituted,
It is characterized in that, is indicated by following structural formula (I)：
Wherein：
X is N；
Y is S；
R1For hydrogen, R2For isobutyl group；
R3For benzyloxy；
R4For methyl.
2. a kind of pyrimidinediamine micromolecular organic compound according to aromatic radical-heterocyclic substituted described in claim 1 or
Its pharmaceutically acceptable salt, which is characterized in that the disubstituted pyrimidinediamine micromolecular organic compound is formed with acid
Acid-addition salts；Wherein, the acid be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid,
P-methyl benzenesulfonic acid, lactic acid, pyruvic acid, maleic acid or succinic acid.
3. the pyrimidinediamine micromolecular organic compound or its pharmacy of aromatic radical-heterocyclic substituted according to claim 1
Upper acceptable salt, which is characterized in that it is with radioactivity, fluorophor or biotin labeling.
4. a kind of pharmaceutical composition, wherein the pyrimidinediamine micromolecular containing aromatic radical-heterocyclic substituted described in claim 1
Organic compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, which is characterized in that described pharmaceutical composition is formulated into injectable stream
Body, aerosol, emulsifiable paste, gelling agent, pill, capsule, syrup, transdermal patch or excipient.
6. the pyrimidinediamine micromolecular organic compound of aromatic radical-heterocyclic substituted described in claim 1 or its pharmaceutically may be used
The salt of receiving is preparing the application in inhibiting tumor cell proliferation, growth, migration and the drug of infiltration；Wherein, the tumour is thin
Born of the same parents are selected from lung carcinoma cell, breast cancer cell, colon cancer cell, prostate gland cancer cell, liver cancer cells, skin cancer cell, cancer of pancreas
Cell, leukaemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell and cancer cell of oral cavity.
7. the pyrimidinediamine micromolecular organic compound of aromatic radical-heterocyclic substituted described in claim 1 or its pharmaceutically may be used
Application of the salt of receiving in the drug for preparing treatment malignant tumour；Wherein, the malignant tumour is selected from lung cancer, colon cancer, breast
Gland cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma, carcinoma of urinary bladder, kidney and carcinoma of mouth.
8. the pyrimidinediamine micromolecular organic compound of aromatic radical-heterocyclic substituted described in claim 1 or its can pharmaceutically connect
Application of the salt received in preparing the drug for the treatment of Malignant tumor of bonal metastasis and recurrence；Wherein, the malignant tumour is selected from lung cancer, knot
Intestinal cancer, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cancer of pancreas, leukaemia, oophoroma, carcinoma of urinary bladder, kidney and carcinoma of mouth.
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