CN107365308A - N- (5- piperonyls thiazol-2-yl) amide derivatives and its application as antineoplastic - Google Patents
N- (5- piperonyls thiazol-2-yl) amide derivatives and its application as antineoplastic Download PDFInfo
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- CN107365308A CN107365308A CN201610316277.4A CN201610316277A CN107365308A CN 107365308 A CN107365308 A CN 107365308A CN 201610316277 A CN201610316277 A CN 201610316277A CN 107365308 A CN107365308 A CN 107365308A
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- piperonyls
- thiazol
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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
- C07D417/06—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 carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
The invention discloses (base of the 5 piperonyl thiazole 2) amide derivatives of the N shown in structural formula I and its pharmaceutically acceptable salt, its preparation method and pharmaceutical composition and its application in cancer therapy drug is prepared：R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Z is selected from：CH2Or O；N is selected from：1st, 2 or 3.
Description
Technical field
The present invention relates to a kind of noval chemical compound, its preparation method and application, specifically N- (5- piperonyls thiazol-2-yl) acid amides spreads out
Biology, its preparation method and its preparing the application of anticarcinogen.
Background technology
Abou-Seri etc. [Eur Med Chem, 2016,107,165-179] describes compound A to VEGF
The IC of acceptor -2 (VEGFR-2) kinases50For 0.40 ± 0.04 μM, with positive control PTK787 (Vatalanib, IC50
=0.18 ± 0.02 μM) it is close；Cytoactive test display, GI of the compound to a variety of cancer cells50Less than positive control
Thing Sorafenib (Sorafenib)；El-Messery etc. [Eur Med Chem, 2012,54,615-625] describes compound B
There is preferable In-vitro Inhibitory Effect to a variety of cancer cells；Under 5 μM of concentration, the compound is to HCT-15 and UO-31
Inhibiting rate be respectively 54.6% and 51.4%；Gurdal etc. [J Enzyme Inhibition and Med Chem, 2015,30,
649-654.] describe GIs of the compound C to HCT-116, MCF-7 and HUH-750Respectively 7.9 μM, 9.2 μM
With 3.1 μM, wherein, to HCT-116 and HUH-7 inhibitory activity better than positive control 5 FU 5 fluorouracil (5-FU,
GI50Respectively 30.66 μM and 18.67 μM)；Biswal etc. [WO2014145642A2,2014] describes to be recorded with consideration convey
Factor Nrf2 is the anticancer compound of target spot, and wherein compound D is good to the inhibitory activity of A549 and H1437 cells.
The content of the invention
Present invention solves the technical problem that be to provide a kind of N- (5- piperonyls thiazol-2-yl) amide derivatives, its preparation method,
Pharmaceutical composition and medical usage.
To solve the technical problem of the present invention, the present invention provides following technical scheme：
The first aspect of technical solution of the present invention there is provided a kind of N- (5- piperonyls thiazol-2-yl) as shown in structural formula I
Amide derivatives and its pharmaceutically acceptable salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Z is selected from：CH2Or O；n
It is selected from：1st, 2 or 3.
The second aspect of technical solution of the present invention there is provided N- (the 5- piperonyl thiazoles -2- described in first aspect shown in formula I
Base) amide derivatives preparation method, it is characterised in that it preparation reaction it is as follows：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Z is selected from：CH2Or O；n
It is selected from：1st, 2 or 3.
The third aspect of technical solution of the present invention is to provide containing compound described in first aspect and its pharmaceutically acceptable salt
Pharmaceutical composition, the pharmaceutical composition contains N- (5- piperonyls thiazol-2-yl) amide derivative of the invention of therapeutically effective amount
Thing and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.It is normal that wherein described pharmaceutical carrier refers to pharmaceutical field
Pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.Can by by the compounds of this invention and its
Pharmaceutically acceptable salt combines with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, is made
Any formulation used suitable for human or animal.The compounds of this invention and its pharmaceutically acceptable salt are in its pharmaceutical composition
Content is usually 0.1%~95% percentage by weight.
The compounds of this invention and its pharmaceutically acceptable salt can be administered in a unit containing its pharmaceutical composition,
Method of administration can be enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa,
Eye, lung and respiratory tract, skin, vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be that solution is (including true
Solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection,
Powder-injection and transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet,
Enteric coatel tablets, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule,
Capsulae enterosolubilis), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；
Semisolid dosage form can be ointment, gel, paste etc..
It is sustained release preparation, controlled release system that the compounds of this invention and its pharmaceutically acceptable salt, which can be made ordinary preparation, also be made,
Agent, targeting preparation and various particulate delivery systems.
In order to which the compounds of this invention and its pharmaceutically acceptable salt are made into tablet, can widely use well known in the art each
Kind excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch,
Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate,
Calcium carbonate etc.；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey,
Glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
Methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant
Can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVPP, cross-linked carboxymethyl fibre
Tie up plain sodium, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfonate
Sodium etc.；Lubricant and glidant can be talcum powder, silica, stearate, tartaric acid, atoleine, poly- second two
Alcohol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double-deck
Piece and multilayer tablet.
In order to which administration unit is made into capsule, can by active ingredient the compounds of this invention and its pharmaceutically acceptable salt with
Diluent, glidant mixing, mixture is placed directly within hard shell capsules or soft capsule.Also can be by active ingredient chemical combination of the present invention
First particle or micropill is made with diluent, binder, disintegrant in thing and its pharmaceutically acceptable salt, then be placed in hard shell capsules or
In soft capsule.For preparing each diluent, binder, wetting of the compounds of this invention and its pharmaceutically acceptable salt tablet
Agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For the compounds of this invention and its pharmaceutically acceptable salt are made into injection, water, ethanol, isopropanol, third can be used
Glycol or their mixture as solvent simultaneously add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, infiltration
Press conditioning agent.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusts agent can
To be phosphate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose,
Phosphate, acetate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can be also added and be used as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition can give prescription known to any
Method is administered.
The fourth aspect of technical solution of the present invention is to provide N- described in first aspect present invention (5- piperonyls thiazol-2-yl) acid amides
The application of derivative and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition in terms of cancer therapy drug is prepared.
Further, (5- piperonyls thiazol-2-yl) amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable
The application of salt and third aspect described pharmaceutical composition in terms of medicament for resisting cervical cancer is prepared.
Further, (5- piperonyls thiazol-2-yl) amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable
The application of salt and third aspect described pharmaceutical composition in terms of anti-human adenocarcinoma of lung medicine is prepared.
Further, (5- piperonyls thiazol-2-yl) amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable
The application of salt and third aspect described pharmaceutical composition in terms of anti-human breast cancer medicines are prepared.
Advantageous effects：N- (5- piperonyls thiazol-2-yl) amide derivatives of the present invention are having for a kind of new construction type
The compound of active anticancer.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide
1.55mmol5- piperonyls -4- the tert-butyl groups-thiazolamine, 1.7mmol triethylamines are dissolved in 15mL dichloromethane,
Stirring is completely dissolved to solid, and the 5mL dichloromethane solutions of 1.7mmol chloracetyl chlorides are slowly added dropwise under ice bath；TLC
Reaction process is tracked, 0.5h reactions are finished, and reaction solution is washed 3 times, anhydrous Na2SO4Dry, rotate dichloromethane, add
Enter a small amount of petroleum ether and ethyl acetate mixtures, slowly separate out white solid, collect white solid, dry, it is solid to obtain white
Body N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide 0.45g, yield 82%, m.p.127~129 DEG C,1H NMR
(400MHz, CDCl3), δ：1.38 (s, 9H, 3 × CH3), 4.15 (s, 2H, CH2), 4.22 (s, 2H, ClCH2),
5.94 (s, 2H, OCH2O), 6.64 (d, J=8.0Hz, 1H, C6H36-H), 6.66 (s, 1H, C6H32-H), 6.74
(d, J=8.0Hz, 1H, C6H3 5-H)。13C NMR (101MHz, CDCl3)δ：30.80,32.54,35.65,
41.91,100.89,108.18,108.75,121.20,125.27,134.03,146.17,147.74,151.86,153.48,
163.58。
Embodiment 2
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamides
The 1.55mmol 5- piperonyls -4- tert-butyl groups-thiazolamine, 1.7mmol triethylamines are dissolved in 15mL dichloromethane,
Stirring is completely dissolved to solid, and the 5mL dichloromethane solutions of 1.7mmol3- chlorpromazine chlorides are slowly added dropwise under ice bath；TLC
Reaction process is tracked, 0.5h reactions are finished, and reaction solution is washed 3 times, anhydrous Na2SO4Dry, rotate dichloromethane, add
Enter a small amount of petroleum ether and ethyl acetate mixtures, slowly separate out white solid, collect white solid, dry, it is solid to obtain white
Body N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamide 0.50g, yield 85%, m.p.143~145 DEG C,1H NMR
(400MHz, CDCl3), δ:1.38 (s, 9H, 3 × CH3), 1.93 (d, J=7.0Hz, 3H, CH3), 4.15
(s, 2H, CH2), 4.54 (q, J=7.0Hz, 1H, CH), 5.94 (s, 2H, OCH2O), 6.65 (d,
J=8.0Hz, 1H, C6H36-H), 6.66 (s, 1H, C6H32-H), 6.73 (d, J=8.0Hz, 1H, C6H3
5-H)。13C NMR(101MHz,CDCl3)δ：22.14,30.77,32.59,35.62,42.59,100.92,108.21,
108.78,121.25,125.09,133.89,146.20,147.75,152.63,153.23,167.05.
Embodiment 3
The synthesis of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- (piperidyl) propionamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamides, 0.83mmol piperidines, 0.8mmol tri-
Ethamine, it is dissolved in 10mL tetrahydrofurans, 24h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, washing one
Secondary, saturated common salt is washed once, anhydrous Na2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, separate out solid,
Filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- (piperidyl) propionamide 0.18g,
Yield 84%, m.p.124~126 DEG C,1H NMR (400MHz, CDCl3) (s, 9H, 3 × CH of δ 1.353), 1.55
(s, 2H, piperidine ring 4-H), 1.70~1.78 (m, 4H, piperidine rings 3,5-H), 2.51 (t, J=5.6Hz, 2H,
CH2), 2.56 (s, 4H, piperidine rings 2,6-H), 2.67 (t, J=5.6Hz, 2H, COCH2), 4.14 (s, 2H,
CH2), 5.92 (s, 2H, OCH2O), 6.63~6.69 (m, 2H, C6H3), 6.71 (d, J=8.0Hz, 1H,
C6H3), 12.90 (bs, 1H, NH).
Embodiment 4
The synthesis of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (morpholinyl) acetamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide, 0.83mmol1- methyl piperazines, 0.8mmol
Triethylamine, it is dissolved in 10mL tetrahydrofurans, 12h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, washing
Once, saturated common salt is washed once, anhydrous Na2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, separate out solid
Body, filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (morpholinyl) acetamide 0.21g,
Yield 90%, m.p.160~162 DEG C,1H NMR (400MHz, CDCl3) (s, 9H, 3 × CH of δ 1.403), 2.59~2.63
(m, 4H, morpholine ring 3,5-H), 3.21 (s, 2H, COCH2), 3.83 (s, 4H, morpholine rings 2,6-H), 4.15 (s, 2H,
CH2), 5.94 (s, 2H, OCH2O), 6.64~6.66 (m, 2H, C6H3), 6.73 (d, J=8.0Hz, 1H, C6H3),
9.91 (s, 1H, NH).13C NMR (101MHz, CDCl3) δ 30.89,32.55,35.65,53.83,61.60,66.70,
100.95,108.24,108.81,121.26,124.45,134.08,146.21,147.79,152.95,167.89.
Embodiment 5
The antitumor activity of N- (5- piperonyls thiazol-2-yl) amide derivatives and its salt
1. antitumor activity principle
Mtt assay biological activity test is also known as MTT colorimetric methods, is a kind of method for detecting cell survival and growth.MTT
Analytic approach is with living cells metabolin reducing agent tetrazolium bromide [3- (4,5- dimethyl -2- thiazoles) -2,5- diphenyl bromination tetrazoles；3-
(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, MTT] based on.MTT is one
Kind can receive the dyestuff of hydrogen atom.The dehydrogenase related to NADP in the cell can be by yellow in living cells mitochondria
MTT changes into the first a ceremonial jade-ladle, used in libation (formazon) of insoluble bluish violet, and dead cell is then without this function.Dissolved with DMSO
After formazon, OD value is determined with ELIASA under certain wavelength, can both quantify the survival rate for measuring cell.According to light
Inhibitory action of the change observation sample of density value to tumour cell.
2. antitumor activity is tested
Sample：Embodiment compound.
Cell line：Cervical cancer tumer line Hela, lung adenocarcinoma cell line A549 and breast cancer cell line MCF-7 are (Central-South big
Xue Xiangya medical colleges cell bank provides).
Reagent：Tetrazolium bromide (MTT), RPMI 1640 culture mediums, NBCS, antibiotic (U.S.'s hero's life
Technology company)；Pancreatin (AMRESCO companies of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Diformazan
Base sulfoxide (Sigma Co., USA).
Instrument：HFsafe-1500 types superclean bench, HF151UV types CO2(Shanghai power Shen scientific instrument have incubator
Limit company)；XSP-15C types inverted microscope (the rectangular optical instrument Co., Ltd in Shanghai)；Multiskan MK3 type enzyme marks
Instrument (Thermo companies of the U.S.)；Ultra-pure water preparing instrument (Milli-Q companies of the U.S.).
Experimental implementation：Test of the sample to Hela cells, A549 cells and MCF-7 cells.The experiment behaviour of every kind of cell
It is identical to make process, in an experimentation, per sample (p.s.) set 5 concentration gradients (10 μM, 30 μM, 100 μM,
300 μM and 1000 μM), each four parallel samples of concentration, every group of experiment is parallel 3 times, and is compareed by blank group
Go out conclusion.ELIASA detects each hole OD values, Detection wavelength 570nm.
3. antitumor activity evaluation
1) cell inhibitory rate calculates：
2)IC50Value calculates
Sample solution concentration logarithm value and cell inhibitory rate linear regression, half-inhibition concentration of the sample to cell is calculated using software
IC50Value.It is preferred that N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- (piperidyl) propionamides are thin to MCF-7 cells, Hela
Born of the same parents and the IC of A549 cells50Respectively 30.8 ± 5.6 μM, 13.8 ± 1.6 μM and 25.7 ± 2.6 μM；N- (5- piperonyl -4- uncles
Butyl thiazol-2-yl) -2- (morpholinyl) acetamides are to the IC of s50For 6.4 ± 2.2 μM.
Active testing result shows, N- (5- piperonyls thiazol-2-yl) amide derivatives to cervical cancer cell (Hela cells),
Human lung adenocarcinoma cell (A549 cells) and human breast cancer cell (MCF-7 cells) have good inhibitory activity, can use
In preparing antineoplastic.
Claims (6)
1. N- (5- piperonyls thiazol-2-yl) amide derivatives shown in a kind of chemical structural formula I and its pharmaceutically acceptable
Salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Z is selected from：CH2Or O；n
It is selected from：1st, 2 or 3.
2. the preparation method of N- (5- piperonyls thiazol-2-yl) amide derivatives described in claim 1, it is characterised in that it
Preparation reaction it is as follows：
In formula, R, Z and n are as claimed in claim 1.
3. N- (the 5- piperonyls thiazol-2-yl) application of amide derivatives in cancer therapy drug is prepared described in claim 1.
4. the answering in medicament for resisting cervical cancer is prepared of N- (5- piperonyls thiazol-2-yl) amide derivatives described in claim 1
With.
5. N- (5- piperonyls thiazol-2-yl) amide derivatives described in claim 1 are in anti-human adenocarcinoma of lung medicine is prepared
Using.
6. N- (5- piperonyls thiazol-2-yl) amide derivatives described in claim 1 are in anti-human breast cancer medicines are prepared
Using.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120172374A1 (en) * | 2010-12-29 | 2012-07-05 | Development Center For Biotechnology | Novel tubulin inhibitors and methods of using the same |
| CN102924400A (en) * | 2012-12-03 | 2013-02-13 | 湖南大学 | N-acyl-4-tertiary butyl-5-benzyl thiazole-2-amine as well as preparation method and application thereof |
| CN102964343A (en) * | 2012-12-10 | 2013-03-13 | 湖南大学 | N-acyl-4-tertiary butyl-5-(1, 2, 4-triazole-1-yl) thiazole-2-amine and preparation method and application thereof |
-
2016
- 2016-05-13 CN CN201610316277.4A patent/CN107365308B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120172374A1 (en) * | 2010-12-29 | 2012-07-05 | Development Center For Biotechnology | Novel tubulin inhibitors and methods of using the same |
| CN102924400A (en) * | 2012-12-03 | 2013-02-13 | 湖南大学 | N-acyl-4-tertiary butyl-5-benzyl thiazole-2-amine as well as preparation method and application thereof |
| CN102964343A (en) * | 2012-12-10 | 2013-03-13 | 湖南大学 | N-acyl-4-tertiary butyl-5-(1, 2, 4-triazole-1-yl) thiazole-2-amine and preparation method and application thereof |
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