CN113121517A - Triazole derivative and preparation method and application thereof - Google Patents

Triazole derivative and preparation method and application thereof Download PDF

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CN113121517A
CN113121517A CN202110206199.3A CN202110206199A CN113121517A CN 113121517 A CN113121517 A CN 113121517A CN 202110206199 A CN202110206199 A CN 202110206199A CN 113121517 A CN113121517 A CN 113121517A
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赵超
徐峻
顾琼
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Sun Yat Sen University
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Abstract

The invention discloses a triazole derivative and a preparation method and application thereof. The triazole derivative has a structure shown in a formula (I):
Figure DDA0002950784700000011
the triazole derivative with a specific structure provided by the invention has high Hsp90 inhibitory activity and low toxicity; can be safely used for preparing Hsp90 inhibitors and anti-cancer metastasis medicaments.

Description

Triazole derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of new application of medicaments, in particular to a triazole derivative and a preparation method and application thereof.
Background
Heat shock protein 90(Hsp90) is an APT-dependent molecular chaperone that is highly conserved in biogenesis andit is widely present in prokaryotic and eukaryotic cell organisms. The primary function of Hsp90 is to properly fold proteins and prevent non-specific aggregation of proteins under stress, which plays a critical role in the normal functioning of signaling pathways. Hsp90 for treating cancer[2]Viral infection[3,4]And neurodegenerative diseases[5]Has good application prospect.
The Hsp90 inhibitors known at present mainly comprise two major classes, one is an inhibitor aiming at an ATP binding pocket at the N-terminal, the other is a protein-protein inhibitor aiming at the C-terminal, and most of the inhibitors are developed aiming at the ATP binding pocket at present. This class of inhibitors mainly includes: 1. natural antibiotics and their derivatives, such as geldanamycin, 17-AAG, etc.; 2. artificially synthesizing small molecules, such as NVP-AUY922, STA-9090 and the like. Hsp90 has been found to be overexpressed in many diseases, particularly cancers, making it interesting for inhibiting cancer cells. Over 300 high-activity Hsp90 inhibitors have been reported, and 11 inhibitors have been used as antitumor drugs in clinical trial studies. The current Hsp90 inhibitors still have strong potential for development, particularly in the area of anticancer metastasis.
Cancer metastasis is a multi-step and multi-link process, which refers to the process that tumor cells are separated from the primary growth site, transported through various pathways, and continuously grow in organs and tissues at distant sites of a body to form tumors with the same properties. The metastasis mechanism is very complex, and various related oncogenes, cancer suppressor genes, adhesion molecules, matrix proteases, cytokines and corresponding signal transduction mechanisms are involved. Invasion and metastasis of cancer cells are important biological properties as a malignant tumor and are also bottlenecks in cancer therapy. Some Hsp90 inhibitors with better inhibitory activity have been reported (for example, CN110151775A, CN106083704A), but they mainly inhibit cancer cells of cancer itself, and there is no suitable drug for treating cancer metastasis at present. Therefore, the development of the Hsp90 inhibitor with better inhibitory activity has important research significance and application value for treating cancer metastasis.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a triazole derivative. The research of the invention finds that the triazole derivative with a specific structure has higher Hsp90 inhibition activity and low toxicity; can be safely used for preparing Hsp90 inhibitors and anti-cancer metastasis medicaments.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
a triazole derivative has a structure shown as a formula (I):
Figure BDA0002950784680000021
wherein R is1Is straight-chain alkyl or substituted straight-chain alkyl, cycloalkyl, five-membered ring or substituted five-membered ring, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle, six-membered ring or benzene ring, six-membered aromatic heterocycle or substituted six-membered aromatic heterocycle containing substituted six-membered ring, benzene ring or substituent;
R2the aromatic heterocyclic compound is linear alkyl or substituted linear alkyl, cycloalkyl, five-membered ring or substituted five-membered ring, five-membered aromatic heterocyclic ring or substituted five-membered aromatic heterocyclic ring, six-membered ring or substituted six-membered ring, benzene ring or substituted benzene ring, six-membered aromatic heterocyclic ring or substituted six-membered aromatic heterocyclic ring containing substituent.
According to the invention, a known Hsp90 inhibitor is split according to a fragment-based drug development method, a dominant fragment is found, the fragment recombination is carried out by a computer according to the rule of click chemistry, an Hsp90 activity inhibition experiment is carried out on the screened compound at the enzyme activity level, and then the further screening is carried out through a cytotoxicity experiment, so that the triazole derivatives with high inhibition activity and low cytotoxicity can effectively inhibit the differentiation of cancer cells such as nasopharyngeal carcinoma, lung cancer, liver cancer and the like and the metastasis of liver cancer cells.
The triazole derivative is different from the molecular skeleton of the known Hsp90 inhibitor, and the compound does not belong to geldanamycin and derivatives thereof, is not radicicol compounds, is not purine compounds, and is a brand-new Hsp90 inhibitor with anti-cancer metastasis activity.
Then, the chemical synthesis method is adopted to synthesize, modify and transform the compounds, so as to obtain a batch of new compounds. And Hsp90 inhibition activity test and cell toxicity test are carried out on the compounds at the cellular level, and a series of compounds with high activity and low toxicity are found. Therefore, the derivatives can be safely used for preparing medicaments for treating cancers.
Preferably, R1Is methyl hexatomic aromatic heterocycle or substituted methyl hexatomic aromatic heterocycle, ethyl hexatomic aromatic heterocycle or substituted ethyl hexatomic aromatic heterocycle, benzene ring or substituted benzene ring, pentatomic aromatic heterocycle or substituted pentatomic aromatic heterocycle, pyridine ring or substituted pyridine ring, pyrimidine ring or substituted pyrimidine ring, pyrazine ring or substituted pyrazine ring.
More preferably, R1Is benzyl or substituted benzyl, benzene ring or substituted benzene ring, pyridine ring or pyridine ring containing substituent, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle, five-membered or six-membered heterocycle.
Further preferably, said R1Is benzyl or substituted benzyl, benzene ring or substituted benzene ring, pyridine ring or pyridine ring containing substituent
Even more preferably, R1Is a benzene ring, a 2-carboxylphenyl group, a 3-carboxylphenyl group, a 4-carboxylphenyl group, a 2-hydroxyphenyl group, a 2-methoxyphenyl group, a 2-methylhydroxyphenyl group, a 2-aminophenyl group, a 2-amidophenyl group, a 2-methylformate phenyl group, a 2-nitrophenyl group, a 2-cyanophenyl group, a 2-6-difluorophenyl group, a 1-2-diaminophenyl group, a 4-trifluoromethoxyphenyl group, a 2-aminophenyl group, a 2-4-dihydroxy-5-isopropylphenyl group, a 2-4-dihydroxy-5-chlorophenyl group, a 2-4-diamino-5-isopropylphenyl group, a 2-4-diamino-5-chlorophenyl group, a benzothiazolyl group, a, Isoquinolinyl, quinolinyl, 1-4-benzodioxanyl, 1-3-benzodioxolyl, 4-tert-butylbenzyl, 3-methoxy-4-tert-butylbenzyl, 3-hydroxy-4-tert-butylbenzyl, 3-5-bistrifluoromethylbenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-5-difluorobenzyl, 4-cyanobenzyl, 3-fluoro-4-methoxybenzyl3-fluoro-4-hydroxybenzyl, 2-trifluoromethylbenzyl, 4-aminobenzyl, 4-hydroxybenzyl, 3-aminobenzyl, 3-hydroxybenzyl, benzyl, 4-trifluoromethoxybenzyl, 3-methoxybenzyl, 4-carboxylbenzyl, 4-phenoxybenzyl, 4-biphenylbenzyl, 2-nitrobenzyl, 2-aminobenzyl, 2-hydroxybenzyl, 2, 4-dihydroxy-5-isopropylbenzyl, 2-4-dihydroxy-5-chlorobenzyl, 2-4-diamino-5-isopropylbenzyl or 2, 4-diamino-5-chlorobenzyl.
Preferably, R2Is methyl hexabasic aromatic heterocycle or substituted methyl hexabasic aromatic heterocycle, ethyl hexabasic aromatic heterocycle or substituted ethyl hexabasic aromatic heterocycle, benzene ring or substituted benzene ring, pyridine ring or substituted pyridine ring.
More preferably, R2Is phenyl or substituted phenyl, pyridine ring or substituted pyridine ring, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle.
Further preferably, said R2Is thiazolyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2-4-dihydroxyphenyl, 2-4-dimethoxyphenyl, 2-amino-4-hydroxyphenyl, 2-amino-4-methoxyphenyl, 2-nitro-4-hydroxyphenyl, 2-nitro-4-methoxyphenyl, 3-4-5-trimethoxyphenyl, 3-4-5-trihydroxyphenyl, 2-4-methylthiazolyl, 4-methyl-5-carboxylic acid ethyl thiazolyl, 4-methyl-5-carboxylic acid methyl ester thiazolyl, 4-methyl-5-formylmorpholine thiazolyl, 4-phenylthiazolyl, thienyl, imidazolyl, pyridyl, 6-methylformate pyridyl, morpholinyl, 2-methylpyridyl, 3-methylpyridyl, 4-methylpyridyl, 5-methylpyridyl, 6-methylpyridyl, 2-cyanopyridyl, 3-cyanopyridyl, 4-cyanopyridyl, 5-cyanopyridyl, 6-cyanopyridyl, 2-nitropyridyl, 3-nitropyridyl, 4-nitropyridyl, 5-nitropyridyl, 6-nitropyridyl, 2-hydroxypyridyl, 3-hydroxypyridyl, 4-hydroxypyridyl, 5-hydroxypyridyl, 6-hydroxypyridyl, 2-methoxypyridyl, 3-methoxypyridyl, 4-methoxypyridyl, pyridinyl, pyrid, 5-methoxypyridyl, 6-methoxypyridyl or 4-hydroisoquinolinyl.
Most preferably, the triazole derivative has the following structural formula:
Figure BDA0002950784680000041
the preparation method of the triazole derivative comprises the following steps: containing substituted halogen molecules R1-X, sodium azide or trimethylsilyl azide, substituted alkynyl containing molecules ≡ -R2 .And reacting to obtain the triazole derivative, wherein X is Cl, Br or I.
The application of the triazole derivative in preparing Hsp90 inhibitor and anti-cancer metastasis drugs is also within the protection scope of the invention.
Preferably, the medicament comprises a pharmaceutically acceptable salt, carrier and/or excipient.
Preferably, the Hsp90 inhibitor is a selective or non-selective inhibitor of four of its subtypes (Hsp90 a, Hsp90 β, GRP94 and TRAP 1); the anti-cancer metastasis drug is an anti-nasopharyngeal cancer metastasis drug, an anti-liver cancer metastasis drug or an anti-lung cancer metastasis drug.
Compared with the prior art, the invention has the following advantages and effects:
(1) the triazole derivative provided by the invention can inhibit osteoclast differentiation to a certain extent, and has good activity inhibition and safety.
(2) The triazole derivative provided by the invention has a simple structure and is easy to synthesize; and the compound has low toxicity and can be safely used for preparing Hsp90 inhibitors and anti-cancer metastasis medicaments.
Drawings
FIG. 1 shows the inhibitory activity of Compound 2 on liver cancer cell metastasis;
FIG. 2 shows the inhibitory activity of Compound 5 on liver cancer cell metastasis;
FIG. 3 shows the inhibitory activity of Compound 8 on liver cancer cell metastasis;
FIG. 4 shows the inhibitory activity of Compound 10 on liver cancer cell metastasis;
FIG. 5 shows structural formulas of compounds 1 to 31.
Detailed Description
The invention is further illustrated by the following examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures without specific conditions noted in the examples below, generally according to conditions conventional in the art or as suggested by the manufacturer; the raw materials, reagents and the like used are, unless otherwise specified, those commercially available from the conventional markets and the like. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
Example 1 in silico drug screening
Collecting molecules that inhibit Hsp 90: the database was constructed by collecting known Hsp90 inhibitors from a database such as PUBMED.
Finding the dominant fragment: through a molecular cutting program DSGA independently researched and developed in the laboratory, the dominant fragments are found and assembled according to a certain rule, then the assembly program is used for assembling according to a click chemistry rule, a virtual compound library is established, and meanwhile, docking software MOE is used for virtual screening to find 20 potential active compounds. After synthesis, the compound 1 (shown in figure 5) is found to have stronger activity.
Example 2 Synthesis of triazole derivatives
Figure BDA0002950784680000061
The synthetic route of the triazole derivative is shown as the formula. The molecule containing the substituted halogen is added to a mixed solvent of methanol (which may be replaced with ethanol or DMSO) and water, while adding sodium azide or trimethylsilylazide, and stirred at room temperature for 0.5 hour. Subsequently, a molecule containing a substituted alkynyl group, CuI and 1, 8-diazabicycloundecen-7-ene (DBU) were added and stirred at 40 ℃ for 8 hours. After extraction with ethyl acetate, the organic layer was spin dried and separated by column chromatography to give the desired molecule.
Synthesis of Compound 1(6- (4- (thiophen-2-yl) -1H-1,2,3-triazol-1-yl) isoquinoline)
The compound containing halogen 6-bromo isoQuinoline (206mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round bottom flask, and solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and purified by column chromatography to give the final product as a yellow solid (239 mg) in 86% yield.1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.56(d,J＝4.0Hz,1H),7.91-8.86(m,3H)，7.39(t,J＝4.0Hz,1H)。13C NMR(100MHz,CDCl3)δ151.7,143.4,133.9,132.9,128.6,126.7,126.4,120.5,118.3.ESI-MS m/z:279.16[M+H]+.
Synthesis of Compound 2(6- (4- (tert-butyl) phenyl) -1H-1,2,3-triazol-1-yl) isoquinoline)
The compound 6-bromoisoquinoline (206mg,1mmol) containing a halogen, CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were charged into a round-bottomed flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (158mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give HI-2 as a final product in a yield of 79% as a white solid, 259mg, by removing the solvent through distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.25(d,J＝8.0Hz,1H),7.98(d,J＝8.0Hz,1H),7.66(s,1H),7.55(s,1H),7.55(d,J＝8.0Hz,2H),7.42-7.40(m,2H),7.05(d,J＝8.0Hz,2H),3.83(s,3H)。13C NMR(100MHz,CDCl3)δ160.6,152.5,148.0,143.4,136.6,131.4,130.2,128.9,127.4,123.9,122.7,120.9,114.8,55.8.ESI-MS m/z:302.11[M+H]+.
Synthesis of Compound 3(6- (4- (4-methoxyphenyl) -1H-1,2,3-triazol-1-yl) isoquinoline)
Adding halogen-containing compound 6-bromoisoquinoline (206mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) to a round bottomIn a flask, a solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-tert-butylacetylene (131mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give final product HI-3 as a white solid 163mg, yield 54% by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.20(d,J＝8.0Hz,1H),8.07(s,1H),7.89(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,2H),7.62(s,1H),7.43(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,2H),1.35(s,9H)。13C NMR(100MHz,CDCl3)δ152.5,151.3,148.0,143.4,136.6,131.4,130.2,128.9,128.0,127.4,127.3,125.5,125.4,123.9,120.9,34.2,31.3.ESI-MS m/z:329.16[M+H]+.
Synthesis of Compound 4(1- (4- (tert-butyl) benzyl) -4- (thiophen-2-yl) -1H-1,2,3-triazole)
The halogen-containing compound 4-methoxyphenylacetylene (212mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were charged to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid, 216mg, yield 73% by distillation under reduced pressure.1H NMR(400MHz,DMSO-d6)δ7.50-7.47(m,4H),7.24-7.22(m,3H),5.48(s,2H),2.21(s,9H)。13C NMR(100MHz,DMSO-d6)δ202.6,175.3,169.4,165.6,158.2,138.3,138.1,114.4,113.9,95.70,91.2,51.3,30.7,21.7.ESI-MS m/z:298.41[M+H]+.
Synthesis of Compound 5(1- (4- (tert-butyl) benzyl) -4- (4- (tert-butyl) phenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (212mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were charged to a round-bottom flaskA solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (158mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 246mg with a yield of 71% after removal of the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.0Hz,2H),7.64(s,1H),7.36-7.33(m,3H),7.16(d,J＝8.0Hz,2H),5.45(s,2H),1.25(s,9H),1.24(s,9H)。13C NMR(100MHz,CDCl3)δ150.8,150.2,147.1,130.7,126.8,126.7,125.0,124.7,124.4,118.2,52.9,33.6,30.2,30.2.ESI-MS m/z:348.24[M+H]+.
Synthesis of Compound 6(1- (4- (tert-butyl) benzyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (212mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-tert-butylacetylene (132mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to obtain the final product as a white solid, 189mg, yield 59%.1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.0Hz,2H),7.50(s,1H),7.32(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),6.84(d,J＝8.0Hz,2H),5.44(s,2H),3.74(s,3H),1.21(s,9H).13C NMR(100MHz,CDCl3)δ158.5,150.8,147.0,130.7,126.8,126.0,125.0,122.3,117.7,113.1,113.1,54.3,52.9,33.6,30.2,28.7.ESI-MS m/z:322.18[M+H]+.
Synthesis of Compound 7(1- (4-phenoxyphenyl) -4- (thiophen-2-yl) -1H-1,2,3-triazole)
The halogen-containing compound 4-bromodiphenyl ether (248mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottomed flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a yellow solid 178mg in 56% yield by removing the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.66-7.62(m,2H),7.41-7.40(m,1H),7.35-7.31(m,2H),7.30-7.27(m,1H),7.11-6.99(m,6H).13C NMR(100MHz,CDCl3)δ156.9,129.0,126.7,124.4,123.5,123.2,121.3,118.4,118.3,116.2,28.7.ESI-MS m/z:320.07[M+H]+.
Synthesis of compound 8(4- (4- (tert-butyl) phenyl) -1- (4-phenoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-bromodiphenyl ether (248mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (157mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product as a white solid 239mg in 65% yield.1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.76(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.43-7.41(m,2H),7.34-7.30(m,2H),7.13-7.06(m,3H),7.02-6.99(m,2H).13C NMR(100MHz,CDCl3)δ156.79,155.35,150.55,147.36,131.31,128.99,126.38,124.82,124.56,123.09,121.22,118.37,118.31,116.39,33.70,30.27.ESI-MS m/z:370.18[M+H]+.
Synthesis of Compound 9(4- (4-methoxyphenyl) -1- (4-phenoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-bromodiphenyl ether (248mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). Stirring at room temperature for 1 hour, and then adding the alkynyl-containing compound 4-Tert-butylacetylene (132mg,1mmol) and DBU (300mg,2mmol) were added to the mixture and stirred at 70 deg.C for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 209mg with a yield of 61% after removal of the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.76(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.35-7.31(m,2H),7.13-7.08(m,4H),6.99-6.91(m,3H),3.79(s,3H).13CNMR(100MHz,CDCl3)δ158.78,156.79,131.31,128.99,126.13,123.10,121.91,121.21,118.39,118.30,115.91,113.31,54.33.ESI-MS m/z:344.13[M+H]+.
Synthesis of Compound 10(4- (thiophen-2-yl) -1- (4- (trifluoromethylphenyl) benzyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-trifluoromethylbromobenzene (225mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 207mg in 67% yield by removing the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.55(s,2H),7.32(d,J＝8.0Hz,2H),7.27(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.19(s,1H),6.98(t,J＝4.0Hz,1H),5.54(s,2H).13C NMR(100MHz,CDCl3)δ142.58,137.45,131.52,127.16,126.62,125.14,125.07,124.24,123.33,118.05,52.53.ESI-MS m/z:310.05[M+H]+.
Synthesis of Compound 11(4- (4- (tert-butyl) phenyl) -1- (4- (trifluoromethyl) benzyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-trifluoromethylbromobenzene (225mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. Stirring at room temperature for 1 hour, and then adding the alkynyl-containing compound 4-tert-butylbenzylBromine (157mg,1mmol) and DBU (300mg,2mmol) were added to the mixture and stirred at 70 deg.C for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid, 183mg, yield 51% by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,2H),7.60(s,1H),7.56(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),5.56(s,2H),1.26(s,9H).13C NMR(100MHz,CDCl3)δ150.50,147.53,137.75,127.07,126.39,125.10,125.07,125.03,124.76,124.44,118.28,52.46,33.65,30.24。ESI-MS m/z:360.05[M+H]+.
Synthesis of Compound 12(4- (4-methoxyphenyl) -1- (4- (trifluoromethylphenyl) benzyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-trifluoromethylbromobenzene (225mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-tert-butylacetylene (132mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to obtain the final product as a white solid (179 mg) with a yield of 54% after removal of the solvent by distillation under the reduced pressure.1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.0Hz,2H),7.58-7.55(m,3H),7.33(d,J＝8.0Hz,2H),6.87(d,J＝8.0Hz,2H),5.55(s,2H),3.76(s,3H).13C NMR(100MHz,CDCl3)δ158.7,147.4,137.7,133.0,127.1,126.0,125.1,125.1,125.0,121.9,117.7,113.2,113.1,54.3,52.5.ESI-MS m/z:334.10[M+H]+.
Synthesis of Compound 13(1- (3,5-bis (trifluoromethyl) benzyl) -4- (thiophen-2-yl) -1H-1,2,3-triazole)
The halogen-containing compound 3, 5-bistrifluoromethylbromobenzene (305mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. Stirring at room temperature for 1 hour, and mixing the alkynyl-containing compound 2-alkynylthiophene (1)08mg,1mmol) and DBU (300mg,2mmol) were added to the mixture and stirred at 70 deg.C for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under the reduced pressure to remove the solvent, and column chromatography purification to give the final product as a white solid 297mg with a yield of 79%.1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.70(s,1H),7.62(s,1H),7.31(d,J＝4.0Hz,1H),7.24(d,J＝4.0Hz,1H),7.00(t,J＝4.0Hz,1H),5.61(s,2H).13C NMR(100MHz,CDCl3)δ142.9,136.1,131.9,131.6,131.3,127.1,126.7,124.5,123.6,121.9,120.5,118.0,52.0.ESI-MS m/z:378.04[M+H]+.
Synthesis of Compound 14(1- (3,5-bis (trifluoromethyl) benzyl) -4- (4- (tert-butyl) phenyl) -1H-1,2,3-triazole)
The halogen-containing compound 3, 5-bistrifluoromethylbromobenzene (305mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (157mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product as a white solid 277mg in 65% yield.1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.69-7.66(m,5H),7.37(d,J＝8.0Hz,2H),5.62(s,2H),1.26(s,9H).13C NMR(100MHz,CDCl3)δ150.7,147.8,136.4,131.8,131.4,126.9,126.9,126.2,124.8,124.5,121.8,121.8,121.7,118.3,51.9,33.7,30.22.ESI-MS m/z:428.14[M+H]+.
Synthesis of Compound 15(1- (3,5-bis (trifluoromethyl) benzyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 3, 5-bistrifluoromethylbromobenzene (305mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent (DMSO: H2O ═ 5:1) was added. After stirring at room temperature for 1 hour, the alkynyl group-containing compound, 4-tert-butylacetylene (132mg,1mmol), and DBU (300mg,2mmol) were addedThe mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 236mg with a yield of 59% by removing the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.65(d,J＝8.0Hz,2H),7.66(s,1H),7.48(s,2H),7.31(d,J＝8.0Hz,2H),5.50(s,2H),3.84(s,3H).13C NMR(100MHz,CDCl3)δ158.7,147.4,137.7,133.0,127.1,126.0,125.1,125.1,125.0,121.9,117.7,113.2,113.1,54.3,52.5.ESI-MS m/z:402.09[M+H]+.
Synthesis of Compound 16(1- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4- (thiophen-2-yl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxane (213mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 131mg in 46% yield by removing the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.92(s,0.5H),8.82(s,0.5H),7.27-7.12(m,2H),7.04-6.90(m,3H),4.24(s,2H).13C NMR(100MHz,CDCl3)δ143.1,131.4,129.6,126.7,124.8,124.3,124.1,123.5,117.0,116.3,112.8,109.3,63.4.ESI-MS m/z:286.05[M+H]+.
Compound 17
Synthesis of (4- (4- (tert-butyl) phenyl) -1- (2, 3-dihydrobenzob [ b ] [1,4] dioxin-6-yl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxane (213mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (157mg,1mmol) and DBU (300mg,2mmol) were added to the mixtureAnd stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under the reduced pressure to remove the solvent, and column chromatography purification to give the final product as a white solid 221mg in 66% yield.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.84(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,2H),7.34(s,1H),7.26(d,J＝8.0Hz,1H),4.34(s,3H),1.39(s,9H).13C NMR(100MHz,CDCl3)δ151.5,148.2,144.1,144.0,131.0,127.5,125.8,125.6,118.0,117.4,113.7,110.2,64.4,64.4,34.7,31.3.ESI-MS m/z:336.16[M+H]+.
Synthesis of Compound 18(1- (2, 3-dihydroxybenzo [ b ] [1,4] dioxin-6-yl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxane (213mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-tert-butylacetylene (132mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 127mg in 51% yield by removing the solvent therefrom by distillation under the reduced pressure.1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.27(s,1H),7.18(d,J＝8.0Hz,2H),6.95(s,1H),6.89-6.77(m,3H),4.30-4.29(m,4H),3.82(s,3H).13C NMR(100MHz,DMSO-d6)δ159.7,147.5,144.3,144.0,130.9,127.1,123.4,119.1,118.4,114.9,113.4,109.6,64.8,64.6,55.7.ESI-MS m/z:310.11[M+H]+.
Synthesis of Compound 19(1- (benzod ] [1,3] dioxol-5-yl) -4- (thiophen-2-yl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxole (200mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2-alkynylthiophene (108mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, 70Stir at celsius for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under the reduced pressure to remove the solvent, and purified by column chromatography to give the final product as a white solid (143 mg) with a yield of 53%.1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.59(d,J＝4.0Hz,1H),7.53(d,J＝4.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.19(t,J＝4.0Hz,1H),7.16(d,J＝8.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ148.7,148.0,142.9,132.9,131.4,128.5,126.3,124.9,119.6,114.4,109.1,102.7,102.5.ESI-MS m/z:272.057[M+H]+.
Synthesis of Compound 20(1- (benzod ] [1,3] dioxol-5-yl) -4- (4- (tert-butyl) phenyl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxole (200mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 4-methoxyphenylacetylene (157mg,1mmol) and DBU (300mg,2mmol) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to obtain the final product in the form of white solid 179mg with a yield of 56% after removal of the solvent by distillation under reduced pressure.1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.75(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.24(d,J＝4.0Hz,1H),7.13(d,J＝8.0Hz,1H),6.85(d,J＝8.0Hz,1H),6.01(s,2H),1.29(s,9H).13C NMR(100MHz,CDCl3)δ150.5,147.6,147.2,146.9,130.6,126.4,124.8,124.5,116.6,113.1,107.5,101.7,101.1,33.7,30.3,28.7.ESI-MS m/z:322.14[M+H]+.
Synthesis of Compound 21(1- (benzol [ d ] [1,3] dioxol-5-yl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 1-bromo-3, 4-benzodioxole (200mg,1mmol), CuI (19mg,0.1mmol) and sodium azide (165mg,3mmol) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, 4-tert-butylacetylene (132mg,1 mmo) as an alkynyl-containing compound was addedl) and DBU (300mg,2mmol) were added to the mixture and stirred at 70 deg.C for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was purified by column chromatography to give the final product as a white solid 126mg in 43% yield by removing the solvent by distillation under reduced pressure.1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.65(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.83(s,1H),6.07(s,2H),3.84(s,3H).13C NMR(100MHz,DMSO-d6)δ160.6,148.8,148.0,131.4,128.5,122.7,121.8,118.9,114.8,114.6,109.3,101.2,55.8.ESI-MS m/z:296.09[M+H]+.
Synthesis of Compound 22(1- (2, 3-dihydroxybenzo [ b ] [1,4] dioxin-6-yl) -5- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compounds 3, 5-bistrifluoromethylbromobenzene (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottomed flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound, 4-tert-butylacetylene (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in a yield of 36%.1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.51(s,1H),7.33(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,1H),6.81(d,J＝8.0Hz,1H),5.45(s,2H),1.24(s,9H).13C NMR(100MHz,DMSO-d6)δ157.7,151.1,147.4,133.7,128.1,127.0,125.9,122.2,120.5,116.1,53.1,34.8,31.5.ESI-MS m/z:308.39[M+H]+.
Synthesis of Compound 23(1- (4- (tert-butyl) benzyl) -4- (2,4-dimethoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound 2, 4-dimethoxyphenylacetylene (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. By usingThe reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was distilled under reduced pressure to remove the solvent and purified by column chromatography to give the final product in 45% yield.1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.02(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,2H),7.27(d,J＝8.0Hz,2H),6.67-6.63(m,2H),5.59(s,2H),3.89(s,3H),3.80(s,3H),1.26(s,9H).13C NMR(100MHz,DMSO-d6)δ158.5,157.9,137.9,132.5,126.1,125.9,118.9,117.7,113.2,110.0,54.3,54.1,53.0,33.8,28.6.ESI-MS m/z:352.44[M+H]+。
Synthesis of Compound 24(2- (1- (4- (tert-butyl) benzyl) -1H-1,2,3-triazol-4-yl) -5-methoxyphenol)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 71% yield.1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.26(s,1H),7.90(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),6.49-6.44(m,2H),5.57(s,2H),3.83(s,3H),1.26(s,9H).13C NMR(100MHz,DMSO-d6)δ157.7,156.5,147.4,135.6,135.2,127.1,127.0,120.6,118.4,116.1,115.5,53.0,34.6,29.7.ESI-MS m/z:338.38[M+H]+。
Synthesis of Compound 25(1- (4- (tert-butyl) benzyl) -4- (4-methoxy-2-nitrophenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. Evaporating the organic layer under reduced pressureThe solvent was removed by distillation and purified by column chromatography to give the final product in 70% yield.1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.0Hz,1H),7.59(s,1H),7.33(d,J＝8.0Hz,2H),7.24-7.09(m,5H),5.47(s,2H),3.82(s,3H),1.34(s,9H).13C NMR(100MHz,DMSO-d6)δ159.8,151.2,149.4,142.2,133.4,131.8,128.2,126.0,123.4,118.9,116.1,109.5,56.6,53.1,34.8,31.5.ESI-MS m/z:367.41[M+H]+。
Synthesis of Compound 26(2- (1- (4- (tert-butyl) benzyl) -1H-1,2,3-triazol-4-yl) -5-methoxyailine)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 58% yield.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.42-7.29(m,4H),6.34-6.18(m,3H),5.59(s,2H),3.35(s,3H),1.26(s,9H).13C NMR(100MHz,DMSO-d6)δ160.2,151.1,148.2,147.6,133.6,129.2,128.2,126.0,120.8,106.6,103.2,100.5,55.2,53.2,34.7,31.5.ESI-MS m/z:337.43[M+H]+。
Synthesis of Compound 27(4- (1- (4- (tert-butyl) benzyl) -1H-1,2,3-triazol-4-yl) -3-nitrophenol)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 78% yield.1H NMR(400MHz,DMSO-d6)δ10.82(brs,1H),8.40(s,1H),7.61(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,2H),7.28(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,1H),7.44-7.11(m,1H),5.60(s,2H),1.27(s,9H).13C NMR(100MHz,DMSO-d6)δ158.4,149.4,142.6,133.5,132.2,128.2,126.0,123.2,120.0,114.8,110.9,53.1,34.8,31.5.ESI-MS m/z:353.38[M+H]+。
Synthesis of Compound 28(1- (4- (tert-butyl) -3-methoxybenzyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 78% yield.1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.0Hz,2H),7.52(s,1H),7.19(s,1H),6.86(d,J＝8.0Hz,2H),6.79-6.71(m,2H),5.43(s,2H),3.75(s,3H),3.72(s,3H),1.28(s,9H).13C NMR(100MHz,CDCl3)δ158.5,158.0,138.0,132.5,126.1,126.0,118.9,117.7,113.2,110.0,54.3,54.1,53.0,33.8,28.6.ESI-MS m/z:352.44[M+H]+。
Synthesis of compound 29(2- (tert-butyl) -5- ((4- (4-hydroxypentyl) -1H-1,2,3-triazol-1-yl) methyl) phenol)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and purified by column chromatography to give the final product in a yield of 56%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.44(s,1H),8.39(s,1H),7.65(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,1H),6.83(d,J＝8.0Hz,2H),6.72-6.55(m,2H),5.48(s,2H),1.31(s,9H).13C NMR(100MHz,DMSO-d6)δ157.7,156.5,147.4,135.6,135.2,127.1,127.0,120.6,118.4,116.1,115.5,53.0,34.6,29.7.ESI-MS m/z:324.38[M+H]+。
Synthesis of Compound 30(1- (4- (tert-butyl) benzyl) -4- (3,4, 5-trimethophenyl) -1H-1,2,3-triazole)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 66% yield.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.33(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),6.96(s,2H),5.46(s,2H),3.83(s,6H),3.79(s,3H),1.24(s,9H).13CNMR(100MHz,CDCl3)δ152.6,150.9,147.1,130.7,126.8,125.0,118.3,101.9,59.9,55.2,52.9,33.6,30.2.ESI-MS m/z:382.46[M+H]+。
Synthesis of Compound 31(5- (1- (4- (tert-butyl) benzyl) -1H-1,2,3-triazol-4-yl) bezene-1, 2,3-triol)
The halogen-containing compound 4-tert-butylbenzylbromide (1eq.), CuI (0.1eq.), and sodium azide (3eq.) were added to a round-bottom flask, and the solvent was added (DMSO: H2O ═ 5: 1). After stirring at room temperature for 1 hour, the alkynyl group-containing compound (1eq.) and DBU (2eq.) were added to the mixture, and the mixture was stirred at 70 ℃ for 8 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added to the mixture, and washed with water 3 times. The organic layer was subjected to distillation under reduced pressure to remove the solvent, and column chromatography purification to give the final product in 73% yield.1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.32(s,1H),8.20(s,1H),7.40(d,J＝8.0Hz,2H),7.28(d,J＝8.0Hz,2H),6.72(d,J＝8.0Hz,1H),5.53(s,2H),1.26(s,9H).13C NMR(100MHz,DMSO-d6)δ151.0,147.7,146.8,133.7,133.6,128.2,125.9,121.7,120.6,104.9,53.1,34.7,31.5.ESI-MS m/z:340.38[M+H]+。
And S3.ATP enzyme activity testing method.
The reaction system treated by the compound for 50min is determined by adopting an adenosine triphosphate enzyme activation method. The absorbance (OD) of the wells was measured using a microplate reader (detection wavelength 340nm, reference wavelength 630 nm).
And S4, result processing.
Measuring A value, plotting A value against time to obtain slope, determining relative activity of each compound, and making inhibition curve to obtain IC of each compound50The value is obtained. Each compound was determined in triplicate for averaging.
Example 3 cancer cell inhibition assay
S1, cell culture.
HepG2, CNE2 and HeLa cells were cultured in vitro. Conventional maintenance culture and passage were carried out at 37 ℃ in a DMEM medium containing 10% fetal bovine serum and 5% carbon dioxide.
S2, compound intervention.
The cells were counted in a cell counting plate and plated in 96-well cell culture plates at 100. mu.L/well and 5000 cells/well. After culturing for 24 hours to allow the cells to adhere to the wall, compounds with different concentrations diluted with the culture medium were added, 100. mu.L per well, and 3 duplicate wells were set. After 72 hours, medium containing 5mg/mL MTT was added to each well except for the blank set of wells and incubation was continued for 4 hours. The medium was then discarded and 100. mu.L DMSO was added to each well. After the product is fully dissolved, the mixture is put into a container,
and S3, testing.
The OD of each well at a wavelength of 570nm was measured on a full-wavelength microplate reader. Cell viability in each sample was calculated by the following formula: cell viability (%) - (OD sample-OD blank)/(OD control-OD blank).
And S4, result processing.
Plotting the inhibition rate of cancer cells as ordinate and the log value of compound concentration as abscissa to obtain a curve of inhibition of cancer cell differentiation by each compound, and calculating the half-effective rate IC according to the inhibition rate of each compound on cancer cell differentiation50I.e. the concentration of the drug at which the differentiation of cancer cells is inhibited by 50%.
In addition, 293T cells were selected to measure CC50 of the compounds to evaluate toxicity of the compounds, and selective inhibition constants of the respective compounds were calculated by (SI) ═ CC50/IC50 to comprehensively analyze the drug effects of the molecules.
As can be seen from the results in Table 1,4 compounds of the present invention, which have different degrees of inhibition on cancer metastasis and no toxicity on cancer cells and general cells, were found by the cancer cell inhibition experiment and the anti-cancer metastasis chamber experiment, among which 10 compounds have the best activity, the highest therapeutic index and the IC of cancer metastasis500.06. mu.M (see FIG. 4, Table 1); second, 2, IC500.11. mu.M (see FIG. 1, Table 1); the next to active is 5, IC500.21. mu.M (see FIG. 2, Table 1); finally, compound 8, IC50It was 0.35. mu.M (see FIG. 3, Table 1).
TABLE 1 inhibition of Hsp90, hepatocarcinoma cell, and common cell differentiation and inhibition of cancer metastasis by drug screening
Figure BDA0002950784680000171
Figure BDA0002950784680000181
Example 4 cancer metastasis inhibition experiment
S1 Material preparation
A photo microscope, a Transwell chamber, a pore size of 8 μm, a cell culture plate 24-well plate, serum-free DMEM, DMEM complete medium, sterile PBS, cotton swabs, pancreatin (0.25% pancreatin), 4% paraformaldehyde stationary liquid or methanol, crystal violet stain (0.1% (g/mL) PBS crystal violet).
S2 preparation of cell suspension
Firstly, before preparing cell suspension, the cells can be starved for 12-24 hours after serum is removed, and the influence of the serum is further removed; ② digesting the cells, centrifuging after terminating digestion and discarding the culture solution, (washing 1-2 times with PBS), resuspending with serum-free culture medium containing BSA, adjusting the cell density to 5 × 105/ml。
S3 seeded cells
Firstly, 100 mu L of cell suspension is taken and added into a Transwell chamber; ② adding complete culture medium into the lower chamber of the 24-pore plate, removing air bubbles, and then placing the small chamber into the culture plate. ③ culturing the cells: and culturing for 24 h.
S3 result processing
Direct counting, "adherent" cell counting, where "adherent" means that cells, after passing through a membrane, can adhere to the lower chamber side of the membrane without falling into the lower chamber, and by staining the cells, the cells can be counted under a microscope. The Transwell chamber was removed, the medium from the wells was discarded, washed 2 times with calcium-free PBS, fixed in methanol for 30 minutes, and the chamber was appropriately air-dried. 0.1% crystal violet stain for 20min, gently wipe off the upper non-migrated cells with a cotton swab, wash 3 times with PBS. Cells were observed at random in five fields under 400 times microscope and counted.
The invention discovers a triazole derivative by a computer-aided drug design similarity retrieval method. Through an ATP enzyme activity inhibition test and a cancer test, the compounds are found to have the liver cancer cell metastasis inhibition activity of 2, 5, 8 and 10 of less than 1 mu M, small cytotoxicity and high therapeutic index. Of these, 10 had the best activity, the highest therapeutic index, IC50At 0.06. mu.M (see FIG. 4, Table 1). The results show that the compounds have high inhibitory activity on cancer cell metastasis and low cytotoxicity, and can be used as a class of Hsp90 inhibitor for preparing anti-cancer metastasis.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (10)

1. A triazole derivative is characterized by having a structure shown as a formula (I):
Figure FDA0002950784670000011
wherein R is1Is straight-chain alkyl or substituted straight-chain alkyl, cycloalkyl, five-membered ring or substituted five-membered ring, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle, six-membered ring or benzene ring, six-membered aromatic heterocycle or substituted six-membered aromatic heterocycle containing substituted six-membered ring, benzene ring or substituent;
R2the aromatic heterocyclic compound is linear alkyl or substituted linear alkyl, cycloalkyl, five-membered ring or substituted five-membered ring, five-membered aromatic heterocyclic ring or substituted five-membered aromatic heterocyclic ring, six-membered ring or substituted six-membered ring, benzene ring or substituted benzene ring, six-membered aromatic heterocyclic ring or substituted six-membered aromatic heterocyclic ring containing substituent.
2. The triazole derivative according to claim 1, wherein R is1Is methyl hexatomic aromatic heterocycle or substituted methyl hexatomic aromatic heterocycle, ethyl hexatomic aromatic heterocycle or substituted ethyl hexatomic aromatic heterocycle, benzene ring or substituted benzene ring, pentatomic aromatic heterocycle or substituted pentatomic aromatic heterocycle, pyridine ring or substituted pyridine ring, pyrimidine ring or substituted pyrimidine ring, pyrazine ring or substituted pyrazine ring;
R2is methyl hexabasic aromatic heterocycle or substituted methyl hexabasic aromatic heterocycle, ethyl hexabasic aromatic heterocycle or substituted ethyl hexabasic aromatic heterocycle, benzene ring or substituted benzene ring, pyridine ring or substituted pyridine ring.
3. The triazole derivative according to claim 2, wherein R is1Is benzyl or substituted benzyl, benzene ring or substituted benzene ring, pyridine ring or pyridine ring containing substituent, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle, five-membered or six-membered heterocycle;
R2is phenyl or substituted phenyl, pyridine ring or substituted pyridine ring, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle.
4. The triazole derivative according to claim 3,R1is benzyl or substituted benzyl, benzene ring or substituted benzene ring, pyridine ring or pyridine ring containing substituent;
R2is phenyl or substituted phenyl, pyridine ring or substituted pyridine ring, five-membered aromatic heterocycle or substituted five-membered aromatic heterocycle.
5. The triazole derivative according to any one of claims 1 to 4, wherein R is1Is a benzene ring, a 2-carboxylphenyl group, a 3-carboxylphenyl group, a 4-carboxylphenyl group, a 2-hydroxyphenyl group, a 2-methoxyphenyl group, a 2-methylhydroxyphenyl group, a 2-aminophenyl group, a 2-amidophenyl group, a 2-methylformate phenyl group, a 2-nitrophenyl group, a 2-cyanophenyl group, a 2-6-difluorophenyl group, a 1-2-diaminophenyl group, a 4-trifluoromethoxyphenyl group, a 2-aminophenyl group, a 2-4-dihydroxy-5-isopropylphenyl group, a 2-4-dihydroxy-5-chlorophenyl group, a 2-4-diamino-5-isopropylphenyl group, a 2-4-diamino-5-chlorophenyl group, a benzothiazolyl group, a, Isoquinolinyl, quinolyl, 1-4-benzodioxanyl, 1-3-benzodioxolyl, 4-tert-butylbenzyl, 3-methoxy-4-tert-butylbenzyl, 3-hydroxy-4-tert-butylbenzyl, 3-5-bistrifluoromethylbenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-5-difluorobenzyl, 4-cyanobenzyl, 3-fluoro-4-methoxybenzyl, 3-fluoro-4-hydroxybenzyl, 2-trifluoromethylbenzyl, 4-aminobenzyl, 4-hydroxybenzyl, 3-aminobenzyl, 3-hydroxybenzyl, benzyl, 4-trifluoromethoxybenzyl, 3-methoxybenzyl, 4-carboxylic acid benzyl, 4-phenoxybenzyl, 4-nitrobenzyl, 4-, 4-biphenylbenzyl, 2-nitrobenzyl, 2-aminobenzyl, 2-hydroxybenzyl, 2, 4-dihydroxy-5-isopropylbenzyl, 2-4-dihydroxy-5-chlorobenzyl, 2-4-diamino-5-isopropylbenzyl or 2, 4-diamino-5-chlorobenzyl;
R2is thiazolyl, 4-methoxybenzene, 4-hydroxybenzene, 2-4-dihydroxybenzene, 2-4-dimethoxybenzene, 2-amino-4-hydroxybenzene, 2-amino-4-methoxybenzene, 2-nitro-4-hydroxybenzene, 2-nitro-4-methoxybenzene, 3-4-5-trimethoxybenzene, 3-4-5-trihydroxybenzene, 2-4-methylthiazolyl, 4-methyl-5-ethyl formate thiazolyl, 4-methyl-5-methyl formate thiazolyl, 4-methyl-5-carboxylic acid thiazolyl, 4-methyl-5-formylmorpholine thiazolyl, 4-phenylthiazolyl, thienyl, m-ethylthiazolyl, m-5-methyl formate, m-ethylthiazolyl, m-thiazolyl, Tooth-stickOxazolyl, pyridyl, 6-methylformate pyridyl, morpholinyl, 2-methylpyridyl, 3-methylpyridyl, 4-methylpyridyl, 5-methylpyridyl, 6-methylpyridyl, 2-cyanopyridyl, 3-cyanopyridyl, 4-cyanopyridyl, 5-cyanopyridyl, 6-cyanopyridyl, 2-nitropyridyl, 3-nitropyridyl, 4-nitropyridyl, 5-nitropyridyl, 6-nitropyridyl, 2-hydroxypyridyl, 3-hydroxypyridyl, 4-hydroxypyridyl, 5-hydroxypyridyl, 6-hydroxypyridyl, 2-methoxypyridyl, 3-methoxypyridyl, 4-methoxypyridyl, pyridinol-O-methyl, pyridyl, morpholinyl, 2-methylpyridinyl, 3, 5-methoxypyridyl, 6-methoxypyridyl or 4-hydroisoquinolinyl.
6. The triazole derivative according to claim 5, having the following structural formula:
Figure FDA0002950784670000031
7. the process for producing a triazole derivative as claimed in any one of claims 1 to 6, which comprises the steps of: containing substituted halogen molecules R1-X, sodium azide or trimethylsilyl azide, substituted alkynyl containing molecules
Figure FDA0002950784670000041
And reacting to obtain the triazole derivative, wherein X is Cl, Br or I.
8. The use of the triazole derivative of any one of claims 1 to 6 in the preparation of Hsp90 inhibitors and drugs for treating cancer metastasis.
9. The use of claim 8, wherein the medicament comprises a pharmaceutically acceptable salt, carrier and/or excipient.
10. The use of claim 8, wherein the inhibitor of Hsp90 is a selective or non-selective inhibitor of Hsp90 a, Hsp90 β, GRP94 or TRAP 1; the anti-cancer metastasis drug is an anti-nasopharyngeal cancer metastasis drug, an anti-liver cancer metastasis drug or an anti-lung cancer metastasis drug.
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