CN115043784B - Biphenyl-1, 2, 3-triazole conjugate and preparation method and application thereof - Google Patents

Biphenyl-1, 2, 3-triazole conjugate and preparation method and application thereof Download PDF

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CN115043784B
CN115043784B CN202210537532.3A CN202210537532A CN115043784B CN 115043784 B CN115043784 B CN 115043784B CN 202210537532 A CN202210537532 A CN 202210537532A CN 115043784 B CN115043784 B CN 115043784B
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沈晨峰
田铠铭
纳尔瓦·苏雷什
常琳茹
张文
赵晓寅
熊绪琼
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a biphenyl-1, 2, 3-triazole conjugate, a preparation method and application thereof, wherein the structural general formula of the biphenyl-1, 2, 3-triazole conjugate is shown as formula (I): the invention takes (2-methyl biphenyl-3-yl) methanol as a raw material, uses propargyl bromide solution to treat the raw material in the presence of sodium hydride to obtain a (2-methyl-3- (2-alkynyloxy) methyl) biphenyl intermediate, and carries out click chemistry reaction with various aromatic azides under the catalysis of sodium aspartate and copper sulfate pentahydrate to design and synthesize biphenyl-1, 2, 3-triazole conjugate (3 a-r,4 a-b). The compounds 4a-b were treated with thionyl chloride to give compounds 5a-b. Various aliphatic amines were reacted with compounds 5a-b in the presence of K 2CO3 and acetonitrile to form compounds 6a-h. Most of the compounds, especially the 4a-b, 5a-b and 6a-h series compounds, have better inhibition activity on the growth of three cancer cells (A549, HCC827 and MDA-MB-231), wherein the compounds 6d, 6e and 6h have obvious toxicological activity on the three cancer cells.

Description

Biphenyl-1, 2, 3-triazole conjugate and preparation method and application thereof
Technical Field
The invention relates to the field of biological medicine, in particular to a biphenyl-1, 2, 3-triazole conjugate and a preparation method and application thereof.
Technical Field
Since the 1967 burn invented the immune system known as immune monitoring for sensitive and specific recognition functions, the field of pharmaceutical chemistry has raised a hurdle in the search for drugs for cancer immunotherapy. Immune Checkpoint Blockade (ICB) anticancer therapies have achieved significant success in the last few years. The most attractive immune checkpoint receptors are the apoptosis protein-1 (PD-1) and the apoptosis ligand-1 (PD-L1). PD-1 is expressed by activated T cells, B cells and natural killer cells; PD-L1 is typically found on Antigen Presenting Cells (APCs) and on the surface of many different tumor cells. In 1992, a team led by the university of Kyoto, tasuku Honjo, japan, discovered the genetic code for PD-1 in a molecular study of programmed death of T cells. The identification of the PD-1 ligand PD-L1 in 2000 and PD-L2 in 2001 revealed that PD-1 is an immunomodulatory receptor, playing an important role in autoimmunity, tumor immunity and immune privilege.
Over-expressed PD-L1 on tumor cells can interact with PD-1 on activated T cells, inducing inhibition of T cell responses and cytotoxic T cell dysfunction. Based on these effects, cancer cells can evade immune surveillance associated with adaptive immune resistance mechanisms using the PD-1/PD-L1 pathway. Early clinical findings of PD-1/PD-L1 pathway blockers point to a broad and diverse opportunity to enhance anti-tumor immunity and enhance T cell responses.
In recent years, research in which the development of immunity anti-tumor drugs for treating cancers is the leading edge of the life science and an important research field. In particular, drug therapy targeting immune checkpoints is an important research development in the future for the treatment of related cancers, such as: treatment of skin cancer, head and neck cancer, lung cancer, breast cancer, lymphoma, gastric cancer, and renal cancer. Until now, six drugs have been marketed by the U.S. FDA based on anti-PD-1/PD-L1 antibodies targeting immune checkpoints (Nivolumab, pembrolizumab, cemiplimab-rwlc, atezolizumab, avelumab, durvalumab). Wherein the first three monoclonal antibodies are targeted PD-1 proteins; and the last three target PD-L1 proteins. The monoclonal antibodies have better performance in treating melanoma, non-small cell lung cancer, head and neck cancer, kidney cancer and other cancers, and are also marketed in China. In China, the research is also popular, and four anti-PD-1 antibody medicines are approved by CFDA and are marketed (Terap Li Shan antibody, xindi Li Shan antibody and the like). Therefore, the development of the anti-tumor immunosuppressant in the aspect of targeting PD-1/PD-L1 is one of the new trends of the important new medicine innovation special items in China at present.
On the other hand, antibody drugs have problems of high production cost, long half-life, poor immunogenicity and the like. Small molecule drugs have significant advantages over monoclonal antibodies, such as oral administration, stability, and membrane permeability. Therefore, the development of small molecule immune checkpoint inhibitors targeting PD-1/PD-L1 would be of great value. Finding potent PD-1/PD-L1 small molecule inhibitors has been a major challenge in pharmaceutical chemistry in the academia and industry. Recently, researchers at Bai-Shi-Miq have reported small molecule (formula A) inhibitors that bind to PD-L1 and thereby inhibit its activity. Aurigene researchers also reported that oxadiazole (formula B) and thiadiazole (formula C), both compounds were able to disrupt small molecules of the PD-1/PD-L1 interaction.
1,2, 3-Triazole is one of the most important nitrogen-containing heterocyclic compounds. The 1,2, 3-triazole compounds can form a plurality of non-covalent bonds with different biological activities, such as hydrogen bonds, hydrophobic interactions, van der Waals forces, dipole bonds and the like. The ceftriaxone-containing 1,2, 3-triazole (formula D) and carboxyamidotriazole (formula E) are useful as anticancer agents. In recent years, many anticancer drugs have been developed based on the hybridization of 1,2, 3-triazole with drugs. These hybrid molecules also exhibit better activity against drug-resistant and drug-sensitive cancers independent of their mechanism of action. Therefore, the invention designs a novel small molecule for inhibiting PD-1/PD-L1, synthesizes a compound containing a1, 2, 3-triazole structural framework, and has anticancer activity and PD-1/PD-L1 inhibition activity worthy of research.
Disclosure of Invention
Aiming at the technical problems existing in the research of the current targeting PD-1/PD-L1 antitumor small molecules, the invention aims to provide a novel biphenyl-1, 2, 3-triazole conjugate containing a 1,2, 3-triazole structure, a preparation method and application thereof, and to determine the antitumor activity and the function capability with PD-1/PD-L1 protein. The compound can well act on the PD-1/PD-L1 protein highly expressed in human cancer cells in vitro, and can inhibit the interaction of the PD-1/PD-L1 protein so as to inhibit the occurrence of immune escape; and screening in vitro toxicological experiments on tumor cells, the series of compounds have stronger inhibition effect on various tumor cells highly expressing PD-L1 protein. The invention has important value for the research and development of newly discovered antitumor small molecule drugs, in particular to the promotion of clinical drug development of 1,2, 3-triazole derivatives.
A biphenyl-1, 2, 3-triazole conjugate has a structural general formula shown in formula (I):
wherein each substituent on the benzene ring in the formula (I) is selected by one of the following conditions:
1) R 4 is H, R 1-R3 is selected from the following substituents, and the rest are H:
R 1 is H, br or CH 3,
R 2 is H, CN, CF 3、OCH3 or CH 2R5,
R 3 is F, br, OCH 3 or CH 2R5,
Wherein:
-R 5 is Cl、OH、N(CH3)(CH2)2OH、NH(CH2)2OH、NH(CH2)2R6 or NH (CH 2)3R6,
R 6 is OH, NHCOCH 3 or N (CH 2CH2OH)2,
2) R 2 is H, R 1 is Br, only one of R 3 and R 4 is selected from the following non-hydrogen substituents, and the other is H:
R 3 is OCF 3, F, cl or NO 2,
R 4 is OCF 3、F、CH3 or CF 3,
3) R 1 and R 3 are each F, and R 2 and R 4 are each H.
Further, the biphenyl-1, 2, 3-triazole conjugate is selected from one of the following:
the preparation method of the biphenyl-1, 2, 3-triazole conjugate comprises the following steps:
1) Reacting (2-methylbiphenyl-3-yl) methanol represented by formula (II) with propargyl bromide in the presence of sodium hydride to obtain (2-methyl-3- (2-alkynyloxy) methyl) biphenyl represented by formula (III);
2) Selecting a tetrahydrofuran/water mixed solution with the volume ratio of 1:0.5-2 as a reaction solvent, carrying out click chemical reaction on (2-methyl-3- (2-alkynyloxy) methyl) biphenyl shown in a formula (III) and various substituted phenyl azides under the catalysis of sodium aspartate and copper sulfate pentahydrate, and carrying out post-treatment on the reaction solution after the reaction is finished to prepare biphenyl-1, 2, 3-triazole conjugate shown as any one of compounds 3a-r and 4 a-b; wherein the substituents on the benzene rings of the substituted phenyl azide are the same as the substituents on the terminal phenyl groups of the corresponding compounds 3a-r, 4 a-b;
3) The compounds 4a-b are treated by thionyl chloride, and after the reaction is finished, the reaction liquid is subjected to post-treatment to prepare biphenyl-1, 2, 3-triazole conjugate shown by the compounds 5 a-b;
4) In the presence of potassium carbonate and acetonitrile, the compounds 5a-b react with various aliphatic amines to obtain biphenyl-1, 2, 3-triazole conjugates shown as the compounds 6 a-h; wherein the fatty amine is NH(CH3)(CH2)2OH、NH2(CH2)2OH、NH2(CH2)2R6 or NH 2(CH2)3R6,R6 is OH, NHCOCH 3 or N (CH 2CH2OH)2;
further, the reaction in the step 1) is carried out at room temperature for 7-10 hours, and the molar ratio of the (2-methylbiphenyl-3-yl) methanol shown in the formula (II) to the propargyl bromide is 1:0.8-1.2. The molar ratio of (2-methylbiphenyl-3-yl) methanol to sodium hydride shown in the formula (II) is 1:2.5-4, preferably 1:3.
Further, the reaction temperature for the ignition chemical reaction in step 2) is room temperature, and the reaction time is 7 to 9 hours, preferably 8 hours. In the step 2), the feeding mole ratio of the (2-methyl-3- (2-alkynyloxy) methyl) biphenyl, the substituted phenyl azide, the copper sulfate pentahydrate and the sodium aspartate is 5.0-5.5:5.0-5.5:0.8-1.2:1, and the preferred mole ratio is 5.25:5.25:1:1;
The post-treatment method in step 2) is as follows: removing tetrahydrofuran under reduced pressure, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain crude product; finally purifying by column chromatography with petroleum ether mixed solvent containing 20% -40% (volume fraction) ethyl acetate as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in any one of compounds 3a-r and 4 a-b.
Further, the reaction temperature in the step 3) is room temperature, and the reaction is stirred for 1.5 to 4 hours, preferably 2 hours; the molar ratio of the compounds 4a-b to thionyl chloride is 1:1.0-3.0, preferably 1:2.0.
The post-treatment method in the step 3) is as follows: after the reaction is completed through TLC detection, saturated sodium bicarbonate aqueous solution is added into the reaction mixture, then dichloromethane is used for extracting a product, an organic layer is collected, anhydrous sodium sulfate is used for drying, and a crude product is obtained through vacuum concentration; finally purifying by column chromatography with petroleum ether mixed solvent containing 10% -30% (volume fraction) ethyl acetate as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in compounds 5 a-b.
Further, the reaction temperature in the step 4) is room temperature, and the reaction is stirred for 6 to 12 hours, preferably 8 hours; the molar ratio of the compounds 5a-b, various aliphatic amines and potassium carbonate is 1:0.8-1.5:1.0-3.0, and the preferable molar ratio is 1:1:1.2-1.5.
Further, the post-treatment method in step 4) is as follows: after the reaction was completed by TLC detection, the solvent was removed by reduced pressure, then extracted with ethyl acetate, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product; finally purifying by column chromatography with 5% -15% (volume fraction) of dichloromethane mixed solvent as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in compounds 6 a-h.
The application of the biphenyl-1, 2, 3-triazole conjugate (3 a-r,4a-b,5a-b,6 a-h) in preparing antitumor drugs specifically comprises the following steps: at the gene molecular level, the target compound acts on the PD-1/PD-L1 protein which is highly expressed in human cancer cells, and can inhibit the interaction of the PD-1/PD-L1 protein so as to inhibit the occurrence of immune escape; at the cellular level, the effect of the target compound on human non-small cell lung cancer A549, HCC827 and breast cancer MDA-MB-231 cells was examined for the inhibition of the growth and migration of the three human cancer cells and the inhibition of the infiltration.
Further, the biphenyl-1, 2, 3-triazole conjugate is used for preparing antitumor drugs for inhibiting A549, HCC827 or MDA-MB-231.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
1) The invention avoids the technical problems of excessive reaction temperature and increased reaction byproducts in the comprehensive reaction, and can ensure reasonable reaction time and improve reaction yield;
2) According to the invention, (2-methyl biphenyl-3-yl) methanol is used as a raw material, propargyl bromide solution is used in the presence of sodium hydride to obtain a (2-methyl-3- (2-alkynyloxy) methyl) biphenyl intermediate, and the intermediate is subjected to click chemistry reaction with various aromatic azides under the catalysis of sodium aspartate and copper sulfate pentahydrate to design and synthesize biphenyl-1, 2, 3-triazole conjugate (3 a-r,4 a-b), the preparation method is simple, the requirement on equipment is low, the yield and purity of the prepared compound are high, the purity is up to more than 98%, and the structure is verified through nuclear magnetism and mass spectrum;
3) The invention carries out the research of selectively inhibiting the binding capacity of PD-1/PD-L1 protein at the molecular level in vitro by applying the prepared compound and the PD-1/PD-L1 protein which is highly expressed in human cancer cells. Homogeneous Time Resolved Fluorescence (HTRF) results indicate: the HTRF profile of most compounds for the binding capacity of highly expressed PD-1/PD-L1 proteins in human cancer cells exhibits an inverted S-shape, meaning that PD-1/PD-L1 protein binding is inhibited under the experimental conditions of the present invention. HTRF experiments show that the 4a-b, 5a-b and 6a-h series biphenyl-1, 2, 3-triazole conjugates have stronger inhibition capability on the mutual combination of PD-1/PD-L1 proteins;
4) The invention carries out research on the toxicity activity of human non-small cell lung cancer cells (A549, HCC 827) and breast cancer cells (MDA-MB-231) from the cell level by using the prepared compound, and the result shows that: most of the compounds, especially the 4a-b, 5a-b, 6a-h series compounds, produced better inhibitory activity against the growth of three cancer cells, with compounds 6d, 6e, 6h producing significant toxicological activity against the three cancer cells.
Drawings
FIG. 1. Effect of Biphenyl-triazole conjugate pair on tumor cell viability of A549, HCC827, MDA-MB-231;
FIG. 2 shows the results of HTRF assay to determine the capacity of biphenyl-triazole conjugates to affect PD-1/PD-L1 interactions.
Detailed Description
The invention is further described below in connection with specific examples, but the scope of the invention is not limited thereto:
The embodiment of the invention gives 30 target compounds of 3a-r, 4a-b, 5a-b and 6a-h, which are prepared by treating (2-methylbiphenyl-3-yl) methanol (II) serving as a raw material with propargyl bromide solution in the presence of sodium hydride, and obtaining an intermediate (2-methyl-3- (2-alkynyloxy) methyl) biphenyl (III) through a click chemistry reaction principle, wherein the intermediate is further reacted with various aromatic azides respectively in a tetrahydrofuran: water=1:1 (volume ratio) system with copper sulfate pentahydrate and sodium aspartate to obtain 3a-r and 4a-b. (4- ((2-methylbiphenyl-3-yl) methoxy) -1h-1,2, 3-triazol-1-yl) phenyl) methanol (4 a-b) was reacted separately in dichloromethane at room temperature to give 5a-b. Various aliphatic amines were reacted with 5a-b in the presence of K 2CO3 and acetonitrile to produce 6a-h. (raw materials purchased from Aladin reagent Co.).
The reaction equation for its preparation is as follows:
In the examples of the present invention, 30 target compounds were synthesized in the first and second steps, wherein compounds 3a-r and 4a-b were synthesized in the third step from 4a-b, and compounds 6a-h were synthesized in the fourth step from 5 a-b.
Example 1. Preparation of compound 3 a.
The synthetic route is as follows:
1) Preparation of intermediate III: to a mixed solution of tetrahydrofuran (5 ml) containing compound II (5.04 mmol) at 0℃were added sodium hydride (15.13 mmol) and propargyl bromide (5.54 mmol), and then the reaction temperature was raised to room temperature and stirred for 8 hours. TCL was checked until the reaction was complete. Water was slowly added to the reaction mixture under cooling, followed by extraction with ethyl acetate (3X 10 ml). The organic layer was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether as eluent to give a brown liquid intermediate III in 79% yield.
Compound iii: 2-methyl-3- (2-propynyloxy) methylbiphenyl,
Brown liquid ,1H-NMR(500MHz,Chloroform-d)δ7.43-7.41(m,2H),7.39–7.35(m,2H),7.31(dd,J＝6.7,1.5Hz,2H),7.27-7.24(m,1H),7.22(dd,J＝7.7,1.9Hz,1H),4.70(s,2H),4.26(d,J＝2.4Hz,2H),2.50(t,J＝2.4Hz,1H),2.26(s,3H).ESI-MS(m/z):calcd.for C17H16O236.12,found 237.19[M+H]+.
2) Preparation of target compound 3 a. Compound III (0.84 mmol) and phenyl azide (0.84 mmol) were added to a 1:1 tetrahydrofuran-water (2 mL) solution by volume, then copper sulfate pentahydrate (0.16 mmol) and sodium aspartate (0.16 mmol) were added to the above reaction solution, and the mixture was stirred at room temperature for 8 hours. TCL was checked until the reaction was complete and tetrahydrofuran was removed using reduced pressure rotary evaporation. The residue was extracted with ethyl acetate, the mixed organic layer was collected, washed with saturated brine solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product. The product is further purified by column chromatography, and the target compound is obtained by column chromatography using petroleum ether mixed solvent containing 30% ethyl acetate by volume fraction as eluent. The structure of the target compound was characterized by 1H NMR、13 C NMR and mass spectrometry (ESI-MS).
The yield, melting point, purity and spectrum data of the target compound are shown below:
compound 3a:4- (((2-Methylbiphenyl-3-yl) methoxy) methyl) -1-phenyl-1H-1, 2, 3-triazole (3 a)
(1) 3A chemical structural formula:
after purification, white solid (3 a) was obtained in a yield of 86.43%; m.p.89-91℃and 99.73% purity (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.77–7.73(m,2H),7.56–7.52(m,2H),7.47–7.45(m,1H),7.43–7.41(m,3H),7.38–7.33(m,1H),7.32–7.29(m,2H),7.28–7.25(m,1H),7.22(dd,J＝7.6,1.6Hz,1H),4.86(s,2H),4.75(s,2H),2.25(s,3H).ESI-MS(m/z):calcd.for C23H21N3O 355.16,found 356.22[M+H]+.
Example 2 preparation of compound 3 b. The following 3b-r and 4a-b are prepared using the same procedure and method as for 3a except that "the substitution is made with an equivalent molar amount of a different substituted phenyl azide compound in which the substituents on the phenyl ring of the substituted phenyl azide are the same as the substituents on the terminal phenyl groups of the corresponding compounds 3a-r, 4 a-b".
Compound 3b:1- (2-bromophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 b)
(1) 3B chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 b) was obtained in 85.96% yield; p.97-99 ℃, 96.24% (HPLC) purity. Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.78(dd,J＝8.0,1.4Hz,1H),7.57(dd,J＝7.9,1.7Hz,1H),7.50(td,J＝7.7,1.4Hz,1H),7.43–7.40(m,4H),7.37–7.34(m,1H),7.32–7.29(m,2H),7.25(d,J＝7.5Hz,1H),7.22(dd,J＝7.6,1.7Hz,1H),4.89(s,2H),4.75(s,2H),2.25(s,3H).ESI-MS(m/z):calcd.for C23H20BrN3O 433.07,found 434.15[M+H]+.
EXAMPLE 3 preparation of Compound 3c
Compound 3c:4- (((2-Methylbiphenyl-3-yl) methoxy) methyl) -1-o-tolyl-1H-1, 2, 3-triazole (3 c)
(1) 3C chemical structural formula:
(2) The chemical reaction steps are as follows:
after purification, brown solid (3 c) was obtained in a yield of 71.21%; m.p.90-92 ℃, purity 94.21% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.76(s,1H),7.42–7.37(m,5H),7.37–7.34(m,1H),7.33–7.32(m,2H),7.30–7.27(m,2H),7.24(d,J＝7.8Hz,1H),7.20(dd,J＝7.6,1.7Hz,1H),4.86(s,2H),4.73(s,2H),2.23(s,3H),2.22(s,3H).13C NMR(151MHz,CDCl3)δ145.15,142.85,142.10,136.53,136.29,134.36,133.71,131.50,129.87,129.41,128.15,128.05,126.86,126.78,126.01,125.43,124.14,71.67,64.00,17.92,16.10.ESI-MS(m/z):calcd.for C24H23N3O 369.18,found 370.25[M+H]+.
EXAMPLE 4 preparation of Compound 3d
Compound 3d:3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzonitrile (3 d)
(1) 3D chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 d) was obtained in a yield of 74.53%; p.96-98℃and 91.62% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.08(t,J＝1.8Hz,1H),8.06(s,1H),8.04(ddd,J＝8.3,2.3,1.2Hz,1H),7.76–7.73(m,1H),7.68(t,J＝7.9Hz,1H),7.44–7.39(m,3H),7.37–7.34(m,1H),7.31–7.29(m,2H),7.28–7.24(m,1H),7.22(dd,J＝7.7,1.7Hz,1H),4.86(s,2H),4.75(s,2H),2.25(s,3H).13C NMR(126MHz,CDCl3)δ146.91,142.88,141.97,137.55,136.04,134.34,132.04,130.90,129.94,129.35,128.07,128.04,126.81,125.42,124.41,123.57,120.41,117.36,114.19,71.90,63.84,16.08.ESI-MS(m/z):calcd.for C24H20N4O 380.16,found 381.21[M+H]+.
EXAMPLE 5 preparation of Compound 3e
Compound 3e:1- (3-methoxyphenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 e)
(1) 3E chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 e) was obtained in 76.07% yield; m.p.95-96℃and 99.46% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.44–7.40(m,4H),7.38–7.34(m,2H),7.33–7.29(m,2H),7.29–7.25(m,2H),7.22(dd,J＝7.6,1.7Hz,1H),6.99(ddd,J＝8.4,2.5,0.9Hz,1H),4.86(s,2H),4.74(s,2H),3.89(s,3H),2.25(s,3H).ESI-MS(m/z):calcd.for C24H23N3O2385.17,found 386.24[M+H]+.
EXAMPLE 6 preparation of Compound 3f
Compound 3f:4- (((2-Methylbiphenyl-3-yl) methoxy) methyl) -1- (3- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole (3 f)
(1) 3F chemical formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 f) was obtained in a yield of 72.54%; p.85-86℃and 97.71% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.06(s,1H),8.05–8.03(m,1H),7.98(dt,J＝7.8,1.8Hz,1H),7.75–7.67(m,2H),7.45–7.40(m,3H),7.38–7.33(m,1H),7.32–7.29(m,2H),7.27(d,J＝6.0Hz,1H),7.23(dd,J＝7.7,1.7Hz,1H),4.87(s,2H),4.75(s,2H),2.26(s,3H).13C NMR(151MHz,CDCl3)δ146.69,142.90,142.03,137.38,136.15,134.38,132.79,132.57,132.35,132.13,130.60,129.94,129.39,128.11,128.06,126.82,126.05,125.44,125.40,125.38,125.35,124.24,123.56,122.44,120.63,117.50,117.47,117.44,117.42,71.88,63.92,16.11.ESI-MS(m/z):calcd.for C24H20F3N3O 423.15,found424.22[M+H]+.
EXAMPLE 7 preparation of Compound 3g
Compound 3g:1- (4-methoxyphenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 g)
(1) 3G of a chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 g) was obtained in 82.82% yield; p.80-81 ℃, 97.67% purity (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.93(s,1H),7.65–7.62(m,2H),7.43–7.40(m,3H),7.37–7.33(m,1H),7.31–7.29(m,2H),7.25(t,J＝7.5Hz,1H),7.21(dd,J＝7.7,1.7Hz,1H),7.05–7.02(m,2H),4.85(s,2H),4.73(s,2H),3.88(s,3H),2.25(s,3H).ESI-MS(m/z):calcd.for C24H23N3O2385.17,found 386.23[M+H]+.
EXAMPLE 8 preparation of Compound 3h
Compound 3h:1- (4-bromophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3H)
(1) 3H chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 h) was obtained in 70.72% yield; m.p.133-135℃and purity 98.75% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.68–7.63(m,4H),7.44–7.39(m,3H),7.38–7.34(m,1H),7.31–7.29(m,2H),7.26(t,J＝7.5Hz,1H),7.22(dd,J＝7.7,1.7Hz,1H),4.85(s,2H),4.74(s,2H),2.25(s,3H).13C NMR(151MHz,CDCl3)δ146.42,142.87,142.04,136.17,136.02,134.37,132.93,129.92,129.39,128.10,128.06,126.81,125.44,122.43,121.94,120.57,71.81,63.94,16.11.ESI-MS(m/z):calcd.for C23H20BrN3O 433.07,found 434.15[M+H]+.
EXAMPLE 9 preparation of Compound 3i
Compound 3i:1- (4-fluorophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 i)
(1) 3I chemical structural formula:
(2) The chemical reaction steps are as follows:
after purification, brown solid (3 i) was obtained in 77.72% yield; m.p.131-132℃and 97.96% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.94(s,1H),7.72–7.69(m,2H),7.42–7.38(m,3H),7.35–7.32(m,1H),7.30–7.27(m,2H),7.24(d,J＝2.6Hz,1H),7.23–7.21(m,2H),7.20–7.19(m,1H),4.83(s,2H),4.72(s,2H),2.23(s,3H).ESI-MS(m/z):calcd.for C23H20FN3O 373.15,found374.22[M+H]+.
EXAMPLE 10 preparation of Compound 3j
Compound 3j:1- (2-bromo-4-chlorophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 j)
(1) 3J chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 j) was obtained in a yield of 82.60%; m.p.87-89 ℃, 96.54% purity (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.79(d,J＝2.0Hz,1H),7.52–7.48(m,2H),7.42-7.39(m,3H),7.37–7.34(m,1H),7.31–7.29(m,2H),7.28–7.25(m,1H),7.22(dd,J＝7.6,1.8Hz,1H),4.87(s,2H),4.74(s,2H),2.24(s,3H).13C NMR(126MHz,CDCl3)δ145.26,142.82,142.03,136.57,136.15,135.21,134.34,133.55,129.87,129.36,128.84,128.79,128.12,128.02,126.76,125.40,124.62,119.09,71.64,63.79,16.09.ESI-MS(m/z):calcd.for C23H19BrClN3O 467.04,found 468.09[M+H]+.
EXAMPLE 11 preparation of Compound 3k
Compound 3k:1- (2-bromo-4- (trifluoromethoxy) phenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 k)
(1) 3K chemical formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 k) was obtained in 78.39% yield; m.p.84-86℃and 98.32% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.68–7.65(m,1H),7.62(d,J＝8.7Hz,1H),7.44–7.39(m,4H),7.37–7.34(m,1H),7.32–7.30(m,2H),7.28–7.24(m,1H),7.23(dd,J＝7.6,1.8Hz,1H),4.89(s,2H),4.76(s,2H),2.26(s,3H).13C NMR(126MHz,CDCl3)δ149.86,149.85,145.35,142.83,142.02,136.14,135.14,134.33,129.87,129.35,129.19,128.11,128.01,126.76,126.17,125.40,124.62,120.74,119.41,71.66,63.77,16.08.ESI-MS(m/z):calcd.for C24H19BrF3N3O2517.06,found 518.12[M+H]+.
EXAMPLE 12 preparation of Compound 3l
Compound 3l:1- (2-bromo-4-nitrophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 l)
(1) 3L chemical formula:
(2) The chemical reaction steps are as follows:
Purification gave a brown solid (3 l) in 83.82% yield; p.133-134℃and 98.37% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.66(d,J＝2.5Hz,1H),8.36(dd,J＝8.7,2.4Hz,1H),8.14(s,1H),7.82(d,J＝8.7Hz,1H),7.44–7.39(m,3H),7.38–7.34(m,1H),7.31–7.29(m,2H),7.26(t,J＝7.5Hz,1H),7.22(dd,J＝7.7,1.8Hz,1H),4.89(s,2H),4.76(s,2H),2.26(s,3H).ESI-MS(m/z):calcd.for C23H19BrN4O3478.06,found 479.14[M+H]+.
EXAMPLE 13 preparation of Compound 3m
Compound 3m:1- (2-bromo-4-fluorophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 m)
(1) 3M chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 m) was obtained in 79.41% yield; m.p.95-97 ℃, 94.46% (HPLC) purity. Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.94(s,1H),7.55(dd,J＝8.8,5.3Hz,1H),7.52(dd,J＝7.8,2.7Hz,1H),7.43–7.39(m,3H),7.37–7.34(m,1H),7.32–7.29(m,2H),7.25–7.24(m,1H),7.23–7.20(m,2H),4.88(s,2H),4.74(s,2H),2.24(s,3H).ESI-MS(m/z):calcd.for C23H19BrFN3O 451.06,found452.11[M+H]+.
EXAMPLE 14 preparation of Compound 3n
Compound 3n:1- (2, 4-difluorophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 n)
(1) 3N chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, white solid (3 n) was obtained in 90.57% yield; m.p.119-121 ℃, purity 96.15% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.04(d,J＝2.8Hz,1H),7.92(td,J＝9.0,8.6,5.7Hz,1H),7.40(ddd,J＝8.1,6.6,4.9Hz,3H),7.36–7.31(m,1H),7.31–7.27(m,2H),7.26–7.22(m,1H),7.20(dd,J＝7.7,1.7Hz,1H),7.10–7.03(m,2H),4.84(s,2H),4.72(s,2H),2.23(s,3H).ESI-MS(m/z):calcd.for C23H19F2N3O 391.14,found 392.21[M+H]+.
EXAMPLE 15 preparation of Compound 3o
Compound 3o:1- (2-bromo-5-methoxyphenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 o)
(1) 3O chemical formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 o) was obtained in 84.43% yield; p.131-133℃and 95.94% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.62(d,J＝8.9Hz,1H),7.43–7.40(m,3H),7.37–7.33(m,1H),7.32–7.29(m,2H),7.25(t,J＝7.5Hz,1H),7.21(dd,J＝7.7,1.7Hz,1H),7.12(d,J＝3.0Hz,1H),6.97(dd,J＝8.9,3.0Hz,1H),4.88(s,2H),4.74(s,2H),3.85(s,3H),2.25(s,3H).13C NMR(151MHz,CDCl3)δ159.57,144.98,142.83,142.09,137.02,136.27,134.38,134.24,129.86,129.41,128.16,128.04,126.77,125.41,124.74,117.74,113.37,108.31,71.60,63.85,55.91,16.13.ESI-MS(m/z):calcd.for C24H22BrN3O2463.08,found 464.15[M+H]+.
EXAMPLE 16 preparation of Compound 3p
Compound 3p:1- (2-bromo-5-fluorophenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 p)
(1) 3P chemical formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (3 p) was obtained in 85.68% yield; m.p.87-89 ℃, 96.77% (HPLC) purity. Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.04(s,1H),7.74(dd,J＝8.9,5.4Hz,1H),7.44–7.40(m,3H),7.39–7.35(m,2H),7.32–7.29(m,2H),7.26(t,J＝7.5Hz,1H),7.22(dd,J＝7.7,1.8Hz,1H),7.19–7.15(m,1H),4.88(s,2H),4.74(s,2H),2.25(s,3H).ESI-MS(m/z):calcd.for C23H19BrFN3O 451.06,found452.12[M+H]+.
EXAMPLE 17 preparation of Compound 3q
Compound 3q:1- (2-bromo-5-methylphenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 q)
(1) 3Q chemical structural formula:
(2) The chemical reaction steps are as follows:
after purification, brown solid (3 q) was obtained in a yield of 75.33%; m.p.98-100℃and 99.39% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.63(d,J＝8.2Hz,1H),7.43–7.38(m,4H),7.37–7.33(m,1H),7.32–7.29(m,2H),7.25(t,J＝7.5Hz,1H),7.21(dt,J＝8.4,1.9Hz,2H),4.88(s,2H),4.74(s,2H),2.40(s,3H),2.24(s,3H).13C NMR(151MHz,CDCl3)δ144.95,142.82,142.11,139.07,136.30,136.22,134.37,133.51,131.99,129.85,129.41,128.78,128.16,128.04,126.77,125.41,124.75,114.91,71.54,63.88,20.80,16.13.ESI-MS(m/z):calcd.for C24H22BrN3O 447.09,found448.16[M+H]+.
EXAMPLE 18 preparation of Compound 3r
Compound 3r:1- (2-bromo-5- (trifluoromethyl) phenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (3 r)
(1) 3R chemical structural formula:
(2) The chemical reaction steps are as follows:
after purification, brown solid (3 r) was obtained in 86.54% yield; p.100-102 ℃, 96.88% purity (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.04(s,1H),7.93(d,J＝8.4Hz,1H),7.86(d,J＝2.1Hz,1H),7.67(dd,J＝8.4,2.2Hz,1H),7.44–7.40(m,3H),7.37–7.34(m,1H),7.32–7.29(m,2H),7.26(t,J＝7.5Hz,1H),7.22(dd,J＝7.7,1.7Hz,1H),4.89(s,2H),4.75(s,2H),2.25(s,3H).ESI-MS(m/z):calcd.for C24H19BrF3N3O 501.06,found 502.15[M+H]+.
EXAMPLE 19 preparation of Compound 4a
Compound 4a:3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzyl alcohol (4 a)
(1) 4A chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, brown solid (4 a) was obtained in 96.93% yield; m.p.109-110 ℃, purity 99.12% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.78(t,J＝1.9Hz,1H),7.65–7.62(m,1H),7.49(t,J＝7.8Hz,1H),7.43–7.39(m,4H),7.37–7.33(m,1H),7.31–7.28(m,2H),7.25(t,J＝7.5Hz,1H),7.21(dd,J＝7.7,1.7Hz,1H),4.83(s,2H),4.79(s,2H),4.73(s,2H),2.24(s,3H).ESI-MS(m/z):calcd.for C24H23N3O2385.17,found 386.25[M+H]+.
EXAMPLE 20 preparation of Compound 4b
Compound 4b:4- (4- (((2-Methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzyl alcohol (4 b)
(1) 4B chemical structural formula:
(2) The chemical reaction steps are as follows:
After purification, white solid (4 b) was obtained in 82.78% yield; m.p.115-117℃and 96.09% purity (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.73(d,J＝8.5Hz,2H),7.54(d,J＝8.6Hz,2H),7.44–7.39(m,3H),7.37–7.33(m,1H),7.32–7.29(m,2H),7.28(s,1H),7.22(dd,J＝7.6,1.5Hz,1H),4.85(s,2H),4.80(s,2H),4.74(s,2H),2.25(s,3H).13C NMR(151MHz,CDCl3)δ146.02,142.86,142.05,141.96,136.18,136.15,134.38,129.90,129.39,128.12,128.05,126.80,125.43,120.82,120.59,71.76,64.24,63.94,16.10.ESI-MS(m/z):calcd.for C24H23N3O2385.17,found 386.22[M+H]+.
example 21 preparation of Compound 5 a.
The synthetic route is as follows:
Preparation of target compound 5 a: after addition of compound 4a (2.59 mmol) to CH 2Cl2 (5 ml) and ice-bath cooling (0 ℃ C.), thionyl chloride (5.19 mmol) was slowly added under inert conditions. The mixture was allowed to stand at room temperature with stirring for 2 hours. TCL was checked until the reaction was complete, saturated sodium bicarbonate solution was added to the reaction mixture in an ice-water bath and extracted with dichloromethane. The mixed organic layer was collected, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The product was further purified by column chromatography using petroleum ether containing 20% ethyl acetate as mobile phase to give the objective compound. The structure of the target compound was characterized by 1 H NMR and mass spectrometry (ESI-MS).
The yield, melting point and spectrum data of the target compound are shown below:
compound 5a:1- (3- (chloromethyl) phenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (5 a)
(1) 5A chemical structural formula:
After purification, brown solid (5 a) was obtained in 78.65% yield; m.p.86-88 ℃, 92.51% (HPLC) purity.
Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.79(t,J＝2.0Hz,1H),7.67(ddd,J＝7.9,2.2,1.1Hz,1H),7.50(t,J＝7.8Hz,1H),7.45(dt,J＝7.7,1.4Hz,1H),7.41–7.38(m,3H),7.35–7.31(m,1H),7.29–7.27(m,2H),7.25–7.22(m,1H),7.20(dd,J＝7.7,1.7Hz,1H),4.84(s,2H),4.72(s,2H),4.63(s,2H),2.23(s,3H).ESI-MS(m/z):calcd.for C24H22ClN3O 403.14,found404.21[M+H]+.
EXAMPLE 22 preparation of Compound 5b
Compound 5b:1- (4- (chloromethyl) phenyl) -4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazole (5 b)
(1) 5B chemical formula:
(2) The chemical reaction steps are as follows:
the experimental procedure and procedure are the same as the preparation procedure of compound 5a in example 21, except that "compound 4a is replaced with an equivalent molar amount of compound 4b". After purification, brown solid (5 b) was obtained in a yield of 75.43%; p.91-92℃and 97.39% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.76(d,J＝8.6Hz,2H),7.57(d,J＝8.5Hz,2H),7.44–7.39(m,3H),7.38–7.33(m,1H),7.30(dd,J＝8.1,1.4Hz,2H),7.27(d,J＝9.0Hz,1H),7.22(dd,J＝7.7,1.7Hz,1H),4.86(s,2H),4.74(s,2H),4.66(s,2H),2.25(s,3H).ESI-MS(m/z):calcd.for C24H22ClN3O 403.14,found 404.23[M+H]+.
EXAMPLE 23 preparation of Compound 6a
The synthetic route is as follows:
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preparation of target compound 6 a: compound 5a (0.74 mmol) was added to acetonitrile (1.5 ml), potassium carbonate (0.15 g) and ethanolamine (0.74 mmol) were added, and the reaction was stirred at room temperature for 8 hours. TCL was checked until the reaction was complete, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate, the combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The product was further purified by column chromatography using 10% methanol in methylene chloride as the mobile phase to give the target compound. The structure of the target compound was characterized by 1H NMR、13 C NMR and mass spectrometry (ESI-MS).
The yield, melting point and spectrum data of the target compound are shown below:
Compound 6a:2- (3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) ethanol (6 a)
(1) 6A chemical structural formula:
After purification, brown solid (6 a) was obtained in 78.12% yield; m.p.109-111 ℃, 97.99% (HPLC) purity. Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.75(t,J＝1.9Hz,1H),7.60(ddd,J＝8.0,2.3,1.2Hz,1H),7.47(t,J＝7.8Hz,1H),7.42–7.38(m,4H),7.36–7.31(m,1H),7.30–7.27(m,2H),7.24(t,J＝7.5Hz,1H),7.20(dd,J＝7.7,1.7Hz,1H),4.83(s,2H),4.72(s,2H),3.91(s,2H),3.70–3.68(m,2H),2.84–2.81(m,2H),2.23(s,3H).ESI-MS(m/z):calcd.for C26H28N4O2428.22,found429.29[M+H]+.
The following 6b-d was prepared using the same procedure and method as for preparation 6a, except "substitution with equivalent molar amounts of different fatty amines". For example, the procedure and steps for the test of compound 6b in example 24 are the same as those for the preparation of compound 6a in example 23, except that "ethanolamine is substituted with an equivalent molar amount of NH (CH 3)(CH2)2 OH").
EXAMPLE 24 preparation of Compound 6b
Compound 6b:2- (N, N-methyl- (3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzyl) amino) ethanol (6 b)
(1) 6B chemical structural formula:
(2) The chemical reaction steps are as follows:
Test methods and procedures reference is made to fig. 6a. After purification, brown solid (6 b) was obtained in 81.87% yield; m.p.81-82 ℃, purity 98.73% (HPLC). Characterization data ：1H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.71(t,J＝1.9Hz,1H),7.61(ddd,J＝8.0,2.3,1.1Hz,1H),7.47(t,J＝7.8Hz,1H),7.41–7.38(m,4H),7.35–7.31(m,1H),7.30–7.27(m,2H),7.24(t,J＝7.5Hz,1H),7.20(dd,J＝7.7,1.7Hz,1H),4.83(s,2H),4.72(s,2H),3.67–3.64(m,4H),2.63(t,J＝5.4Hz,2H),2.26(s,3H),2.23(s,3H).ESI-MS(m/z):calcd.for C27H30N4O2442.23,found 443.31[M+H]+.
EXAMPLE 25 preparation of Compound 6c
Compound 6c: n- (2- (3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) ethyl) acetamide (6 c)
(1) 6C chemical structural formula:
(2) The chemical reaction steps are as follows:
test methods and procedures reference is made to fig. 6a. After purification, brown solid (6 c) was obtained in a yield of 76.91%; m.p.105-106℃and 98.56% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.03(s,1H),7.80(t,J＝1.9Hz,1H),7.59(ddd,J＝8.0,2.3,1.1Hz,1H),7.47(t,J＝7.8Hz,1H),7.41–7.37(m,4H),7.35–7.32(m,1H),7.30–7.27(m,2H),7.24(t,J＝7.5Hz,1H),7.20(dd,J＝7.6,1.7Hz,1H),6.15(s,1H),4.83(s,2H),4.72(s,2H),3.89(s,2H),3.37(q,J＝5.7Hz,2H),2.81(t,J＝5.8Hz,2H),2.23(s,3H),1.98(s,3H).ESI-MS(m/z):calcd.for C28H31N5O2469.24,found 470.29[M+H]+.
EXAMPLE 26 preparation of Compound 6d
Compound 6d:2,2' - (3- (3- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) propanimine) diethanol (6 d)
(1) 6D chemical structural formula:
(2) The chemical reaction steps are as follows:
Test methods and procedures reference is made to fig. 6a. After purification, brown solid (6 d) was obtained in 84.21% yield; m.p.116-118℃and purity 98.17% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.12(s,1H),7.78(t,J＝1.8Hz,1H),7.65–7.62(m,1H),7.46(t,J＝7.8Hz,1H),7.41–7.37(m,4H),7.35–7.31(m,1H),7.30–7.27(m,2H),7.23(t,J＝7.5Hz,1H),7.19(dd,J＝7.7,1.7Hz,1H),4.83(s,2H),4.71(s,2H),3.84(s,2H),3.60(t,J＝5.2Hz,4H),2.77(t,J＝6.1Hz,2H),2.64(t,J＝6.2Hz,2H),2.59(t,J＝5.2Hz,4H),2.23(s,3H),1.69(p,J＝6.1Hz,2H).ESI-MS(m/z):calcd.for C31H39N5O3529.30,found 530.37[M+H]+.
EXAMPLE 27 preparation of Compound 6e
Compound 6e:2- (4- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) ethanol (6 e)
(1) 6E chemical structural formula:
(2) The chemical reaction steps are as follows:
Test methods and procedures referring to fig. 6a, the difference is "compound 5a is replaced with an equivalent molar amount of compound 5b". After purification, brown solid (6 e) was obtained in 78.61% yield; m.p.114-116 ℃, 97.85% (HPLC) purity. Characterization data:
1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.70(d,J＝8.5Hz,2H),7.50(d,J＝8.5Hz,2H),7.43–7.39(m,3H),7.37–7.33(m,1H),7.31–7.29(m,2H),7.25(t,J＝7.5Hz,1H),7.22(dd,J＝7.7,1.7Hz,1H),4.85(s,2H),4.74(s,2H),3.91(s,2H),3.72–3.70(m,2H),2.87–2.84(m,2H),2.24(s,3H).ESI-MS(m/z):calcd.for C26H28N4O2428.22,found 429.29[M+H]+.
EXAMPLE 28 preparation of Compound 6f
Compound 6f:2- (N, N-methyl- (4- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzyl) amino) ethanol (6 f)
(1) 6F chemical structural formula:
(2) The chemical reaction steps are as follows:
Test methods and procedures referring to 6b, the difference is "compound 5a is replaced with an equivalent molar amount of compound 5b". After purification, brown solid (6 f) was obtained in a yield of 87.13%; p.83-84 deg.C, 99.03% (HPLC). Characterization data ：1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.69(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.41-7.38(m,3H),7.36–7.31(m,1H),7.29(dd,J＝6.9,1.7Hz,2H),7.24(t,J＝7.5Hz,1H),7.20(dd,J＝7.7,1.7Hz,1H),4.84(s,2H),4.72(s,2H),3.66(t,J＝5.4Hz,2H),3.63(s,2H),2.63(t,J＝5.4Hz,2H),2.26(s,3H),2.23(s,3H).ESI-MS(m/z):calcd.for C27H30N4O2442.23,found443.29[M+H]+.
EXAMPLE 29 preparation of Compound 6g
Compound 6g: n- (2- (4- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) ethyl) acetamide (6 g)
(1) 6G of a chemical structural formula:
(2) The chemical reaction steps are as follows:
Test methods and procedures reference 6c. Except that "compound 5a was replaced with an equivalent molar amount of compound 5b". After purification, a white solid (6 g) was obtained in 75.9% yield; m.p.110-112 ℃, purity 99.63% (HPLC). Characterization data ：1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.67(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.42–7.38(m,3H),7.35–7.31(m,1H),7.29–7.27(m,2H),7.24(t,J＝7.5Hz,1H),7.20(dd,J＝7.6,1.7Hz,1H),6.17(s,1H),4.83(s,2H),4.72(s,2H),3.85(s,2H),3.37(q,J＝5.7Hz,2H),2.78(t,J＝5.9Hz,2H),2.23(s,3H),1.98(s,3H).13C NMR(151MHz,CDCl3)δ170.38,146.05,142.85,142.05,140.98,136.21,136.00,134.34,129.87,129.37,129.36,128.09,128.03,126.78,125.40,120.77,120.63,71.73,63.96,52.82,48.21,39.19,23.31,16.08.ESI-MS(m/z):calcd.for C28H31N5O2469.24,found 470.31[M+H]+.
EXAMPLE 30 preparation of Compound 6h
Compound 6h:2,2' - (3- (4- (4- (((2-methylbiphenyl-3-yl) methoxy) methyl) -1H-1,2, 3-triazol-1-yl) benzylamino) propylimine) diethanol (6H)
(1) 6H of chemical structural formula:
(2) The chemical reaction steps are as follows:
test methods and procedures reference 6d. Except that "compound 5a was replaced with an equivalent molar amount of compound 5b". After purification, brown solid (6 h) was obtained in 79.12% yield; m.p.120-121 ℃, purity 99.37% (HPLC). Characterization data:
1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.72–7.67(m,2H),7.50(d,J＝8.5Hz,2H),7.43–7.38(m,3H),7.37–7.33(m,1H),7.30(dd,J＝6.9,1.7Hz,2H),7.27(d,J＝4.6Hz,1H),7.21(dd,J＝7.6,1.7Hz,1H),4.85(s,2H),4.73(s,2H),3.85(s,2H),3.64(t,J＝5.2Hz,4H),2.79(t,J＝6.0Hz,2H),2.68(t,J＝6.2Hz,2H),2.63(t,J＝5.2Hz,4H),2.24(s,3H),1.71(p,J＝6.1Hz,2H).13C NMR(151MHz,CDCl3)δ145.98,142.83,142.07,140.03,136.22,136.05,134.34,129.84,129.77,129.38,128.09,128.03,126.76,125.40,120.84,120.64,71.68,63.92,59.72,56.20,53.22,52.98,47.80,26.82,16.08.ESI-MS(m/z):calcd.for C31H39N5O3529.30,found 530.38[M+H]+.
example 31. Effects of 30 compounds of the invention on cancer cell cytotoxicity, CCK-8 experimental analysis:
Cells were incubated in RPMI 1640, 10% FBS, penicillin-streptomycine medium at 37℃in 5% CO 2. Then, the cells were seeded in 96-well plates in 95. Mu.L of cell suspension at 5000 cells per well and cultured for 4 hours. Again, 5. Mu.L of DMSO solutions containing different concentrations of the compound and medium mixtures (1. Mu.L of DMSO solution containing the compound was added to 4. Mu.L of cell culture medium) were added to each well of the 96-well plate to give a concentration of the compound in each well (0.2,0.4,0.8,1.6,3.2,6.4. Mu.M), 5. Mu.L of DMSO without the compound and medium mixtures (1. Mu. LDMSO was added to 4. Mu.L of cell culture medium) were added to the control group, and the incubation was continued at 37℃for 48 hours in 5% CO 2. Finally, 10 mu L of CCK-8 reagent is added into each well plate, the culture is continued for 1h at the constant temperature of 37 ℃, an enzyme-labeled instrument Molecular Devices M is used for reading the absorbance value of each well of the 96 well plate at the light wavelength of 450nm, the proliferation activity of the cells is calculated, the average value of the three experimental results is +/-SD as the final experimental result, and Prism 8.0 is used for plotting (see figure 1). Paclitaxel (Paclitaxel) and BMS202 (PD-L1 inhibitor) served as positive controls. Cell proliferation activity calculation formula: cell viability (%) = [ a (dosing group) -a (blank group) ]/[ a (0 dosing group) -a (blank group) ]x100; wherein, a (dosing group): absorbance of wells with cells, CCK-8 reagent and compound solution; a (blank): absorbance of wells with medium and CCK-8 reagent without cells; a (0 dosing group): absorbance of wells with cells, CCK-8 reagent, 1% dmso without drug solution. The results of the toxicity activity test of the compounds 6d, 6e and 6h on human non-small cell lung cancer cells (A549, HCC 827) and breast cancer cells (MDA-MB-231) are shown in the half inhibition concentration IC 50 (mu M) of the compounds in the table 1. The effect of the biphenyl-triazole conjugates on the viability of HCC827, A549, MDA-MB-231 tumor cells is shown in FIG. 1. Wherein the abscissa of plot A, B, C in FIG. 1 is left to right for 1% DMSO, paclitaxel, BMS202, and compounds 3a-r, 4a-b, 5a-b, and 6a-h, respectively, at a concentration of 10. Mu.M. The abscissa of plot D, E, F in FIG. 1 is tested for 1% DMSO and concentrations of 0.2,0.4,0.8,1.6,3.2, 6.4. Mu.M Paclitoxel, 6d, 6e, and 6h, respectively. The ordinate in fig. 1 shows the tumor cell survival.
TABLE 1 half-inhibitory concentration IC for Compounds 6d, 6e, 6h against three cancer cells 50(μM)a
a Mean ± standard deviation (n=3) (P < 0.05).
Example 32. Effect of 30 compounds of the invention on PD-1/PD-L1 blocking Activity HTRF experiments were analyzed.
Firstly, diluting proteins to the respective required concentration, thawing a Tag1-PD-L1 protein solution, and diluting 5 times by using PPI europium detection buffer solution; thawing the Tag2-PD1 protein solution, and diluting 5 times with PPI europium detection buffer solution; thawing the anti-Tag1-Eu3+ solution, and diluting 100 times with PPI europium detection buffer solution; thawing the anti-Tag2-XL665 solution, and diluting 25 times with PPI europium detection buffer; the 10mM compound was thawed and diluted to 0.32mM with PPI europium detection buffer.
Then 2. Mu.L of inhibitor small molecule solution and control antibody solution with different gradients, 4. Mu.L of 1-Tag1 and 4. Mu.L of 1-Tag2, were added to each well of the experimental group in 384 well plates. Preserving for 15min at room temperature. Then 5. Mu.L of a mixture of anti-Tag1-Eu 3+ and 5. Mu.L of anti-Tag2-XL665 is added, and the mixture is stored for 2 hours at room temperature in a sealed and light-proof manner.
Negative and positive control groups were set: positive control (BMS 202), negative control (PPI europium detection buffer) such that the solution volume per well is 20 μl, was performed as in the experimental group. Finally, fluorescence emission at 665nm and 620nm are detected under excitation of 320nm excitation wavelength, data are processed according to the formula ratio= (Signal 665 nm)/(Signal 620 nm). Times.10 4, and Signal 665nm and Signal 620nm respectively represent fluorescence emission Signal intensities at 665nm and 620 nm. The results of the HTRF method for determining the influence of small molecules on PD-1/PD-L1 interactions are shown in FIG. 2. The results show that compound 5a has the best ability to inhibit PD-1/PD-L1 interactions, with good biological activity, as shown in figure 2. The abscissa in FIG. 2 shows BMS202 at a concentration of 32. Mu.M and compounds 3a-r, 4a-b, 5a-b and 6a-h, respectively, from left to right. The ordinate in FIG. 2 shows PD-1/PD-L1 binding activity.

Claims (11)

1. The application of the biphenyl-1, 2, 3-triazole conjugate in preparing antitumor drugs is characterized in that the biphenyl-1, 2, 3-triazole conjugate is used for preparing antitumor drugs for inhibiting A549, HCC827 or MDA-MB-231 tumor cells;
the biphenyl-1, 2, 3-triazole conjugate is selected from one of the following:
when the A549 tumor cells are inhibited, the biphenyl-1, 2, 3-triazole conjugate is a compound 3o, 6a, 6c, 6d, 6e, 6g or 6h;
When HCC827 tumor cells are inhibited, the biphenyl-1, 2, 3-triazole conjugate is compound 3c, 3l, 3m, 3o, 6a, 6b, 6c, 6d, 6e, 6g, or 6h;
When MDA-MB-231 tumor cells are inhibited, the biphenyl-1, 2, 3-triazole conjugate is a compound 3a, 3b, 3c, 3e, 6a, 6c, 6d, or 6e.
2. The application of the biphenyl-1, 2, 3-triazole conjugate in preparing antitumor drugs, which is characterized in that the preparation method of the biphenyl-1, 2, 3-triazole conjugate comprises the following steps:
1) Reacting (2-methylbiphenyl-3-yl) methanol represented by formula (II) with propargyl bromide in the presence of sodium hydride to obtain (2-methyl-3- (2-alkynyloxy) methyl) biphenyl represented by formula (III);
2) Selecting a tetrahydrofuran/water mixed solution with the volume ratio of 1:0.5-2 as a reaction solvent, carrying out click chemical reaction on (2-methyl-3- (2-alkynyloxy) methyl) biphenyl shown in a formula (III) and various substituted phenyl azides under the catalysis of sodium aspartate and copper sulfate pentahydrate, and carrying out post-treatment on the reaction solution after the reaction is finished to prepare biphenyl-1, 2, 3-triazole conjugate shown as any one of compounds 3a-o and 4 a-b; wherein the substituents on the benzene rings of the substituted phenyl azide are the same as the substituents on the terminal phenyl groups of the corresponding compounds 3a-o, 4 a-b;
3) The compounds 4a-b are treated by thionyl chloride, and after the reaction is finished, the reaction liquid is subjected to post-treatment to prepare biphenyl-1, 2, 3-triazole conjugate shown by the compounds 5 a-b;
4) In the presence of potassium carbonate and acetonitrile, the compounds 5a-b react with various aliphatic amines to obtain biphenyl-1, 2, 3-triazole conjugates shown as the compounds 6 a-h; wherein the fatty amine is NH(CH3)(CH2)2OH、NH2(CH2)2OH、NH2(CH2)2R6 or NH 2(CH2)3R6,R6 is OH, NHCOCH 3 or N (CH 2CH2OH)2;
3. The application of the biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 2, wherein the reaction in the step 1) is performed at room temperature for 7-10 hours, the feeding mole ratio of (2-methylbiphenyl-3-yl) methanol to propargyl bromide shown in the formula (II) is 1:0.8-1.2, and the feeding mole ratio of (2-methylbiphenyl-3-yl) methanol to sodium hydride shown in the formula (II) is 1:2.5-4.
4. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 3, wherein in step 1), the molar ratio of (2-methylbiphenyl-3-yl) methanol to sodium hydride represented by formula (ii) is 1:3.
5. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 2, wherein the reaction temperature of the ignition chemical reaction in step 2) is room temperature, and the reaction time is 7-9 hours;
In the step 2), the feeding mole ratio of the (2-methyl-3- (2-alkynyloxy) methyl) biphenyl, the substituted phenyl azide, the copper sulfate pentahydrate and the sodium aspartate is 5.0-5.5:5.0-5.5:0.8-1.2:1;
The post-treatment method in step 2) is as follows: removing tetrahydrofuran under reduced pressure, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain crude product; finally purifying by column chromatography with petroleum ether mixed solvent containing 20% -40% ethyl acetate as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in any one of compounds 3a-o and 4 a-b.
6. The use of a biphenyl-1, 2, 3-triazole conjugate in the manufacture of an antitumor drug according to claim 5, wherein the reaction time for the ignition chemical reaction in step 2) is 8 hours;
In the step 2), the feeding mole ratio of the (2-methyl-3- (2-alkynyloxy) methyl) biphenyl, the substituted phenyl azide, the copper sulfate pentahydrate and the sodium aspartate is 5.25:5.25:1:1.
7. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 2, wherein the reaction temperature in step 3) is room temperature, and the reaction is stirred for 1.5-4 hours; the feeding mole ratio of the compounds 4a-b to thionyl chloride is 1:1.0-3.0;
The post-treatment method in the step 3) is as follows: after the reaction is completed through TLC detection, saturated sodium bicarbonate aqueous solution is added into the reaction mixture, then dichloromethane is used for extracting a product, an organic layer is collected, anhydrous sodium sulfate is used for drying, and a crude product is obtained through vacuum concentration; finally, purifying by column chromatography with petroleum ether mixed solvent containing 10% -30% ethyl acetate as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in compounds 5 a-b.
8. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 7, wherein the reaction is carried out for 2 hours with stirring in step 3); the molar ratio of the compounds 4a-b to thionyl chloride was 1:2.0.
9. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 2, wherein the reaction temperature in step 4) is room temperature, and the reaction is stirred for 6-12 hours; the molar ratio of the compound 5a-b to the various aliphatic amine to the potassium carbonate is 1:0.8-1.5:1.0-3.0.
10. The use of a biphenyl-1, 2, 3-triazole conjugate in preparing an antitumor drug according to claim 9, wherein in step 4) the reaction is stirred for 8 hours; the molar ratio of the compound 5a-b to the various aliphatic amine to the potassium carbonate is 1:1:1.2-1.5.
11. The use of a biphenyl-1, 2, 3-triazole conjugate according to claim 2 for preparing an antitumor drug, characterized in that the post-treatment method in step 4) is as follows: after the reaction was completed by TLC detection, the solvent was removed by reduced pressure, then extracted with ethyl acetate, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product; finally purifying by column chromatography with dichloromethane mixed solvent containing 5% -15% methanol as eluent to obtain biphenyl-1, 2, 3-triazole conjugate shown in compounds 6 a-h.
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