CN108864067B - 2-propargyl sulfydryl-5-cyanopyrimidine derivative and preparation method and application thereof - Google Patents

2-propargyl sulfydryl-5-cyanopyrimidine derivative and preparation method and application thereof Download PDF

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CN108864067B
CN108864067B CN201810639072.9A CN201810639072A CN108864067B CN 108864067 B CN108864067 B CN 108864067B CN 201810639072 A CN201810639072 A CN 201810639072A CN 108864067 B CN108864067 B CN 108864067B
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刘宏民
郭倩
马立英
周文娟
杨菲菲
赵文
郑甲信
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Zhengzhou University
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention provides a 2-propargyl mercapto-5-cyanopyrimidine derivative with a structure shown in a formula I, and the 2-propargyl mercapto-5-cyanopyrimidine derivative has a better inhibiting effect on DCN1-UBC12 protein-protein interaction than clinically used antitumor drugs 5-fluorouracil. According to the description of the embodiment, the 2-propargyl sulfydryl-5-cyanopyrimidine derivative has better inhibitory activity on DCN1-UBC12 protein-protein interaction.

Description

2-propargyl sulfydryl-5-cyanopyrimidine derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a 2-propargyl sulfydryl-5-cyanopyrimidine derivative and a preparation method and application thereof.
Background
Tumors are diseases which are seriously harmful to human health and difficult to overcome, and a plurality of antitumor drugs are available on the market at present, but the drugs have problems, such as high toxicity, weak targeting property, easy generation of drug resistance and the like. Therefore, the research and development of novel antitumor drugs are very important.
Ubiquitination modifications are involved in post-translational modification of proteins to regulate cellular processes. Studies show that different ubiquitination processes can often cause various diseases, such as Parkinson's disease, Alzheimer's disease, rectal cancer, breast cancer and other human diseases. Neddylation modification, which is similar to ubiquitination modification, is a series of enzymatic reactions that accomplish protein modification and thus regulate cellular activities. The Neddylation process has close relationship with tumor and immune system related diseases, such as metabolic syndrome, liver cancer, lung cancer, gastric cancer and the like. In the Neddylation regulation process, DCN1 of E3 ligase plays an important role in the process of disease occurrence and development. Structurally, DCN1 contains a UBA domain that can form a complex with the E2 coupling enzyme UBC12 to modify the substrate downstream of Neddylation. Therefore, the design and development of a small molecule inhibitor of DCN1-UBC12 protein-protein interaction with high biological activity, high selectivity and low toxic and side effects has become a hot spot of drug research.
Disclosure of Invention
The invention aims to provide a 2-propargyl sulfydryl-5-cyanopyrimidine derivative with high biological activity, high selectivity and low toxic and side effects and protein-protein interaction of DCN1-UBC 12.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a 2-propargyl sulfydryl-5-cyanopyrimidine derivative which has a structure shown in a formula I:
Figure BDA0001701815470000011
in the formula I, R1Is composed of
Figure BDA0001701815470000012
Figure BDA0001701815470000013
Figure BDA0001701815470000021
R2Is composed of
Figure BDA0001701815470000022
Figure BDA0001701815470000023
Preferably, said R is1Is composed of
Figure BDA0001701815470000024
Figure BDA0001701815470000025
The R is2Is composed of
Figure BDA0001701815470000026
Preferably, the 2-propargyl sulfydryl-5-cyanopyrimidine derivative is
Figure BDA0001701815470000027
Figure BDA0001701815470000028
Figure BDA0001701815470000031
The invention also provides a preparation method of the 2-propargyl sulfydryl-5-cyanopyrimidine derivative, which comprises the following steps:
ethyl cyanoacetate, thiourea and R2-CHO, an alkali reagent and a solvent I are mixed to carry out cyclization reaction to obtain a compound with a structure shown in a formula II;
mixing the compound with the structure shown in the formula II, bromopropyne, phosphorus oxychloride and a solvent II to perform a substitution reaction I to obtain a compound with the structure shown in the formula III;
the compound with the structure shown as the formula III and R1Mixing the-H and a solvent III to perform a substitution reaction II to obtain a 2-propargyl sulfydryl-5-cyanopyrimidine derivative;
Figure BDA0001701815470000032
preferably, the temperature of the cyclization reaction is 0-90 ℃, and the time of the cyclization reaction is 11-13 hours.
Preferably, the temperature of the substitution reaction I is 0-90 ℃, and the time of the substitution reaction I is 5-7 hours.
Preferably, the temperature of the substitution reaction II is 0-90 ℃, and the time of the substitution reaction II is 9-11 hours.
Preferably, the solvent I, the solvent II and the solvent III are independently one or more of acetone, N-dimethylformamide, acetonitrile, methanol, isopropanol, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane and water.
Preferably, the alkali reagent is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate dodecahydrate, potassium phosphate, potassium bicarbonate, sodium bicarbonate and triethylamine.
The invention also provides application of the 2-propargyl sulfydryl-5-cyanopyrimidine derivative in preparing antitumor drugs.
The invention provides a 2-propargyl mercapto-5-cyanopyrimidine derivative with a structure shown in a formula I, and the 2-propargyl mercapto-5-cyanopyrimidine derivative has a better inhibiting effect on DCN1-UBC12 protein-protein interaction than clinically used antitumor drugs 5-fluorouracil. According to the description of the embodiment, the 2-propargyl sulfydryl-5-cyanopyrimidine derivative has better inhibitory activity on DCN1-UBC12 protein-protein interaction.
Detailed Description
The invention provides a 2-propargyl sulfydryl-5-cyanopyrimidine derivative which has a structure shown in a formula I:
Figure BDA0001701815470000041
in the formula I, R1Is composed of
Figure BDA0001701815470000042
Figure BDA0001701815470000043
R2Is composed of
Figure BDA0001701815470000044
Figure BDA0001701815470000045
In the present invention, said R1Preferably, it is
Figure BDA0001701815470000051
Figure BDA0001701815470000052
Figure BDA0001701815470000053
The R is2Preferably, it is
Figure BDA0001701815470000054
Figure BDA0001701815470000055
In the present invention, the 2-propargyl mercapto-5-cyanopyrimidine derivative is preferably a compound represented by the formula
Figure BDA0001701815470000056
Figure BDA0001701815470000061
The invention also provides a preparation method of the 2-propargyl sulfydryl-5-cyanopyrimidine derivative, which comprises the following steps:
ethyl cyanoacetate, thiourea and R2-CHO, an alkali reagent and a solvent I are mixed to carry out cyclization reaction to obtain a compound with a structure shown in a formula II;
mixing the compound with the structure shown in the formula II, bromopropyne, phosphorus oxychloride and a solvent II to perform a substitution reaction I to obtain a compound with the structure shown in the formula III;
the compound with the structure shown as the formula III and R1Mixing the-H and a solvent III to perform a substitution reaction II to obtain a 2-propargyl sulfydryl-5-cyanopyrimidine derivative;
Figure BDA0001701815470000062
in the present invention, all the raw materials are commercially available products well known to those skilled in the art unless otherwise specified.
The invention uses ethyl cyanoacetate, thiourea and R2-CHO, an alkali reagent and a solvent I are mixed to carry out cyclization reaction, and a compound with a structure shown in a formula II is obtained. In the present invention, said R2-CHO R2Is composed of
Figure BDA0001701815470000063
Figure BDA0001701815470000064
Preferably, it is
Figure BDA0001701815470000065
Figure BDA0001701815470000066
In the invention, the alkali reagent is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate dodecahydrate, potassium phosphate, potassium bicarbonate, sodium bicarbonate and triethylamine; when the alkali agent is two or more of the above specific choices, the specific ratio of the specific substances in the present invention is not particularly limited, and the specific substances may be mixed at any ratio.
In the invention, the solvent I is preferably one or more of acetone, N-dimethylformamide, acetonitrile, methanol, isopropanol, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane and water; when the solvent i is two or more of the above specific choices, the present invention does not have any particular limitation on the ratio of the specific substances, and the specific substances may be mixed in any ratio.
In the invention, the cyanoacetic acid ethyl ester, thiourea and R2The molar ratio of-CHO and alkaline agent is preferably (1.8-2.2): (2.8-3.2): (2.8-3.2): (2.8-3.2): (4.8-5.2), more preferably (1.9-2.1): (2.9-3.1): (2.9-3.1): (2.9-3.1): (4.9-5.1).
In the present invention, the volume ratio of the amount of the ethyl cyanoacetate to the solvent i is preferably (0.3 to 0.5) mol: 1mL, more preferably (0.32 to 0.48) mol: 1mL, most preferably (0.35 to 0.45) mol: 1 mL.
The mixing order is not particularly limited in the present invention, and the mixing can be performed in any mixing order. In the present invention, the mixing sequence may specifically be: mixing ethyl cyanoacetate, an alkaline reagent and ethanol to obtain a mixture I; mixing thiourea with R2-CHO is mixed with mixture I.
In the invention, the mixing temperature of the ethyl cyanoacetate, the alkali reagent and the ethanol is preferably 80-100 ℃, more preferably 85-95 ℃, and most preferably 88-92 ℃; in the present invention, the mixing of the ethyl cyanoacetate, the alkali agent and the ethanol is preferably performed under stirring, and the stirring is not particularly limited in the present invention, and the stirring may be performed by a stirring process known to those skilled in the art to achieve sufficient dissolution.
In the present invention, the thiourea and R2The mixing temperature of the-CHO and the mixture I is preferably 80-100 ℃, more preferably 85-95 ℃, and most preferably 88-92 ℃; in the invention, the mixing is preferably carried out under the condition of stirring, and the stirring time is preferably 8-12 hours, and more preferably 9-11 hours; the stirring rate is not particularly limited in the present invention, and the stirring may be performed at a stirring rate known to those skilled in the art.
In the invention, the temperature of the cyclization reaction is preferably 0-90 ℃, more preferably 10-80 ℃, and most preferably 30-50 ℃; the time of the cyclization reaction is preferably 11 to 13 hours, more preferably 11.5 to 12.5 hours, and most preferably 11.8 to 12.2 hours.
In the present invention, the cyclization reaction is preferably judged to be completed by TLC follow-up detection.
After the cyclization reaction is finished, the invention preferably performs suction filtration and recrystallization on the obtained reaction product to obtain the compound with the structure shown in the formula II. The invention does not have any special limitation on the suction filtration and recrystallization, and the suction filtration and recrystallization processes which are well known by the technical personnel in the field are adopted to achieve the purposes of solid-liquid separation and product purification.
After the compound with the structure shown in the formula II is obtained, the compound with the structure shown in the formula II, bromopropyne, phosphorus oxychloride and a solvent II are mixed to carry out a substitution reaction I, so that the compound with the structure shown in the formula III is obtained. In the invention, the solvent II is preferably one or more of acetone, N-dimethylformamide, acetonitrile, methanol, isopropanol, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane and water; when the solvent ii is two or more of the above specific choices, the present invention does not have any particular limitation on the ratio of the specific substances, and the specific substances may be mixed in any ratio.
In the invention, the molar ratio of the compound having the structure shown in the formula II, the bromopropyne and the phosphorus oxychloride is preferably (1.8-2.2): (2.8-3.2): (2.8-3.2); more preferably (1.9-2.1): (2.9-3.1): (2.9-3.1).
In the present invention, the volume ratio of the amount of the substance of the compound having the structure represented by formula II to the solvent II is preferably (1.8 to 2.2) mol: (4.8 to 5.2) mL, more preferably (1.9 to 2.1) mol: (4.9-5.1) mL.
In the invention, the temperature of the substitution reaction I is preferably 0-90 ℃, more preferably 10-80 ℃, and most preferably 30-50 ℃; the time of the substitution reaction I is preferably 5 to 7 hours, more preferably 5.5 to 6.5 hours, and most preferably 5.8 to 6.2 hours.
In the present invention, the substitution reaction I preferably comprises two reaction stages:
mixing a compound with a structure shown in a formula II, bromopropyne and a solvent II to perform a first-stage reaction to obtain a mixed solution after the reaction;
and mixing the reacted mixed solution with phosphorus oxychloride to perform a second-stage reaction to obtain the compound with the structure shown in the formula III.
In the present invention, the compound having the structure represented by the formula ii, the propargyl bromide and the solvent ii are preferably mixed by mixing the compound having the structure represented by the formula ii with the solvent ii and then adding the propargyl bromide dropwise to the resultant; the dropping rate is not limited in any way, and the dropping is carried out according to the dropping method known to those skilled in the art to achieve the purpose of dropping.
In the invention, the temperature of the first stage reaction is preferably 0-90 ℃, more preferably 10-80 ℃, and most preferably 30-50 ℃; in the invention, the time of the first stage reaction is preferably 3-5 hours, more preferably 3.5-4.5 hours, and most preferably 3.8-4.2 hours; in the present invention, the first-stage reaction is preferably checked for completion of the substitution 1 reaction by TLC.
In the present invention, the first-stage reaction is preferably carried out under stirring, and the stirring conditions in the present invention are not particularly limited, and may be carried out under conditions well known to those skilled in the art.
In the invention, the temperature of the second-stage reaction is preferably 0-90 ℃, more preferably 10-80 ℃, and most preferably 30-50 ℃; the time of the second stage reaction is preferably 0.5 to 1 hour, more preferably 0.6 to 0.9 hour, and most preferably 0.7 to 0.8 hour.
After the substitution reaction I is finished, the reaction product is preferably mixed with ice water, and after a solid is separated out, the compound with the structure shown in the formula III is obtained by suction filtration and column chromatography. In the present invention, the mixing of the reaction product with ice water is preferably performed under stirring conditions; the stirring is not limited in any way, and the stirring is carried out according to the stirring process known by the person skilled in the art; the invention has no special limitation on the suction filtration and column chromatography, and can achieve the purposes of solid-liquid separation and product purification by adopting the suction filtration and column chromatography processes known to the technical personnel in the field.
After obtaining the compound with the structure shown in the formula III, the invention uses the compound with the structure shown in the formula III and R1Mixing the-H and a solvent III to carry out a substitution reaction II to obtain the 2-propargyl sulfydryl-5-cyanopyrimidine derivative.
In the present invention, said R1R in-H1Preferably is
Figure BDA0001701815470000091
Figure BDA0001701815470000092
Figure BDA0001701815470000093
More preferably
Figure BDA0001701815470000094
Figure BDA0001701815470000095
In the invention, the compound with the structure shown in the formula III and R1The molar ratio of-H is preferably (0.8-1.2): (1.8-2.2), more preferably (0.9-1.1): (1.9-2.1); in the invention, the volume ratio of the substance amount of the compound with the structure shown in the formula III to the solvent III is preferably 1mol (18-22) L, more preferably 1mol: (19-31) L.
In the invention, the solvent III is preferably one or more of acetone, N-dimethylformamide, acetonitrile, methanol, isopropanol, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane and water; when the solvent iii is two or more of the above specific choices, the present invention does not have any particular limitation on the ratio of the specific substances, and the specific substances may be mixed at any ratio.
In the invention, the compound with the structure shown in the formula III and R1Mixing the compound with the structure shown in the formula III and the solvent III to obtain a mixture II; then mixing the mixture II with R1-H mixing. In the present invention, the mixing of the compound having the structure represented by the formula iii and the solvent iii is preferably performed by adding the solvent iii to the compound having the structure represented by the formula iii; the temperature and time of mixing are not particularly limited in the present invention, and mixing is performed at a mixing temperature and time known to those skilled in the art for the purpose of achieving sufficient dissolution. After the mixing is finished, the mixture II is preferably heated to 55-65 ℃, and more preferably to 58-62 ℃. In the present invention, the mixture II is heated first and then mixed with R1The mixture of-H can fully dissolve the mixture II, and is more favorable for the reaction.
In the present invention, the mixtures II and R1The mixing of-H is preferably carried out under stirring, which is not subject to any particular limitation in the present invention, and may be carried out under conditions well known to those skilled in the art.
In the invention, the temperature of the substitution reaction II is preferably 0-90 ℃, more preferably 10-80 ℃, and most preferably 30-50 ℃; in the present invention, the substitution reaction II is preferably carried out under heating reflux; the time of the substitution reaction II is preferably 9 to 11 hours, more preferably 9.5 to 10.5 hours, and most preferably 9.8 to 10.2 hours; and the substitution reaction II is followed by TLC to detect whether the reaction is finished.
After the substitution reaction II is finished, the invention preferably carries out post-treatment on the reaction product; the work-up preferably comprises condensation, precipitation of solids, suction filtration and recrystallization. The present invention does not have any particular limitation in the condensation, solid precipitation, suction filtration and recrystallization, and may be carried out under conditions known to those skilled in the art.
The invention also provides application of the 2-propargyl sulfydryl-5-cyanopyrimidine derivative in preparing antitumor drugs. In the present invention, the antitumor drug is preferably targeted at the protein-protein interaction of DCN1-UBC 12.
The 2-propargyloxymercapto-5-cyanopyrimidine derivatives provided by the present invention will be described in detail with reference to the following examples, which should not be construed as limiting the scope of the present invention.
Example 1
Ethyl cyanoacetate (2.3g,20mmol) and potassium hydroxide (1.2g,30mmol) were added to 50mL of ethanol (AR), dissolved with stirring at 90 deg.C, thiourea (2.3g,30mmol) and coumarin-6-carbaldehyde (5.22g,30mmol) were added to the reaction system, stirring was continued at 90 deg.C for 10h, and TLC follow-up was performed. After the reaction is finished, carrying out suction filtration and recrystallization to obtain a compound with a structure shown as a formula II-1;
Figure BDA0001701815470000101
a compound having a structure represented by the formula II-1 (6.7g,20mmol) was mixed with 1, 4-dioxane (AR, 50mL), bromopropyne (3.6g,30mmol) was added dropwise to the resulting solution, and the reaction was stirred with heating at 60 ℃. Monitoring the reaction process by TLC until the reaction is completed; directly dropwise adding phosphorus oxychloride (4.6g,30mmol) into the reaction system without separation, after the reaction is finished, pouring the obtained reaction product into ice water, stirring, separating out solids, carrying out suction filtration to obtain solids, and carrying out column chromatography to obtain the compound with the structure shown in III-1. The compound with the structure shown in III-1 is a yellow solid, the melting point is 188-189 ℃, and the yield is 52.1%.
Figure BDA0001701815470000102
The analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.42(d,J＝2.2Hz,1H,-CH＝),8.26(dd,J＝8.7,2.2Hz,1H,-CH＝),8.21(d,J＝9.6Hz,1H,Ar-H),7.66(d,J＝8.7Hz,1H,Ar-H),6.63(d,J＝9.6Hz,1H,Ar-H),4.15(d,J＝2.6Hz,2H,-CH2-),3.27(t,J＝2.6Hz,1H,≡C-H).HR-MS(ESI),calcd.C17H8ClN3O2S,[M+Na]+m/z:375.9923,found:375.9925。
adding a compound (353mg and 1mmol) with a structure shown in formula III-1 into a 50mL round-bottom flask, adding 20mL ethanol, dissolving, heating to 60 ℃, adding 1-methyl-5-mercapto-1H-tetrazole (116mg and 2mmol) under stirring, heating for reflux reaction, and tracking and monitoring by TLC. After the reaction is finished, condensing, separating out solid, carrying out suction filtration, and recrystallizing with ethanol to obtain the compound with the structure shown in the formula I-1. The compound with the structure shown in the formula I-1 is a white solid, the melting point is 184-186 ℃, and the yield is 88.5%.
Figure BDA0001701815470000111
The analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.36(d,J＝1.7Hz,1H,Ar-H),8.22(dd,J＝6.2,4.0Hz,2H,Ar-H),7.66(d,J＝14.7Hz,1H,Ar-H),6.62(d,J＝9.6Hz,1H,Ar-H),4.14(s,3H,-CH3),3.57(d,2H,-CH2-),3.17(s,1H,J＝2.5Hz,≡C-H).HR-MS(ESI),calcd.C19H11N7O2S2,[M+Na]+m/z:456.0313,found:456.0315。
example 2
The compound of the structure shown in the formula II-2 was obtained by the same preparation method as that for the compound of the structure shown in the formula II-1 in example 1 except that coumarin-6-carbaldehyde was replaced with thiophenal;
Figure BDA0001701815470000112
obtaining a compound with a structure shown in a formula III-2 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 1;
Figure BDA0001701815470000113
obtaining a compound having a structure represented by formula I-2 by the same preparation method as that for the compound having a structure represented by formula I-1 in example 1; the compound with the structure shown as the formula I-2 is a white solid, the melting point is 183-184 ℃, and the yield is 83.9%;
Figure BDA0001701815470000114
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.32(s,1H,Ar-H),8.13(d,J＝4.1Hz,1H,Ar-H),7.39(s,1H,Ar-H),4.11(s,3H,-CH3),3.59(d,2H,-CH2-),3.15(t,1H,≡C-H).HR-MS(ESI),calcd.C14H9N7S3,[M+Na]+m/z:393.9979,found:393.9982。
example 3
The compound of the structure shown in the formula II-3 is obtained by the same preparation method as the compound of the structure shown in the formula II-1 in the example 1, except that the coumarin-6-formaldehyde is replaced by indole aldehyde;
Figure BDA0001701815470000121
obtaining a compound having a structure shown in a formula III-3 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000122
the compound having the structure shown in formula I-3 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-3 is a white solid product, the melting point is 227 ℃, and the yield is 86.6%;
Figure BDA0001701815470000123
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ12.37(s,1H,NH,D2Oexchangeable),8.63(d,J＝3.0Hz,1H,-CH＝),8.41(d,J＝7.8Hz,1H,Ar-H),7.57(d,J＝7.9Hz,1H,Ar-H),7.29(t,J＝7.3Hz,1H,Ar-H),7.24(t,J＝7.5Hz,1H,Ar-H),4.13(s,3H,-CH3),3.59(d,J＝2.3Hz,2H,-CH2-),3.17(t,J＝2.4Hz,1H,≡C-H).HR-MS(ESI),calcd.C18H12N8S2,[M+Na]+m/z:427.0524,found:427.0525。
example 4
A compound having a structure represented by formula ii-4 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with 2-pyrrolealdehyde;
Figure BDA0001701815470000124
obtaining a compound having a structure shown in a formula III-4 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000125
obtaining a compound having a structure represented by formula I-4 by the same preparation method as that for the compound having a structure represented by formula I-1 in example 1; the compound with the structure shown in the formula I-4 is a white solid product, the melting point is 189-190 ℃, and the yield is 51.6%;
Figure BDA0001701815470000131
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ12.08(s,1H,NH,D2Oexchangeable),7.49(s,1H,-CH＝),7.29(s,1H,-CH＝),6.53–6.32(m,1H,-CH＝),4.10(s,3H,-CH3),3.69(d,J＝2.6Hz,2H,-CH2-),3.15(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C14H10N8S2,[M+Na]+m/z:418.0521,found:418.0521。
example 5
A compound having a structure represented by formula ii-5 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with p-chlorobenzaldehyde;
Figure BDA0001701815470000132
obtaining a compound having a structure shown in a formula III-5 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000133
the compound having the structure shown in formula I-5 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-5 is a white solid product, the melting point is 179 ℃, and the yield is 87.7%;
Figure BDA0001701815470000134
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.02(s,1H,Ar-H),7.97(d,J＝7.9Hz,1H,Ar-H),7.81–7.75(m,1H,-CH＝),7.69(t,J＝7.9Hz,1H,-CH＝),4.99(t,J＝6.6Hz,2H,-CH2-),3.69(t,J＝5.1Hz,2H,-CH2-),3.67(d,J＝2.2Hz,2H,-CH2-),3.21(t,J＝2.4Hz,1H,≡C-H),2.84(s,6H,-CH3).HR-MS(ESI),calcd.C19H17ClN8S2,[M+H]+m/z:457.0784,found:457.0785。
example 6
A compound having a structure represented by formula ii-6 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with benzaldehyde;
Figure BDA0001701815470000141
obtaining a compound having a structure shown in a formula III-6 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000142
the compound having the structure shown in formula I-6 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-6 is a white solid product, the melting point is 156-158 ℃, and the yield is 89.8%;
Figure BDA0001701815470000143
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.21(d,J＝3.3Hz,1H,-CH＝),8.12(d,J＝3.3Hz,1H,-CH＝),7.93(d,J＝8.1Hz,2H,Ar-H),7.43(d,J＝8.1Hz,2H,Ar-H),3.80(d,J＝2.5Hz,2H,-CH2-),3.15(t,J＝2.4Hz,1H,≡C-H),2.41(d,J＝6.0Hz,3H,-CH3).HR-MS(ESI),calcd.C18H12N4S3,[M+Na]+m/z:403.0122,found:403.0123。
example 7
A compound having a structure represented by formula ii-7 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with m-chlorobenzaldehyde;
Figure BDA0001701815470000144
obtaining a compound having a structure shown in a formula III-7 by the same preparation method as the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000145
the compound having the structure represented by formula I-7 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 1; the compound with the structure shown in the formula I-7 is a white solid product, the melting point is 174-175 ℃, and the yield is 67.1%;
Figure BDA0001701815470000151
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.86(d,J＝4.9Hz,2H,-CH＝),7.94(d,J＝8.0Hz,2H,Ar-H),7.55(t,J＝4.9Hz,1H,-CH＝),7.44(d,J＝8.0Hz,2H,Ar-H),3.90(d,J＝2.2Hz,2H,-CH2-),3.16(s,1H,≡C-H),2.43(s,3H,-CH3).HR-MS(ESI),calcd.C19H13N5S2,[M+Na]+m/z:398.0510,found:398.0508。
example 8
A compound having a structure represented by formula ii-8 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with p-tolualdehyde;
Figure BDA0001701815470000152
obtaining a compound with a structure shown in a formula III-8 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 1;
Figure BDA0001701815470000153
the compound having the structure shown in formula I-8 is obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-8 is a white solid product, the melting point is 189-192 ℃, and the yield is 89.9%;
Figure BDA0001701815470000154
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.56(s,1H,Ar-H),7.54(d,J＝3.7Hz,2H,Ar-H),7.25(dt,J＝6.9,2.2Hz,1H,Ar-H),4.12(s,3H,-CH3),3.84(s,3H,-CH3),3.61(d,J＝2.4Hz,2H,-CH2-),3.17(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C17H13N7OS2,[M+Na]+m/z:418.0521,found:418.0521。
example 9
A compound having a structure represented by formula ii-9 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with m-p-dichlorobenzaldehyde;
Figure BDA0001701815470000155
obtaining a compound having a structure shown in a formula III-9 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000161
the compound having the structure shown in formula I-9 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-9 is a white solid product, the melting point is 136 ℃, and the yield is 73.2%;
Figure BDA0001701815470000162
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.21(t,J＝10.7Hz,1H,-CH＝),8.13(d,J＝3.3Hz,1H,-CH＝),8.03(d,J＝8.6Hz,2H,Ar-H),7.71(d,J＝8.6Hz,2H,Ar-H),3.79(d,J＝2.4Hz,2H,-CH2-),3.15(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C17H9ClN4S3,[M+Na]+m/z:422.9576,found:422.9578。
example 10
A compound having a structure represented by formula ii-10 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with p-bromobenzaldehyde;
Figure BDA0001701815470000163
obtaining a compound having a structure shown in a formula III-10 by the same preparation method as the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000164
obtaining a compound having a structure represented by formula I-10 by the same preparation method as that for the compound having a structure represented by formula I-1 in example 1; the compound with the structure shown in the formula I-10 is a white solid product, the melting point is 159-160 ℃, and the yield is 89%;
Figure BDA0001701815470000165
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.94(d,J＝8.5Hz,2H,Ar-H),7.86(d,J＝8.5Hz,2H,Ar-H),4.13(s,3H,-CH3),3.59(d,J＝2.1Hz,2H,-CH2-),3.15(s,1H,≡C-H).HR-MS(ESI),calcd.C16H10BrN7S2,[M+Na]+m/z:418.0521,found:418.0520。
example 11
The compound having the structure represented by formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by formula II-1 in example 1 except that coumarin-6-carbaldehyde was replaced with m-p-m-trimethoxybenzaldehyde;
Figure BDA0001701815470000171
obtaining a compound having a structure shown in a formula III-11 by the same preparation method as the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000172
the compound having the structure shown in formula I-11 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the compound with the structure shown in the formula I-11 is a white solid product, the melting point is 179-180 ℃, and the yield is 80%;
Figure BDA0001701815470000173
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.40(s,2H,Ar-H),4.12(s,3H,-CH3),3.87(s,6H,-CH3),3.80(s,3H,-CH3),3.67(d,J＝2.2Hz,2H,-CH2-),3.20(t,J＝2.3Hz,1H,≡C-H).HR-MS(ESI),calcd.C19H17N7O3S2,[M+Na]+m/z:478.0732,found:478.0733。
example 12
Obtaining a compound with a structure shown in a formula II-1 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 1;
obtaining a compound with a structure shown in a formula III-1 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 1;
the compound having the structure shown in formula I-12 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; the compound with the structure shown in the formula I-12 is a yellow solid product, the melting point is 197-198 ℃, and the yield is 72.4%;
Figure BDA0001701815470000181
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.39(s,1H,Ar-H),8.27–8.19(m,2H,Ar-H),7.66(d,J＝8.7Hz,1H,Ar-H),6.63(d,J＝9.6Hz,1H,Ar-H),5.00(t,J＝6.5Hz,2H,-CH2-),3.69(d,J＝4.9Hz,2H,-CH2-),3.66(d,J＝1.9Hz,2H,-CH2-),3.23(t,J＝2.3Hz,1H,≡C-H),2.83(s,6H,-CH3).HR-MS(ESI),calcd.C22H18N8O2S2,[M+Na]+m/z:513.0892,found:513.0893。
example 13
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-13; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; the compound with the structure shown in the formula I-13 is a yellow solid product, the melting point is 197-198 ℃, and the yield is 75.9%;
Figure BDA0001701815470000182
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.42(s,2H,Ar-H),4.99(t,J＝6.6Hz,2H,-CH2-),3.87(s,6H,-CH3),3.79(s,3H,-CH3),3.72(d,J＝2.3Hz,2H,-CH2-),3.69(t,J＝6.6Hz,2H,-CH2-),3.25(t,J＝2.5Hz,1H,≡C-H),2.83(s,6H,-CH3).HR-MS(ESI),calcd.C22H24N8O3S2,[M+Na]+m/z:513.1491,found:513.1491。
example 14
Obtaining a compound with a structure shown in a formula II-8 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 8;
obtaining a compound having a structure shown in a formula III-8 by the same preparation method as the compound having a structure shown in the formula III-1 in example 8;
the compound having the structure represented by formula I-14 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 8; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; the compound with the structure shown in the formula I-14 is a white solid product, the melting point is 141-142 ℃, and the yield is 83.4%;
Figure BDA0001701815470000191
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.95(d,J＝3.9Hz,2H,Ar-H),7.50(d,J＝8.0Hz,2H,Ar-H),4.14(d,J＝4.0Hz,3H,-CH3),3.60(s,2H,-CH2-),3.15(t,J＝2.5Hz,1H,≡C-H),3.05–2.96(m,1H,-CH),1.25(d,J＝6.8Hz,6H,-CH3).HR-MS(ESI),calcd.C19H17N7S2,[M+Na]+m/z:430.0885,found:430.0886。
example 15
Obtaining a compound with a structure shown in a formula II-5 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 5;
obtaining a compound with a structure shown in a formula III-5 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 5;
the compound having the structure shown in formula I-15 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 5; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; (ii) a The compound with the structure shown in the formula I-15 is a white solid product, the melting point is 171-172 ℃, and the yield is 65.4%;
Figure BDA0001701815470000192
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.24–8.21(m,1H,Ar-H),8.13(d,J＝2.9Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.96(d,J＝7.6Hz,1H,Ar-H),7.75(d,J＝8.0Hz,1H,-CH＝),7.66(t,J＝7.8Hz,1H,-CH＝),3.80(s,2H,-CH2-),3.15(s,1H,≡C-H).HR-MS(ESI),calcd.C17H9ClN4S3,[M+Na]+m/z:422.9576,found:422.9577。
example 16
Obtaining a compound having a structure represented by formula II-7 by the same preparation method as that for the compound having a structure represented by formula II-1 in example 7;
obtaining a compound having a structure represented by the formula III-7 by the same preparation method as that for the compound having a structure represented by the formula III-1 in example 7;
the compound having the structure represented by formula I-16 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 7; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; (ii) a The compound with the structure shown in the formula I-16 is a white solid product, the melting point is 130-131 ℃, and the yield is 81.9%;
Figure BDA0001701815470000201
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.17(d,J＝7.5Hz,2H,Ar-H),8.07(s,1H,Ar-H),7.59–7.55(m,2H,Ar-H),4.10(s,3H,-CH3),3.67(d,2H,-CH2-),3.11(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C16H11N7S2,[M+Na]+m/z:388.0415,found:388.0415。
example 17
Obtaining a compound having a structure represented by formula II-9 by the same preparation method as that for the compound having a structure represented by formula II-1 in example 9;
obtaining a compound having a structure represented by formula III-9 by the same preparation method as that for the compound having a structure represented by formula III-1 in example 9;
the compound having the structure represented by formula I-17 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 9; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1- (2- (dimethylamino) ethyl) -5-mercapto-1H-tetrazole; the compound with the structure shown in the formula I-17 is a white solid product, the melting point is 213-215 ℃, and the yield is 62.9%;
Figure BDA0001701815470000202
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.87(d,J＝4.0Hz,2H,-CH＝),8.04(d,J＝7.6Hz,2H,Ar-H),7.72(d,J＝7.8Hz,2H,Ar-H),7.57(s,1H,-CH＝),3.89(s,2H,-CH2-),3.15(s,1H,≡C-H).HR-MS(ESI),calcd.C18H10ClN5S2,[M+Na]+m/z:417.9964,found:417.9960。
example 18
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-18; the compound with the structure shown in the formula I-18 is a white solid product, the melting point is 176-178 ℃, and the yield is 32.8%;
Figure BDA0001701815470000211
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.62(s,1H,-CH＝),7.38(s,2H,Ar-H),7.22(s,1H,-CH＝),3.87(s,6H,-CH3),3.79(s,3H,-CH3),3.68(s,2H,-CH2-),3.67(s,3H,-CH3),3.20(t,J＝2.2Hz,1H,≡C-H).HR-MS(ESI),calcd.C21H19N5O3S2,[M+Na]+m/z:476.0827,found:476.0828。
example 19
Obtaining a compound with a structure shown in a formula II-1 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 1;
obtaining a compound with a structure shown in a formula III-1 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 1;
the compound having the structure shown in formula I-19 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 1; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-19 is a yellow solid product, the melting point is 226-228 ℃, and the yield is 90.8%;
Figure BDA0001701815470000212
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.37(d,J＝1.9Hz,1H,Ar-H),8.23(d,J＝3.3Hz,1H,Ar-H),8.22(d,J＝2.5Hz,1H,-CH＝),8.20(s,1H,-CH＝),8.13(d,J＝3.3Hz,1H,-CH＝),7.64(d,J＝8.7Hz,1H,-CH＝),6.62(d,J＝9.6Hz,1H,Ar-H),3.80(d,J＝2.4Hz,2H,-CH2-),3.16(t,J＝2.4Hz,1H,≡C-H).HR-MS(ESI),calcd.C20H10N4O2S3,[M+Na]+m/z:456.9864,found:456.9862。
example 20
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-20; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-20 is a white solid product, the melting point is 172-174 ℃, and the yield is 72.4%;
Figure BDA0001701815470000221
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm),8.20(d,J＝3.2Hz,1H,-CH＝),8.11(d,J＝3.2Hz,1H,-CH＝),7.42(s,2H,Ar-H),3.87(s,6H,-CH3),3.85(s,2H,-CH2-),3.79(s,3H,-CH3),3.18(s,1H,≡C-H).HR-MS(ESI),calcd.C20H16N4O3S3,[M+Na]+m/z:479.0282,found:479.0284。
example 21
Obtaining a compound having a structure represented by formula II-9 by the same preparation method as that for the compound having a structure represented by formula II-1 in example 9;
obtaining a compound having a structure represented by formula III-9 by the same preparation method as that for the compound having a structure represented by formula III-1 in example 9;
the compound having the structure represented by formula I-21 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 9; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-21 is a white solid product, the melting point is 142-143 ℃, and the yield is 88.0%;
Figure BDA0001701815470000222
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.23(d,J＝3.1Hz,2H,Ar-H),8.13(d,J＝3.3Hz,1H,Ar-H),7.98(dd,J＝8.4,1.7Hz,1H,-CH＝),7.91(d,J＝8.4Hz,1H,-CH＝),3.80(d,J＝2.3Hz,2H,-CH2-),3.15(s,1H,≡C-H).HR-MS(ESI),calcd.C17H8Cl2N4S3,[M+Na]+m/z:456.9186,found:456.9187。
example 22
Obtaining a compound with a structure shown in a formula II-8 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 8;
obtaining a compound having a structure shown in a formula III-8 by the same preparation method as the compound having a structure shown in the formula III-1 in example 8;
the compound having the structure represented by formula I-22 was obtained by the same preparation method as that for the compound having the structure represented by formula I-1 in example 8; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-22 is a white solid product, the melting point is 164-165 ℃, and the yield is 83.1%;
Figure BDA0001701815470000231
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.92(d,J＝8.2Hz,2H,Ar-H),7.44(d,J＝8.1Hz,2H,Ar-H),4.13(s,3H,-CH3),3.56(t,J＝20.3Hz,2H,-CH2-),3.15(t,J＝2.5Hz,1H,≡C-H),2.42(s,3H,-CH3).HR-MS(ESI),calcd.C17H13N7S2,[M+Na]+m/z:402.0572,found:402.0573。
example 23
Obtaining a compound with a structure shown in a formula II-5 by adopting the same preparation method as the compound with the structure shown in the formula II-1 in the example 5;
obtaining a compound with a structure shown in a formula III-5 by adopting the same preparation method as the compound with the structure shown in the formula III-1 in the example 5;
the compound having the structure shown in formula I-23 was obtained by the same preparation method as that for the compound having the structure shown in formula I-1 in example 5; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-23 is a white solid product, the melting point is 163-164 ℃, and the yield is 87.7%;
Figure BDA0001701815470000232
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.02(d,J＝8.4Hz,2H,Ar-H),7.74(t,J＝19.1Hz,2H,Ar-H),4.13(s,3H,-CH3),3.59(s,2H,-CH2-),3.15(s,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C16H10ClN7S2,[M+Na]+m/z:422.0025,found:422.0025。
example 24
Obtaining a compound having a structure represented by formula II-10 by the same preparation method as that for the compound having a structure represented by formula II-1 in example 10;
obtaining a compound having a structure represented by formula III-10 by the same preparation method as that for the compound having a structure represented by formula III-1 in example 10;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 10 was employed to obtain a compound having the structure represented by formula I-24; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-24 is a white solid product, the melting point is 238-239 ℃, and the yield is 78.1%;
Figure BDA0001701815470000233
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.23(d,J＝3.3Hz,1H,-CH＝),8.13(d,J＝3.3Hz,1H,-CH＝),7.97–7.91(m,2H,Ar-H),7.88–7.82(m,2H,Ar-H),3.79(d,J＝2.6Hz,2H,-CH2-),3.14(t,J＝2.6Hz,1H,≡C-H).HR-MS(ESI),calcd.C17H9BrN4S3,[M+Na]+m/z:466.9070,found:466.9073。
example 25
A compound having a structure represented by formula ii-25 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 1, except that coumarin-6-carbaldehyde was replaced with 4-pyridylaldehyde;
Figure BDA0001701815470000241
obtaining a compound having a structure shown in a formula III-25 by using the same preparation method as that for the compound having a structure shown in the formula III-1 in example 1;
Figure BDA0001701815470000242
obtaining a compound having a structure represented by formula I-25 by the same preparation method as that for the compound having a structure represented by formula I-1 in example 1; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by mercaptothiazole; the compound with the structure shown in the formula I-25 is a white solid product, the melting point is 189-192 ℃, and the yield is 76.3%;
Figure BDA0001701815470000243
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.87(dd,J＝4.5,1.5Hz,2H,Ar-H),8.24(d,J＝3.3Hz,1H,-CH＝),8.14(d,J＝3.3Hz,1H,-CH＝),7.91(dd,J＝4.5,1.6Hz,2H,Ar-H),3.79(d,J＝2.5Hz,2H,-CH2-),3.14(t,J＝2.6Hz,1H,≡C-H).HR-MS(ESI),calcd.C16H9N5S3,[M+Na]+m/z:389.9918,found:389.9919。
example 26
A compound having a structure represented by formula ii-11 was obtained by the same preparation method as that for the compound having a structure represented by formula ii-1 in example 11 except that coumarin-6-carbaldehyde was replaced with m, p, m-trimethoxybenzaldehyde;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-26; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 5-mercapto-1, 3, 4-thiadiazole; the compound with the structure shown in the formula I-26 is a white solid product, the melting point is 228 ℃, and the yield is 81.1%;
Figure BDA0001701815470000251
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ9.96(s,1H,-CH＝),7.45(s,2H,Ar-H),3.94(d,J＝2.5Hz,2H,-CH2-),3.87(s,6H,-CH3),3.79(s,3H,-CH3),3.20(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C19H15N5O3S3,[M+H]+m/z:452.0851,found:452.0850。
example 27
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-27; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 2-mercapto-3 aminothiazole; the compound with the structure shown in the formula I-27 is a yellow solid product, the melting point is 189-192 ℃, and the yield is 89.3%;
Figure BDA0001701815470000252
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.87(s,2H,-CH＝),7.42(s,2H,Ar-H),3.95(d,J＝2.1Hz,2H,-CH2-),3.86(s,6H,-CH3),3.79(s,3H,-CH3),3.17(d,J＝2.2Hz,1H,≡C-H).HR-MS(ESI),calcd.C21H18N4O3S3,[M+Na]+m/z:493.0439,found:493.0438。
example 28
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-28; the difference is that 1-methyl-5-mercapto-1H-tetrazole is replaced by 2-amino-5-mercapto-1, 3, 4-thiadiazole; the compound with the structure shown in the formula I-28 is a white solid product, the melting point is 181-182 ℃, and the yield is 65.1%;
Figure BDA0001701815470000261
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.83(s,2H,NH,D2Oexchangeable),7.43(d,J＝0.6Hz,2H,Ar-H),3.94(t,J＝7.4Hz,2H,-CH2-),3.87(s,6H,-CH3),3.79(d,J＝0.8Hz,3H,-CH3),3.18(dd,J＝2.5,1.6Hz,1H,≡C-H).HR-MS(ESI),calcd.C19H16N6O3S3,[M+H]+m/z:458.0415,found:458.0414。
example 29
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-29; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by aminopyrimidine; the compound with the structure shown in the formula I-29 is a white solid product, the melting point is 205-206 ℃, and the yield is 72.7%;
Figure BDA0001701815470000262
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.86(d,J＝4.9Hz,2H,-CH＝),7.55(t,J＝4.9Hz,1H,-CH＝),7.44(s,2H,Ar-H),3.94(d,J＝2.5Hz,2H,-CH2-),3.87(s,6H,-CH3),3.79(s,3H,-CH3),3.21(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C21H17N5O3S2,[M+H]+m/z:407.0619,found:407.0618。
example 30
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-30; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1-mercapto-benzo [ d ] thiazole; the compound with the structure shown in the formula I-30 is a white solid product, the melting point is 223-334 ℃, and the yield is 69.0%;
Figure BDA0001701815470000271
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ8.25–8.17(m,1H,Ar-H),8.10(d,J＝7.6Hz,1H,Ar-H),7.58(dtd,J＝16.4,7.3,1.3Hz,2H,Ar-H),7.47(s,2H,Ar-H),3.92(d,J＝2.4Hz,2H,-CH2-),3.88(s,6H,-CH3),3.80(s,3H,-CH3),3.15(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C24H18N4O3S3,[M+Na]+m/z:529.0439,found:529.0439。
example 31
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-31; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by 1-methyl-5-amino-1H-tetrazole; the compound with the structure shown in the formula I-31 is a yellow solid product, the melting point is 205 ℃, and the yield is 94.1%;
Figure BDA0001701815470000272
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ7.38(s,2H,Ar-H),3.93(s,3H,-CH3),3.87(s,6H,-CH3),3.85(d,J＝1.8Hz,2H,-CH2-),3.78(s,3H,-CH3),3.16(t,J＝2.5Hz,1H,≡C-H).HR-MS(ESI),calcd.C19H18N8O3S,[M+Na]+m/z:461.1120,found:461.1122。
example 32
The compound having the structure represented by the formula II-11 was obtained by the same preparation method as that for the compound having the structure represented by the formula II-1 in example 11;
obtaining a compound having a structure represented by the formula III-11 by the same production method as that for the compound having a structure represented by the formula III-1 in example 11;
the same preparation method as that for the compound having the structure represented by formula I-1 in example 11 was employed to obtain a compound having the structure represented by formula I-32; the difference is only that 1-methyl-5-mercapto-1H-tetrazole is replaced by piperazine; the compound with the structure shown in the formula I-32 is a white solid product, the melting point is 242 ℃, and the yield is 89.0%;
Figure BDA0001701815470000281
the analytical results were as follows:1H NMR(400MHz,DMSO-d6,ppm)δ9.72(s,1H,NH,D2Oexchangeable),7.30(s,2H,Ar-H),4.19(s,4H,-CH2-),4.03(d,J＝2.1Hz,2H,-CH2-),3.86(s,6H,-CH3),3.77(s,3H,-CH3),3.34(s,4H,-CH2-),3.21(t,J＝2.3Hz,1H,≡C-H).HR-MS(ESI),calcd.C21H23N5O3S,[M+H]+m/z:426.1600,found:426.1602。
example 33
The inhibitory activity of the compound obtained in example 1 to 32 on DCN1-UBC12 protein-protein interaction was measured as follows:
the compound obtained in example 1-32 was added to 4. mu.L of DMSO solution and mixed with the pre-incubated protein/probe complex solution (196. mu.L) in assay buffer;
add test plate, incubate at room temperature for 30 minutes and shake gently. The final concentrations of DCN1 protein and fluorescent probe were 50nM and 5nM, respectively;
each test plate contained a negative control (containing only protein/probe complexes) and a positive control (containing only free probes);
IC50 values were determined by dose response inhibition equation in Prism/GraphPad software (four parameters, variable slope) using a non-linear regression fit of the competition curve;
the test results are shown in table 1:
TABLE 1 pairing of DCN1-UBC12 protein-protein with the compounds obtained in examples 1 to 32
Inhibitory Activity data on interactions
Figure BDA0001701815470000282
Figure BDA0001701815470000291
The above examples show that the 2-propargyl mercapto-5-cyanopyrimidine derivative has a structure shown in formula I, and has a better inhibiting effect on DCN1-UBC12 protein-protein interaction than clinically used antitumor drugs, namely 5-fluorouracil. According to the description of the embodiment, the 2-propargyl sulfydryl-5-cyanopyrimidine derivative has better inhibitory activity on DCN1-UBC12 protein-protein interaction.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A2-propargyl sulfydryl-5-cyanopyrimidine derivative has a structure shown in a formula I:
Figure FDA0002427730770000011
in the formula I, R1Is composed of
Figure FDA0002427730770000012
Figure FDA0002427730770000013
R2Is composed of
Figure FDA0002427730770000014
Figure FDA0002427730770000015
2. The 2-propargyl mercapto-5-cyanopyrimidine derivative of claim 1 wherein R is2Is composed of
Figure FDA0002427730770000016
Figure FDA0002427730770000017
3. The 2-propargylthio-5-cyanopyrimidine derivative according to claim 1 or 2, wherein the 2-propargylthio-5-cyanopyrimidine derivative is
Figure FDA0002427730770000018
Figure FDA0002427730770000021
4. A process for preparing a 2-propargyl mercapto-5-cyanopyrimidine derivative as claimed in any one of claims 1 to 3, comprising the steps of:
ethyl cyanoacetate, thiourea and R2-CHO, an alkali reagent and a solvent I are mixed to carry out cyclization reaction to obtain a compound with a structure shown in a formula II;
mixing the compound with the structure shown in the formula II, bromopropyne, phosphorus oxychloride and a solvent II to perform a substitution reaction I to obtain a compound with the structure shown in the formula III;
the compound with the structure shown as the formula III and R1Mixing the-S-H and a solvent III to perform a substitution reaction II to obtain a 2-propargyl sulfydryl-5-cyanopyrimidine derivative;
Figure FDA0002427730770000031
5. the method according to claim 4, wherein the temperature of the cyclization reaction is 0 to 90 ℃ and the time of the cyclization reaction is 11 to 13 hours.
6. The process according to claim 4, wherein the temperature of the substitution reaction I is 0 to 90 ℃ and the time of the substitution reaction I is 5 to 7 hours.
7. The process according to claim 4, wherein the temperature of the substitution reaction II is 0 to 90 ℃ and the time of the substitution reaction II is 9 to 11 hours.
8. The method according to claim 4, wherein the solvent I, the solvent II and the solvent III are independently one or more selected from the group consisting of acetone, N-dimethylformamide, acetonitrile, methanol, isopropanol, 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane and water.
9. The method of claim 4, wherein the base reagent is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate dodecahydrate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, and triethylamine.
10. The use of the 2-propargyl mercapto-5-cyanopyrimidine derivative according to any one of claims 1 to 3 for the preparation of an antitumor agent.
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