Amino dithioester derivatives containing amide structural units, and methods of making and using the same

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to an aminodithioester derivative containing an amide structural unit, a preparation method and application thereof. The aminodithioester derivative containing a double amide structural unit provided by the present application has good inhibitory activity on lysine-specific demethylase 1 (LSD1) by competitively binding to an active pocket of an important cofactor FAD of LSD1, and has the characteristics of low toxicity, high selectivity and high activity. According to the test results of the embodiments, it can be seen that the aminodithioester derivative provided by the present application can inhibit tumor proliferation at a high concentration and has small toxic and side effects when MGC-803 cells are transplanted into 615 immune normal mice, and it is proved to be an immune-related LSD1 small molecule inhibitor, which can provide a potential lead compound for developing a new anti-gastric cancer drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to an amino dithioester derivative containing an amide structural unit, its preparation method, and its application. Background Technology

[0002] Influenced by environmental pollution, unhealthy lifestyle habits, and genetic factors, cancer has become a leading cause of death threatening human health. Numerous studies have shown that the occurrence and development of cancer are related to epigenetics. Histone modifications (such as acetylation, methylation, phosphorylation, hydroxylation, and ubiquitination) strictly regulate gene expression and play a crucial role in cancer and many other diseases. Histone lysine-specific demethylase 1 (LSD1) was the first demethylase discovered. Studies have shown that knocking out LSD1 can inhibit the proliferation and metastasis of various tumor cells. Therefore, the development of LSD1 inhibitors is particularly important.

[0003] Currently, six TCP-based LSD1 inhibitors are in clinical trials, either alone or in combination with other therapies. However, due to their irreversible binding to endogenous small molecule FADs or their multiple targeting effects in vivo, they all have certain side effects. Summary of the Invention

[0004] The purpose of this invention is to provide an amino dithioester derivative containing an amide structural unit, its preparation method, and its application. The amino dithioester derivative containing an amide structural unit provided by this invention can inhibit tumor proliferation and has few toxic side effects.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides an amino dithioester derivative containing an amide structural unit, the structure of which is shown in Formula I:

[0007]

[0008] In formula I, n is 1 or 2;

[0009] R1 is CH2, HN, CH3CH2N, PhCH2N. Or O;

[0010] R2 is phenyl, halophenyl, methylphenyl, methoxyphenyl, pyridyl, C3H2NS, or C 10 H7O2.

[0011] Preferably, in the amino dithioester derivative containing the amide structural unit, when n is 1, R1 is HN and R2 is...

[0012] When n is 2, R1 is CH2, HN, CH3CH2N, PhCH2N, Or O, R2 is

[0013] Preferably, the amino dithioester derivative containing the amide structural unit is any one of formulas I-1 to I-35:

[0014] When n is 1

[0015] Equation I-1R1=HN, Equation I-2R1=HN, Equation I-3R1=HN, Equation I-4R1=HN, Equation I-5R1=HN, Equation I-6R1=HN, Formula I-7R1=HN, Equation I-8R1=HN, When n is 2

[0016] Equation I-9R1=CH2, Equation I-10R1=HN, Equation I-11R1=HN, Equation I-12R1=HN, Equation I-13R1=HN, Equation I-14R1=HN, Equation I-15R1=HN, Equation I-16R1=HN, Equation I-17R1=HN, Equation I-18R1=CH3CH2N, Equation I-19R1=CH3CH2N,

[0017] Equation I-20R1=CH3CH2N,

[0018] Equation I-21R1=CH3CH2N,

[0019] Equation I-22R1=CH3CH2N,

[0020] Equation I-23R1=PhCH2N,

[0021] Formula I-24

[0022] Formula I-25

[0023] Formula I-26

[0024] Formula I-27

[0025] Formula I-28

[0026] Equation I-29R1=O,

[0027] Equation I-30R1=HN,

[0028] Equation I-31R1=HN,

[0029] Equation I-32R1=HN,

[0030] Formula I-33

[0031] Formula I-34

[0032] Formula I-35

[0033] The present invention also provides a method for preparing the amino dithioester derivative containing the amide structural unit described in the above-described scheme, comprising the following steps:

[0034] (1) Sodium dodecahydrate, carbon disulfide, bromopropyne, and a first good solvent were mixed to carry out a first substitution reaction to give a compound having the structure shown in Formula II:

[0035]

[0036] (2) Sodium azide and a second good solvent were mixed to carry out a second substitution reaction to give a compound having the structure shown in Formula III:

[0037]

[0038] (3) The compound having the structure shown in Formula II, the compound having the structure shown in Formula III, the catalyst and the third good solvent are mixed and subjected to a click reaction to obtain an amino dithioester derivative containing an amide structural unit;

[0039] There is no requirement for the time order of steps (1) and (2).

[0040] Preferably, the temperature of the first substitution reaction is room temperature, and the reaction time is 1.0 to 3.5 hours.

[0041] Preferably, the second substitution reaction is carried out at room temperature for 6 to 15 hours.

[0042] Preferably, the click reaction is performed at room temperature for 0.5 to 5 hours.

[0043] Preferably, the first good solvent, the second good solvent, and the third good solvent independently include one or more of ethanol, methanol, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, and water.

[0044] Preferably, the catalyst comprises one or more of sodium vitamin C, copper sulfate pentahydrate, cuprous iodide, and copper oxide.

[0045] The present invention also provides the application of the amino dithioester derivatives containing amide structural units described in the above-described schemes, or the amino dithioester derivatives containing amide structural units obtained by the preparation method described in the above-described schemes, in the preparation of antitumor drugs or immunotherapy combination products.

[0046] This invention provides an aminodithioester derivative containing an amide structural unit, the structure of which is shown in Formula I. The aminodithioester derivative provided by this invention competitively binds to the active pocket of histone lysine-specific demethylase 1 (LSD1) via FAD, thereby exhibiting good inhibitory activity against LSD1, characterized by low toxicity, high selectivity, and high activity. Test results from examples show that when MGC-803 cells were transplanted into 615 immunocompetent mice, the aminodithioester derivative provided by this invention can inhibit tumor proliferation at high concentrations with minimal toxicity and side effects. Furthermore, it has been proven to be a small-molecule inhibitor of immune-related LSD1, providing a potential lead compound for the development of novel anti-gastric cancer drugs.

[0047] This invention also provides a method for preparing the amino dithioester derivatives containing amide structural units as described above. The preparation method provided by this invention is simple in steps, convenient to operate, and has the potential for large-scale industrial production.

[0048] This invention also provides the application of the amino dithioester derivatives containing amide structural units described in the above-described schemes, or the amino dithioester derivatives containing amide structural units obtained by the preparation methods described in the above-described schemes, in the preparation of antitumor drugs or immunotherapy combination products. The amino dithioester derivatives provided by this invention can be used to prepare antitumor drugs or for immunotherapy combination products, and are particularly suitable for LSD1 small molecule inhibitors. Detailed Implementation

[0049] This invention provides an amino dithioester derivative containing an amide structural unit, the structure of which is shown in Formula I:

[0050]

[0051] In formula I, n is 1 or 2;

[0052] R1 is CH2, HN, CH3CH2N, PhCH2N. Or O;

[0053] R2 is phenyl, halophenyl, methylphenyl, methoxyphenyl, pyridyl, C3H2NS, or C 10 H7O2.

[0054] In this invention, R2 is preferably...

[0055] In this invention, for the amino dithioester derivative containing an amide structural unit, when n is 1, R1 is preferably HN and R2 is preferably HN.

[0056] In this invention, when n is 2, R1 is preferably CH2, HN, CH3CH2N, PhCH2N, Or O, R2 is preferred

[0057] In this invention, the amino dithioester derivative containing an amide structural unit is preferably any one of formulas I-1 to I-35:

[0058] When n is 1

[0059] Equation I-1R1=HN, Equation I-2R1=HN,

[0060] Equation I-3R1=HN, Equation I-4R1=HN,

[0061] Equation I-5R1=HN, Equation I-6R1=HN,

[0062] Formula I-7R1=HN, Equation I-8R1=HN,

[0063] When n is 2

[0064] Equation I-9R1=CH2, Equation I-10R1=HN,

[0065] Equation I-11R1=HN, Equation I-12R1=HN,

[0066] Equation I-13R1=HN, Equation I-14R1=HN,

[0067] Equation I-15R1=HN, Equation I-16R1=HN,

[0068] Equation I-17R1=HN, Equation I-18R1=CH3CH2N,

[0069] Equation I-19R1=CH3CH2N, Equation I-20R1=CH3CH2N,

[0070] Equation I-21R1=CH3CH2N, Equation I-22R1=CH3CH2N,

[0071] Equation I-23R1=PhCH2N, Formula I-24

[0072] Formula I-25 Formula I-26

[0073] Formula I-27 Formula I-28

[0074] Equation I-29R1=O, Formula I-30R1=HN,

[0075] Equation I-31R1=HN, Equation I-32R1=HN,

[0076] Formula I-33 Formula I-34

[0077] Formula I-35

[0078] The present invention also provides a method for preparing the amino dithioester derivative containing the amide structural unit described in the above-described scheme, comprising the following steps:

[0079] (1) Sodium dodecahydrate, carbon disulfide, bromopropyne, and a first good solvent were mixed to carry out a first substitution reaction to give a compound having the structure shown in Formula II:

[0080]

[0081] (2) Sodium azide and a second good solvent are mixed to carry out a second substitution reaction to give a compound having the structure shown in Formula III:

[0082]

[0083] (3) The compound having the structure shown in Formula II, the compound having the structure shown in Formula III, the catalyst and the third good solvent are mixed and subjected to a click reaction to obtain an amino dithioester derivative containing an amide structural unit;

[0084] There is no requirement for the time order of steps (1) and (2).

[0085] This invention will Sodium phosphate dodecahydrate, carbon disulfide, bromopropyne, and a first good solvent are mixed to carry out a first substitution reaction to obtain a compound having the structure shown in Formula II. In this invention, the... The molar ratio of sodium phosphate dodecahydrate to sodium phosphate is preferably 0.8–1.2:0.4–0.8, more preferably 0.9–1.1:0.5–0.7, and even more preferably 1.0:0.6; The molar ratio of carbon disulfide to carbon disulfide is preferably 0.8–1.2:2.0–3.5, more preferably 0.9–1.1:2.5–3.2, and even more preferably 1.0:2.9–3.1; The molar ratio of propyne to bromopropyne is preferably 0.8–1.2:1.0–2.0, more preferably 0.9–1.1:1.1–1.8, and even more preferably 1.0:1.3–1.5; The preferred molar volume ratio of the first good solvent to the first good solvent is (0.8-1.2) mmol:(15-25) mL, more preferably (0.9-1.1) mmol:(17-23) mL, and even more preferably 1.0 mmol:(19-21) mL.

[0086] In this invention, when n is 1, the... R1 is preferably HN; when n is 2, the R1 is preferably CH2, HN, CH3CH2N, PhCH2N, Or O. In this invention, the... More preferably, it is one or more of Boc-piperazine, piperidine, N-ethylpiperazine, N-benzylmethylpiperazine and morpholine.

[0087] In this invention, the first good solvent preferably includes one or more of ethanol, methanol, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, and water, and more preferably one or more of ethanol, methanol, and dioxane.

[0088] In this invention, the temperature of the first substitution reaction is preferably room temperature, and the reaction time is preferably 1.0 to 3.5 hours, more preferably 1.5 to 3 hours, and even more preferably 2 to 2.5 hours.

[0089] In this invention, the first substitution reaction preferably includes a first-stage substitution reaction and a second-stage substitution reaction; the temperature of the first-stage substitution reaction is preferably room temperature, and the reaction time is preferably 0.5 to 1 hour, more preferably 0.7 to 0.9 hours, and even more preferably 0.8 hours; the completion of the first-stage reaction is preferably detected by TLC; the temperature of the second-stage substitution reaction is preferably room temperature, and the reaction time is preferably 0.5 to 2.5 hours, more preferably 1.0 to 2.0 hours, and even more preferably 1.5 hours; the completion of the second-stage substitution reaction is preferably detected by TLC.

[0090] In this invention, the The preferred mixture of sodium dodecahydrate, carbon disulfide, bromopropyne, and the first good solvent is: Sodium dodecahydrate, carbon disulfide, and a first good solvent are mixed to carry out a first-stage substitution reaction to obtain a pre-reaction solution; the pre-reaction solution is then mixed with bromopropyne to carry out a second-stage substitution reaction.

[0091] In this invention, the first mixing is preferably stirring; the second mixing is preferably adding bromopropyne dropwise to the pre-reaction solution.

[0092] In this invention, after the first substitution reaction, the resulting reaction product is preferably subjected to vacuum filtration (referred to as first vacuum filtration), filtrate concentration (referred to as first filtrate concentration), dissolution (referred to as first dissolution), washing (referred to as first washing), drying (referred to as first drying) and organic phase concentration (referred to as first organic phase concentration).

[0093] In this invention, the endpoint of the first filtrate concentration is preferably the concentration until solid precipitates.

[0094] In this invention, the first dissolution is preferably a mixture of the residue obtained by concentrating the filtrate and ethyl acetate.

[0095] In this invention, the first washing is preferably performed by washing the dissolved product with water and then washing it with saturated saline solution.

[0096] In this invention, the first drying process preferably uses anhydrous Na2SO4.

[0097] In this invention, the first organic phase concentration is preferably carried out under vacuum conditions.

[0098] This invention will Sodium azide and a second good solvent are mixed (denoted as the third mixture) to carry out a second substitution reaction, yielding a compound having the structure shown in Formula III. In this invention, the... The molar ratio of sodium azide to sodium azide is preferably 0.8–1.2:1.5–3.5, more preferably 0.9–1.1:2.1–3.1, and even more preferably 1.0:2.6; The preferred molar volume ratio of the second good solvent is (0.8–1.2) mmol:(7–15) mL, more preferably (0.9–1.1) mmol:(8–12) mL, and even more preferably 1.0 mmol:(9–11) mL.

[0099] In this invention, the In the case where n=1, R2 is preferably the optimal value. When n=2, R2 is preferred.

[0100] In this invention, the More preferably, 2-chloro-N-phenylacetamide, 2-chloro-N-(2-fluorophenyl)acetamide, 2-chloro-N-(2-chlorophenyl)acetamide, 2-chloro-N-(4-chlorophenyl)acetamide, 2-chloro-N-(2,4-dichlorophenyl)acetamide, 2-chloro-N-(4-methylphenyl)acetamide, 2-chloro-N-(4-methoxyphenyl)acetamide, 2-chloro-N-(2-pyridine)acetamide, 2-chloro-N-((2-methoxyphenyl)carbamoyl)acetamide, 2-chloro-N-(phenylcarbamoyl)acetamide, 2-chloro-N-((2-fluorophenyl)carbamoyl)acetamide, One or more of the following: 2-chloro-N-((2-chlorobenzene)carbamoyl)acetamide, 2-chloro-N-((2,4-dichlorobenzene)carbamoyl)acetamide, 2-chloro-N-((4-methylbenzene)carbamoyl)acetamide, 2-chloro-N-((2,4-dimethoxybenzene)carbamoyl)acetamide, 2-chloro-N-((2-pyridine)carbamoyl)acetamide, 2-chloro-N-((3-pyridine)carbamoyl)acetamide, 2-chloro-N-(thiazole-2-carbamoyl)acetamide, and 2-chloro-N-(4-methyldihydrocoumarin-7-carbamoyl)acetamide.

[0101] In this invention, the second good solvent preferably includes one or more of ethanol, methanol, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, and water, and more preferably one or more of ethanol, methanol, 1,2-dichloroethane, dichloromethane, dioxane, and water.

[0102] In this invention, the temperature of the second substitution reaction is preferably room temperature, and the reaction time is preferably 6 to 15 hours, more preferably 9 to 11 hours, and even more preferably 10 hours; the completion of the second substitution reaction is preferably determined by TLC tracking and detection.

[0103] In this invention, the third mixing is preferably stirring.

[0104] In this invention, after the second substitution reaction, the resulting reaction product is preferably subjected to concentration (referred to as second concentration), dissolution (referred to as second dissolution), washing (referred to as second washing), drying (referred to as second drying) and organic phase concentration (referred to as second organic phase concentration) in sequence.

[0105] In this invention, the endpoint of the second concentration is preferably concentration to the point of precipitated solid.

[0106] In this invention, the second dissolution is preferably achieved by mixing the concentrated product with ethyl acetate.

[0107] In this invention, the second washing is preferably a water wash.

[0108] In this invention, the second drying process preferably uses anhydrous Na2SO4.

[0109] In this invention, the second organic phase concentration is preferably carried out under vacuum conditions.

[0110] After obtaining compounds having the structure shown in Formula II and compounds having the structure shown in Formula III, the present invention mixes the compounds having the structure shown in Formula II, the compounds having the structure shown in Formula III, a catalyst, and a third good solvent (denoted as the fourth mixture) and performs a click reaction to obtain an amino dithioester derivative containing an amide structural unit. In this invention, the molar ratio of the compound having the structure shown in Formula II to the compound having the structure shown in Formula III is preferably 0.8–1.2:0.8–1.2, more preferably 0.9–1.1:0.9–1.1, and even more preferably 1:1; the molar ratio of the compound having the structure shown in Formula II to the catalyst is preferably 0.8–1.2:0.05–0.25, more preferably 0.9–1.1:0.1–0.2, and even more preferably 1:0.15; the molar volume ratio of the compound having the structure shown in Formula II to the third good solvent is preferably (0.8–1.2) mmol:(7–15) mL, more preferably (0.9–1.1) mmol:(8–12) mL, and even more preferably 1.0 mmol:(9–11) mL.

[0111] In this invention, the catalyst preferably includes one or more of sodium vitamin C (VcNa), copper sulfate pentahydrate, cuprous iodide, and copper oxide.

[0112] In this invention, the third good solvent preferably includes one or more of ethanol, methanol, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, and water, and more preferably one or more of ethanol, methanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, and water.

[0113] In this invention, the temperature of the click reaction is preferably room temperature, the reaction time is preferably 0.5 to 5 hours, more preferably 1 to 4 hours, and even more preferably 2 to 3 hours; the click reaction is preferably detected by TLC to determine whether the reaction is complete.

[0114] In this invention, the fourth mixing is preferably: premixing a compound having the structure shown in Formula II and a compound having the structure shown in Formula III with a third good solvent, and then mixing the resulting premix with a catalyst.

[0115] In this invention, the fourth mixing is preferably stirring.

[0116] In this invention, after the click reaction, the resulting reaction product is preferably subjected to rotary evaporation (referred to as the third rotary evaporation), dissolution (referred to as the third dissolution), washing (referred to as the third washing), drying (referred to as the third drying), organic phase concentration (referred to as the third organic phase concentration), recrystallization (referred to as the third recrystallization), redissolution (referred to as the third redissolution), acidification (referred to as the third acidification), neutralization (referred to as the third neutralization), vacuum filtration (referred to as the third vacuum filtration), and washing (referred to as the fourth washing).

[0117] In this invention, the endpoint of the third rotary evaporation is preferably concentration until solid precipitates. This invention removes a third good solvent through the third rotary evaporation.

[0118] In this invention, the third dissolution is preferably achieved by mixing the product obtained by rotary evaporation with ethyl acetate to obtain a third mixture; the mass concentration of the third mixture is preferably 0.8 to 1.2 g / mL, more preferably 0.9 to 1.1 g / mL.

[0119] In this invention, the third washing is preferably performed by washing the dissolved product with water and then washing it with saturated saline solution.

[0120] In this invention, the third drying process preferably uses anhydrous Na2SO4.

[0121] In this invention, the concentration of the third organic phase is preferably carried out under vacuum conditions.

[0122] In this invention, the recrystallization is preferably carried out using ethyl acetate; after recrystallization, the resulting crystals are preferably left to stand and dry.

[0123] In this invention, the third redissolution is preferably: mixing the solid obtained from recrystallization with ethyl acetate to obtain a fourth mixture; the mass concentration of the fourth mixture is preferably 0.8 to 1.2 g / mL, more preferably 0.9 to 1.1 g / mL.

[0124] In this invention, the third acidification is preferably performed by mixing the fourth mixture with a hydrochloric acid-ethyl acetate solution; the mass concentration of the hydrochloric acid-ethyl acetate solution is 0.05-0.10 g / mL, more preferably 0.06-0.08 g / mL; the volume ratio of the fourth mixture to the hydrochloric acid-ethyl acetate solution is preferably 0.8-1.0:9.0-9.5, more preferably 1.0:9.0.

[0125] In this invention, the neutralizing reagent is preferably an aqueous solution of sodium hydroxide; the target pH value for neutralization is preferably 7-9, more preferably 7-8.

[0126] In this invention, the fourth washing is preferably performed by washing the neutralized product with water and then washing it with ethyl ester.

[0127] The present invention also provides the application of the amino dithioester derivatives containing amide structural units described in the above-described schemes, or the amino dithioester derivatives containing amide structural units obtained by the preparation method described in the above-described schemes, in the preparation of antitumor drugs or immunotherapy combination products.

[0128] In this invention, the antitumor drug preferably targets LSD1.

[0129] To further illustrate the present invention, the following detailed description of the embodiments is provided in conjunction with the present invention, but these descriptions should not be construed as limiting the scope of protection of the present invention.

[0130] Example 1

[0131] Carbon disulfide (30 mmol) was added dropwise to a solution of Boc-piperazine (10 mmol) and Na3PO4·12H2O (6 mmol) in ethanol (40 mL), and the reaction was carried out with stirring at room temperature for 0.5 h. Bromopropyne (20 mmol) was then added dropwise, and the mixture was stirred for another 0.5 h at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous Na2SO4, and the organic phase was concentrated under vacuum to obtain a compound with the structure shown in Formula II-1.

[0132]

[0133] 2-Chloro-N-phenylacetamide (10 mmol) and sodium azide (30 mmol) were reacted overnight in 1,4-dioxane / water solution. The mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4, and the organic phase was concentrated under vacuum to give a compound having the structure shown in Formula III-1.

[0134]

[0135] Equimolar amounts (10 mmol) of the compounds with structures shown in Formula II-1 and Formula III-1 were added to a tetrahydrofuran / aqueous solution. While stirring at room temperature, VcNa (1 mmol) powder and CuSO4·5H2O (0.5 mmol) aqueous solution were added sequentially. After the reaction was complete, the tetrahydrofuran was removed by rotary evaporation. The residue was dissolved in ethyl acetate and washed with water and saturated brine, respectively. The mixture was dried over anhydrous Na2SO4, and the organic phase was concentrated under vacuum. Ethyl acetate was recrystallized to give a yellow solid. After the solid dried, 5 mmol of the yellow solid was dissolved in ethyl acetate solvent. While stirring, a 4 mol / L solution of hydrochloric acid in ethyl acetate was added dropwise. After monitoring the reaction to completion, NaOH aqueous solution was added to adjust the pH to neutral or weakly alkaline. The mixture was filtered, washed with water, and washed with ethyl acetate to obtain a compound with the structure shown in Formula I-1. The compound with the structure shown in Formula I-1 is a white solid with a melting point of 202–203 °C.

[0136]

[0137] The analysis results are as follows: 1 H NMR (400MHz, DMSO-d6, ppm) δ10.59(s,1H,NH,D2Oexchangeable),8.10(s,1H,Ar-H),7.58(d,J=7.9Hz,2H,Ar-H),7.33(t,J=7.7Hz, 2H,Ar-H),7.08(s,1H,Ar-H),5.31(s,2H,-CH2-),4.62(s,2H,-CH2-),4.26(s,2H,-CH2-),3.90(s,2H,-CH2-),3.36(s,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ164.16,141.88,138.42,128.86,125.34,123.71,119.17,52.15,31.29.HR-MS(ESI),calcd.C 16 H 19 FN6OS2,[M+H] + m / z:377.1218,found:377.1219.

[0138] Example 2

[0139] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0140] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-2 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(2-fluorophenyl)acetamide;

[0141]

[0142] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-2 was obtained; the compound with the structure shown in Formula I-2 is a white solid with a melting point of 151-152°C.

[0143]

[0144] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ10.42(s,1H,NH,D2Oexchangeable),8.10(s,1H,Ar-H),7.89(s,1H,Ar-H),7.34-7.24(m,1H,Ar-H), 7.38-7.11(m,3H,Ar-H),5.40(s,2H,-CH2-),4.61(s,2H,-CH2-),4.15(s,2H,-CH2-),3.80(s,2H,-CH2-),3.20-2.69(m,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ164.78,154.71,141.89,125.50,125.20-125.08,124.43,123.82,115.58,51.92,31.29.HR-MS(ESI),calcd.C 16 H 19 FN6OS2,[M+H] + m / z:395.1124,found:395.1124.

[0145] Example 3

[0146] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0147] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-3 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(2-chlorophenyl)acetamide;

[0148]

[0149] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-3 was obtained; the compound with the structure shown in Formula I-3 is a white solid with a melting point >200℃;

[0150]

[0151] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ10.06(s,1H,NH,D2Oexchangeable),8.12(s,1H,Ar-H),7.73(d,J=7.8Hz,1H,Ar-H),7.52(d,J=7.8Hz,1H,Ar-H),7.34(t,J=7.6Hz,1H ,Ar-H),7.23(d,J=7.1Hz,1H,Ar-H),5.41(s,2H,-CH2-),4.64(s,2H,-CH2-),4.34 (s,2H,-CH2-),4.15(s,3H,-CH2-),4.09-4.02(s,2H,-CH2-),3.22(s,1H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.51,193.40,164.83,141.75,134.11,129.60,127. 53,126.70,125.84,125.40,79.01,74.24,51.89,49.61,47.43.HR-MS(ESI),calcd.C 16 H 19 ClN6OS2,[M+H] + m / z:411.0829,found:411.0827.

[0152] Example 4

[0153] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0154] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-4 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(4-chlorophenyl)acetamide;

[0155]

[0156] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-4 was obtained; the compound with the structure shown in Formula I-4 is a white solid with a melting point >200℃;

[0157]

[0158] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ10.91(s,1H,NH,D2Oexchangeable),8.10(s,1H,Ar-H),7.62(d,J=8.8Hz,2H,Ar-H),7.39(d,J=8. 8Hz,2H,Ar-H),5.33(s,2H,-CH2-),4.61(s,2H,-CH2-),4.17(s,2H,-CH2-),3.82(s,2H,-CH2-),2.96(d,J=165.1Hz,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ164.41,141.89,137.47,128.76,127.23,125.32,120.79,52.14,31.29.HR-MS(ESI),calcd.C 16 H 19 ClN6OS2,[M+H] + m / z:411.0829, found:411.0830.

[0159] Example 5

[0160] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0161] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-5 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(2,4-dichlorophenyl)acetamide;

[0162]

[0163] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-5 was obtained; the compound with the structure shown in Formula I-5 is a white solid with a melting point of 155-156°C.

[0164]

[0165] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.26(s,1H,NH,D2Oexchangeable),8.10(s,1H,Ar-H),7.85-7.58(m,2H,Ar-H),7.42(d,J=8 .6Hz,1H,Ar-H),5.41(s,2H,-CH2-),4.61(s,2H,-CH2-),4.17(s,2H,-CH2-),3.81(s,2H,-CH2-),3.21-2.66(m,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ165.06,141.96,133.63,129.63,129.01,127.62,127.24,126.88,125.35,124.44,51.94,31.26.HR-MS(ESI),calcd.C 16 H 19 Cl2N6OS2,[M+H] + m / z:445.0439, found:445.0440.

[0166] Example 6

[0167] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0168] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-6 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(4-methylphenyl)acetamide;

[0169]

[0170] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-6 was obtained; the compound with the structure shown in Formula I-6 is a white solid with a melting point >200℃;

[0171]

[0172] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.45(s,1H,NH,D2Oexchangeable),8.09(s,1H,Ar-H),7.46(d,J=7.9Hz,2H,Ar-H),7.13(d,J=8.0Hz,2H,Ar-H),5.28(s ,2H,-CH2-),4.62(s,2H,-CH2-),4.25(s,2H,-CH2-),3.90(s,2H,-CH2-),3. 49(s,1H,-CH2-),2.88(dd,J=120.0,79.1Hz,3H,-CH2-),2.25(s,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ163.87,135.89,132.69,129.24,125.35,119.18,52.14,20.41.HR-MS(ESI),calcd.C 17 H 22 N6OS2,[M+H] + m / z:391.1375,found:391.1375.

[0173] Example 7

[0174] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0175] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-7 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(4-methoxyphenyl)acetamide;

[0176]

[0177] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-7 was obtained; the compound with the structure shown in Formula I-7 is a white solid with a melting point of 181-182°C.

[0178]

[0179] The analysis results are as follows: 1H NMR (400MHz, DMSO-d6, δ, ppm) δ10.44(s,1H,NH,D2Oexchangeable),8.09(s,1H,Ar-H),7.49(d,J=8.6 Hz,2H,Ar-H),6.90(d,J=8.7 Hz,2H,Ar-H),5.27(s,2H,-CH2-),4.61(s,2H,-CH2-),4.17(s,2H,-CH2-),3.86( s,2H,-CH2-),3.72(s,3H,-OCH3),3.54(s,1H,-CH2-),3.24-2.71(m,3H,-CH2-). 13 C NMR(100 MHz,DMSO-d6,δ,ppm)δ 13 C NMR (101 MHz, DMSO) δ163.61,155.47,141.84,131.54,125.29,120.73,113.95,55.99,55.12,52.09,31.29,18.53.HR-MS(ESI),calcd.C 17 H 22 N6O2S2,[M+H] + m / z:407.1324,found:407.1325.

[0180] Example 8

[0181] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0182] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-8 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(2-pyridine)acetamide;

[0183]

[0184] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-8 was obtained; the compound with the structure shown in Formula I-8 is a white solid with a melting point >200℃;

[0185]

[0186] The analysis results are as follows: 1H NMR(400 MHz, DMSO-d6, δ, ppm) δ11.02(s,1H,NH,D2Oexchangeable),8.36(d,J=4.0 Hz,1H,Ar-H),8.11(s,1H,Ar-H),7.99(d,J=7.9 Hz,1H,Ar-H),7.80(s,1H,Ar-H),7.17-7.11(m,1H,Ar-H),5.39(s,2H,-CH2-),4.62(s,2H ,-CH2-),4.17(s,2H,-CH2-),3.81(s,2H,-CH2-),2.76(s,4H,-CH2-),1.24(s,1H,-NH-). 13 CNMR (100MHz, DMSO-d6, δ, ppm) δ 13 C NMR (101 MHz, DMSO) δ165.10,151.37,148.13,141.88,138.39,125.40,119.86,113.46,52.09,31.31.HR-MS(ESI),calcd.C 15 H 19 N7OS2, [M+H] + m / z:378.1171,found:378.1173.

[0187] Example 9

[0188] Using the same preparation method as the compound with the structure shown in Formula II-1 in Example 1, the compound with the structure shown in Formula II-2 was obtained, the only difference being that Boc-piperazine was replaced with piperidine;

[0189]

[0190] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-9 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2-methoxyphenyl)carbamoyl)acetamide;

[0191]

[0192] Equimolar amounts (10 mmol) of the compound with the structure shown in Formula II-2 and the compound with the structure shown in Formula III-9 were added to a tetrahydrofuran / aqueous solution. While stirring at room temperature, VcNa (1 mmol) powder and CuSO4·5H2O (0.5 mmol) aqueous solution were added sequentially. After the reaction was complete, the tetrahydrofuran was removed by rotary evaporation. The residue was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous Na2SO4, and the organic phase was concentrated under vacuum. The ethyl acetate was recrystallized to obtain the compound with the structure shown in Formula I-9. The compound with the structure shown in Formula I-9 is a white solid with a melting point of 197–198 °C.

[0193]

[0194] The analysis results are as follows: 1 H NMR(400 MHz,DMSO-d6,δ,ppm)δ11.15(s,1H,NH,D2Oexchangeable),10.42(s,1H,NH,D2O exchangeable),8.18-8.11(m,2H,Ar-H),7.04(t,J=6.4Hz,2H,Ar-H),6.97-6.89(m,1H,Ar-H),5.39(s,2H,-CH2-),4.65(s, 2H,-CH2-),4.23(s,2H,-CH2-),3.90(s,J=17.1Hz,2H,-CH2-),3.82(s,3H,-OCH3),1.78-1.54(m,J=25.2,4.2Hz,6H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ192.53,168.46,149.95,148.01,126.69,123.72,120.55,11 9.08,110.84,55.90,52.60,51.88,51.01,31.37,25.81,25.21,23.48.HR-MS(ESI),calcd.C 19 H 24 N6O3S2,[M+Na] + m / z:471.1249,found:471.1253.

[0195] Example 10

[0196] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0197] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-10 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(phenylcarbamoyl)acetamide;

[0198]

[0199] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-10 was obtained; the compound with the structure shown in Formula I-10 is a white solid with a melting point of 166-167°C.

[0200]

[0201] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.40(s,1H),NH,D2Oexchangeable,8.07(s,1H,Ar-H),7.57(d,J=8.0Hz,2H,Ar-H),7.28(t,J=7.8Hz,2H,Ar-H ),7.01(s,1H,Ar-H),5.39(s,2H,-CH2-),4.62(s,2H,-CH2-),4.19(s,2H,-CH2-),3.84(s,2H,-CH2-),3.46(s,2H,-CH2-),2.75(s,2H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.67,141.77,139.04,128.66,125.39,122.70,119.23,117.64,31.39.HR-MS(ESI),calcd.C 17 H 20 ClN7O2S2,[M+H] + m / z:420.1276,found:420.1277.

[0202] Example 11

[0203] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0204] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-11 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2-fluorophenyl)carbamoyl)acetamide;

[0205]

[0206] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-11 was obtained; the compound with the structure shown in Formula I-11 is a white solid with a melting point of 190-193°C.

[0207]

[0208] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ10.67(s,1H,NH,D2Oexchangeable),8.09(s,2H,Ar-H),7.31-7.23(m,1H,Ar-H),7.17(t,J=7.2Hz,1H, Ar-H),7.13-7.08(m,1H,Ar-H),5.38(s,2H,-CH2-),4.62(s,2H,-CH2-),4.18(s,2H,-CH2-),3.82(s,2H,-CH2-),2.75(s,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.30,169.37,155.67,153.78,151.43,126.05,1 25.39,124.60,124.23,121.93,115.14,52.41,45.36,31.30.HR-MS(ESI),calcd.C 17 H 20 ClN7O2S2,[M+H] + m / z:438.1182,found:438.1183.

[0209] Example 12

[0210] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0211] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-12 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2-chlorophenyl)carbamoyl)acetamide;

[0212]

[0213] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-12 was obtained; the compound with the structure shown in Formula I-12 is a white solid with a melting point of 174-175°C.

[0214]

[0215] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.39(s,1H,NH,D2Oexchangeable),10.55(s,1H,NH,D2O exchangeable),8.26-8.18(m,2H,Ar-H),7.50(d,J=7.9Hz,1H,Ar-H),7.36(t,J=7.8Hz,1H,Ar-H ),7.14(t,J=7.7Hz,1H,Ar-H),5.46(s,2H,-CH2-),4.79(s,2H,-CH2-),4.31-3.48(m,8H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.52,168.89,150.05,134.33,129.30,127.89,124.89,122.38,121.38,52.08,30.82.HR-MS(ESI),calcd.C 17 H 20 ClN7O2S2,[M+H] + m / z:454.0887,found:454.0889.

[0216] Example 13

[0217] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0218] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-13 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2,4-dichlorophenyl)carbamoyl)acetamide;

[0219]

[0220] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-13 was obtained; the compound with the structure shown in Formula I-13 is a white solid with a melting point >200℃;

[0221]

[0222] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.45(s,1H,NH,D2Oexchangeable),10.64(s,1H,NH,D2O exchangeable),8.26(d,J=9.0Hz,1H,Ar-H),8.14(s,1H,Ar-H),7.70(d,J=2.4Hz,1H,Ar-H),7.45(dd,J=8.9,2.4Hz,1H,Ar-H),5.42( s,2H,-CH2-),4.65(s,2H,-CH2-),4.34(s,2H,-CH2-),4.16(d,J=2.6Hz,3H,-CH2-),4.10(m,2H,-CH2-),3.22(d,J=2.6Hz,1H,-CH2). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ169.13,150.08,133.59,128.72,127.95,127.86,125.51,123.32,122.36,51.85,31.25.HR-MS(ESI),calcd.C 17 H 19 Cl2N7O2S2,[M+H] + m / z:488.0497,found:488.0496.

[0223] Example 14

[0224] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0225] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-14 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((4-methylphenyl)carbamoyl)acetamide;

[0226]

[0227] The compound with the structure shown in Formula I-14 was obtained by the same preparation method as the compound with the structure shown in Formula I-1 in Example 1; the compound with the structure shown in Formula I-14 is a white solid with a melting point >200℃;

[0228]

[0229] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.79(s,1H,NH,D2Oexchangeable),8.07(s,1H,Ar-H),7.43(d,J=8.3Hz,2H,Ar-H),7.10(d,J=8.2Hz,2H,Ar-H ),5.40(s,2H,-CH2-),4.61(s,2H,-CH2-),4.18(s,2H,-CH2-),3.83(s,2H,-CH2-),3.46(s,2H,-CH2-),2.75(s,2H,-CH2-),2.25(s,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.30,168.46,141.89,135.85,132.05,129. 15,128.90,125.39,119.40,52.46,45.49,31.28,20.36.HR-MS(ESI),calcd.C 18 H 23 N7O3S2,[M+H] + m / z:434.1433,found:434.1434.

[0230] Example 15

[0231] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0232] Compounds with the structure shown in Formula III-9 in Example 9;

[0233] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-15 was obtained; the compound with the structure shown in Formula I-15 is a white solid with a melting point >200℃;

[0234]

[0235] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.03(s,1H,NH,D2Oexchangeable),10.70(s,1H,NH,D2O exchangeable),8.17(d,J=7.7Hz,1H,Ar-H),7.26-6.85(m,4H,Ar-H),4.56(d,J=4.9Hz,2H,-CH2-),4.36(s,2H, -CH2-),4.34-4.14(m,4H,-CH2-),3.94(d,J=19.4Hz,1H,-CH2-),3.85(s,3H,-CH2-),3.02-2.86(m,3H,-OCH3). 13 CNMR(100MHz,DMSO-d6,δ,ppm)δ194.54,169.66,150.25,147.93,126.92,123.50,120 .56,118.93,110.81,56.03,55.90,49.51,47.66,45.63,42.70.HR-MS(ESI),calcd.C 18 H 23 N7O3S2,[M+H] + m / z:450.1382, found:450.1385.

[0236] Example 16

[0237] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0238] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-15 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2,4-dimethoxyphenyl)carbamoyl)acetamide;

[0239]

[0240] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-16 was obtained; the compound with the structure shown in Formula I-16 is a white solid with a melting point >200℃;

[0241]

[0242] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.09(s,1H,NH,D2Oexchangeable),10.22(s,1H,NH,D2O exchangeable),8.14(s,1H,Ar-H),7.98(d,J=8.9Hz,1H,Ar-H),6.64(d,J=2.5Hz,1H,Ar-H),6.51(dd,J=8.9,2.5Hz,1H,Ar-H),5.38(s,2H,-CH2-),4.65(s,2 H,-CH2-),4.35(s,2H,-CH2-),4.16(d,J=2.5Hz,3H,-CH2-),4.10(s,2H,-CH2- ),3.81(s,3H,-OCH3),3.74(s,3H,-OCH3),3.22(dd,J=3.2,1.9Hz,1H,-CH2-). 13 CNMR(100MHz,DMSO-d6,δ,ppm)δ194.78,168.34,156.09,149.85,149.40,141.87,125.51 ,120.20,119.90,104.24,98.72,55.99,55.31,51.81,49.57,47.65.HR-MS(ESI),calcd.C 19 H 25 N7O4S2,[M+H] + m / z:480.1488,found:480.1485.

[0243] Example 17

[0244] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0245] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-16 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((2-pyridine)carbamoyl)acetamide;

[0246]

[0247] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-17 was obtained; the compound with the structure shown in Formula I-17 is a white solid with a melting point of 176-177°C.

[0248]

[0249] The analysis results are as follows:1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.27(s,1H,NH,D2Oexchangeable),10.40(s,1H,NH,D2O exchangeable),8.29(d,J=4.4Hz,1H,Ar-H),8.13(s,1H,Ar-H),7.93(d,J=8.2Hz,1H,Ar-H),7.83(dd,J=11.1,4.5Hz,Ar-H),7.1 7-7.10(m,1H,Ar-H),5.46(s,2H,-CH2-),4.66(s,2H,-CH2-),4.36(s,2H,-CH2-),4.11(m,2H,-CH2-),4.06-3.50(m,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.46,168.80,150.76,150.03,148.15,141.92,1 38.64,125.50,119.72,112.99,52.24,49.51,47.54,31.24.HR-MS(ESI),calcd.C 16 H 20 N8O2S2,[M+H] + m / z:421.1229,found:421.1230.

[0250] Example 18

[0251] Using the same preparation method as the compound with the structure shown in Formula II-1 in Example 1, the compound with the structure shown in Formula II-3 was obtained, the only difference being that Boc-piperazine was replaced with N-ethylpiperazine;

[0252]

[0253] Compounds with the structure shown in Formula III-12 in Example 12;

[0254] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-18 were obtained; the compounds with the structures shown in Formula I-18 are yellow solids with melting points of 164-165°C.

[0255]

[0256] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.38(s,1H,NH,D2Oexchangeable),10.59(s,1H,NH,D2O exchangeable),8.24(d,J=8.0Hz,1H,Ar-H),8.16(s,1H,Ar-H),7.51(d,J=7.2Hz,1H,Ar-H),7.36(t,J=7.8Hz,1H,Ar-H),7.14(dd,J=11.1,4.2Hz,1H,Ar-H),5 .44(s,2H,-CH2-),4.69(s,2H,-CH2-),4.24(s,2H,-CH2-),3.90(s,2H,-CH2-) ,2.45(s,4H,-CH2-),2.36(d,J=6.1Hz,2H,-CH2-),1.00(t,J=7.1Hz,3H,-CH3). 13 CNMR(100MHz,DMSO-d6,δ,ppm)δ193.64,168.94,150.07,134.34,129.30,127.88,125.64,124.89 ,124.50,122.39,121.38,51.98,51.67,51.27,50.93,31.04,30.67,11.80.HR-MS(ESI),calcd.C 19 H 24 ClN7O2S2,[M+H] + m / z:482.1200, found:482.1196.

[0257] Example 19

[0258] The compound using the structure shown in Formula II-3 of Example 18;

[0259] Compounds with the structure shown in Formula III-13 in Example 14;

[0260] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-19 were obtained; the compounds with the structures shown in Formula I-19 were yellow solids with melting points of 184-185°C.

[0261]

[0262] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.45(s,1H,NH,D2Oexchangeable),10.63(s,1H,NH,D2O exchangeable),8.36-8.03(m,2H,Ar-H),7.70(d,J=2.2Hz,1H,Ar-H),7.45(dd,J=8.9,2.1Hz,1H,Ar-H),5.43(s,2H,-CH2-),4.64(s,2H,- CH2-),4.28(s,2H,-CH2-),3.94(s,2H,-CH2-),2.58(d,J=15.2Hz,4H,-CH2-),1.19(d,J=34.8Hz,2H,-CH2-),1.04(t,J=6.9Hz,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ 13 C NMR(101MHz,DMSO)δ194.20,169.13,150.07,133.58,128.71,127.89,125.5 5,123.28,122.31,68.66,56.62,51.85,51.34,50.90,31.43,29.51,11.37.

[0263] Example 20

[0264] The compound using the structure shown in Formula II-3 of Example 18;

[0265] Compounds with the structure shown in Formula III-9 in Example 9;

[0266] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-20 were obtained; the compounds with the structures shown in Formula I-20 were yellow solids with melting points of 203-204°C.

[0267]

[0268] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.15(s,1H,NH,D2Oexchangeable),10.43(s,1H,NH,D2O exchangeable),8.20-8.09(m,2H,Ar-H),7.05(d,J=3.9Hz,2H,Ar-H),6.96-6.86(m,1H,Ar-H),5.39(s,2H,-CH2-),4.63(s,2H,-CH2-),4.24 (s,2H,-CH2-),3.95-3.86(m,2H,-CH2-),3.82(s,3H,-OCH3),2.45(s,4H,-CH2-),2.36(q,J=7.2Hz,2H,-CH2-),1.01(t,J=7.2Hz,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.89,168.48,149.95,148.02,142.03,126.70,125.47,123.72,120.5 5,119.10,110.85,66.99,56.02,55.90,51.83,50.98,49.65,31.40,25.10,11.86.HR-MS(ESI),calcd.C 20 H 27 N7O3S2,[M+H] + m / z:478.1695, found:478.1693.

[0269] Example 21

[0270] The compound using the structure shown in Formula II-3 of Example 18;

[0271] Compounds with the structure shown in Formula III-15 in Example 17;

[0272] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-21 were obtained; the compounds with the structures shown in Formula I-21 are yellow solids with melting points >200℃;

[0273]

[0274] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.09(s,1H,NH,D2Oexchangeable),10.21(s,1H,NH,D2O exchangeable),8.13(s,1H,Ar-H),7.99(d,J=8.8Hz,1H,Ar-H),6.64(d,J=2.4Hz ,1H,Ar-H),6.51(dd,J=8.9,2.4Hz,1H,Ar-H),5.38(s,2H,-CH2-),4.63(s,2H,-CH 2-),4.26(s,2H,-CH2-),3.92(s,2H,-CH2-),3.81(s,3H,-OCH3),3.74(s,3H,-OCH 3),2.55(d,J=7.8Hz,4H,-CH2-),2.45(s,2H,-CH2-),1.03(t,J=7.0Hz,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ 13 C NMR(101MHz,DMSO)δ194.08,168.35,156.07,149.85,149.38,125.53,120.16,119.90, 104.20,98.71,55.98,55.29,51.81,51.50,50.92,31.42,11.59.HR-MS(ESI),calcd.C 21 H 29 N7O4S2,[M+H] + m / z:508.1801, found:508.1797.

[0275] Example 22

[0276] The compound using the structure shown in Formula II-3 of Example 18;

[0277] Compounds with the structure shown in Formula III-16 of Example 18;

[0278] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-22 were obtained; the compounds with the structures shown in Formula I-22 were yellow solids with melting points of 162-163°C.

[0279]

[0280] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.28(s,1H,NH,D2Oexchangeable),10.38(s,1H,NH,D2O exchangeable),8.30(s,1H,Ar-H),8.15(s,1H,Ar-H),7.92(s,1H,Ar-H),7.83(t,J=7.6Hz,1H,Ar-H),7.18*7.08(m,1H,Ar-H),5.48(s,2H ,-CH2-),4.72(s,2H,-CH2-),4.24(s,2H,-CH2-),3.90(s,2H,-CH2-),2.46(s,4H,-CH2-),2.36(s,2H,-CH2-),0.99(t,J=6.8Hz,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.65,168.72,154.17,150.75,150.02,148.11,138.62,125 .63,124.50,119.75,113.03,52.42,51.65,50.91,49.82,31.05,11.81.HR-MS(ESI),calcd.C 18 H 24 N8O2S2,[M+H] + m / z:449.1542,found:449.1543.

[0281] Example 23

[0282] Using the same preparation method as the compound with the structure shown in Formula II-1 in Example 1, the compound with the structure shown in Formula II-4 was obtained, the only difference being that Boc-piperazine was replaced with N-phenylmethylpiperazine;

[0283]

[0284] Compounds with the structure shown in Formula III-16 of Example 18;

[0285] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-23 were obtained; the compounds with the structures shown in Formula I-23 were yellow solids with melting points of 162-163°C.

[0286]

[0287] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.26(s,1H,NH,D2Oexchangeable),10.40(s,1H,NH,D2O exchangeable),8.30(d,J=4.1Hz,1H,Ar-H),8.10(s,1H,Ar-H),7.92(d,J=8.2Hz ,1H,Ar-H),7.86-7.79(m,1H,Ar-H),7.37-7.29(m,4H,Ar-H),7.27(td,J=5.9,2. 4Hz,1H,Ar-H),7.16-7.10(m,1H,Ar-H),5.46(s,2H,-CH2-),4.62(s,2H,-CH2-), 4.26(s,2H,-CH2-),3.90(s,2H,-CH2-),3.52(s,2H,-CH2-),2.46(s,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.97,168.81,150.77,150.03,148.15,142.00,138.63,137.53,128.92, 128.23,127.10,125.43,119.71,112.99,61.24,52.23,51.92,51.08,49.69,31.44.HR-MS(ESI),calcd.C 23 H 26 N8O2S2,[M+H] + m / z:511.1698, found:511.1700.

[0288] Example 24

[0289] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0290] The compound adopts the structure shown in Formula III-11 in Example 11;

[0291] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-24 were obtained; the compounds with the structures shown in Formula I-24 were yellow solids with melting points of 187-188°C.

[0292]

[0293] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.28(s,1H,NH,D2Oexchangeable),10.29(s,1H,NH,D2O exchangeable),8.11(dd,J=7.0,5.6Hz,2H,Ar-H),7.28(d,J=11.1Hz,1H,Ar-H),7.23*7.06(m,2H,Ar-H),5.42(s,2H ,-CH2-),4.63(s,2H,-CH2-),4.24(s,2H,-CH2-),3.93(s,2H,-CH2-),3.54*3.43(m,4H,-CH2-),1.41(s,9H,-OCH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.53,169.01,153.65,151.15,150.06,141.93,1 25.47,124.75,121.58,115.19,79.37,51.90,31.38,27.98.HR-MS(ESI),calcd.C 17 H 20 ClN7O2S2,[M+H] + m / z:538.1706, found:538.1708.

[0294] Example 25

[0295] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0296] Compounds with the structure shown in Formula III-12 in Example 12;

[0297] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-25 were obtained; the compounds with the structures shown in Formula I-25 were yellow solids with melting points of 197-198°C.

[0298]

[0299] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.36(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),8.24(dd,J=8.3,1.3Hz,1H,Ar-H),8.13(s,1H,Ar-H),7.51(dd,J=8.0,1.3Hz,1H,Ar-H),7.43*7.29(m,1H,Ar-H),7.14(td,J=7.8 ,1.4Hz,1H,Ar-H),5.42(s,2H,-CH2-),4.64(s,2H,-CH2-),4.24(s,2H,-CH2-),3.93(s,2H,-CH2-),3.52*3.42(m,4H,-CH2-),1.41(s,9H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.49,169.04,153.64,150.09,134.36,129.30,127. 89,125.51,124.89,122.39,121.40,79.38,51.84,31.36,27.99.HR-MS(ESI),calcd.C 22 H 28 ClN7O4S2,[M*H] + m / z:552.1254,found:552.1253.

[0300] Example 26

[0301] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0302] Compounds with the structure shown in Formula III-9 in Example 9;

[0303] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-26 were obtained; the compounds with the structures shown in Formula I-26 were yellow solids with melting points of 199-200°C.

[0304]

[0305] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.14(s,1H,NH,D2Oexchangeable),10.42(s,1H,NH,D2O exchangeable),8.14(m,2H,Ar-H),7.06(s,1H,Ar-H),7.05(s,1H,Ar-H),6.96*6.91(m,1H,Ar-H),5.39(s,2H,-CH2-),4.6 4(s,2H,-CH2-),4.24(s,2H,-CH2-),3.93(s,2H,-CH2-),3.82(s,3H,-OCH3),3.50*3.43(m,4H,-CH2-),1.41(s,9H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.47,168.47,153.64,149.95,148.01,126.70,125.56, 123.72,120.55,119.09,110.85,79.38,55.90,51.85,31.33,27.99.HR-MS(ESI),calcd.C 23 H 31 N7O5S2,[M+H] + m / z:548.1750,found:548.1748.

[0306] Example 27

[0307] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0308] Compounds with the structure shown in Formula III-14 in Example 15;

[0309] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-27 were obtained; the compounds with the structures shown in Formula I-27 were yellow solids with melting points of 198-199°C.

[0310]

[0311] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.98(s,1H,NH,D2Oexchangeable),9.94(s,1H,NH,D2O exchangeable),8.10(s,1H,Ar-H),7.39(d,J=8.4Hz,2H,Ar-H),7.13(d,J=8.3Hz,2H,Ar-H),5.41(s,2H,-CH2-),4.63( s,2H,-CH2-),4.24(s,2H,-CH2-),3.93(s,2H,-CH2-),3.49-3.40(m,4H,-CH2-),2.26(s,3H,-CH3),1.41(s,9H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.53,168.50,153.65,150.10,141.90,134.82,132. 85,129.30,125.44,119.71,79.38,51.92,31.38,27.99,20.35.HR-MS(ESI),calcd.C 23 H 31 N7O4S2,[M+H] + m / z:534.1957, found:534.1958.

[0312] Example 28

[0313] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0314] Compounds with the structure shown in Formula III-16 of Example 18;

[0315] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-28 were obtained; the compounds with the structures shown in Formula I-28 are yellow solids with melting points of 189-190°C.

[0316]

[0317] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.26(s,1H,NH,D2Oexchangeable),10.40(s,1H,NH,D2O exchangeable),8.30(d,J=4.6Hz,1H,Ar-H),8.11(s,1H,Ar-H),7.93(d,J=8.3Hz,1H,Ar-H),7.87-7.78(m,1H,Ar-H),7.14(dd,J=6.8,5.4H z,1H,Ar-H),5.46(s,2H,-CH2-),4.64(s,2H,-CH2-),4.25(s,2H,-CH2-),3.93(s,2H,-CH2-),3.52-3.42(m,4H,-CH2-),1.42(s,9H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.53,168.81,153.65,150.76,150.02,148.15,141. 91,138.62,125.46,119.70,112.98,79.37,52.22,31.38,27.99.HR-MS(ESI),calcd.C 21 H 28 N8O4S2,[M+H] + m / z:521.1753,found:521.1754.

[0318] Example 29

[0319] The same preparation method was used to obtain the compound with the structure shown in Formula II-4 in Example 1, except that Boc-piperazine was replaced with morpholine.

[0320]

[0321] Compounds with the structure shown in Formula III-16 of Example 18;

[0322] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-29 were obtained; the compounds with the structures shown in Formula I-29 were white solids with melting points of 200-201°C.

[0323]

[0324] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.26(s,1H,NH,D2Oexchangeable),10.40(s,1H,NH,D2O exchangeable),8.30(d,J=4.2Hz,1H,Ar-H),8.12(s,1H,Ar-H),7.93(d,J=8.2Hz,1H,Ar-H),7.87-7.77(m,1H,Ar-H),7.14(dd ,J=6.8,5.4Hz,1H,Ar-H),5.46(s,2H,-CH2-),4.65(s,2H,-CH2-),4.23(s,2H,-CH2-),3.92(s,2H,-CH2-),3.67(s,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.53,168.78,150.76,150.03,148.15,142.07,138. 63,125.51,119.72,113.00,65.55,52.27,51.38,50.32,31.16.HR-MS(ESI),calcd.C 16 H 19 N7O3S2,[M+Na] + m / z:444.0888,found:444.0892.

[0325] Example 30

[0326] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0327] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-17 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-((3-pyridine)carbamoyl)acetamide;

[0328]

[0329] The compound with the structure shown in Formula I-30 was obtained by the same preparation method as the compound with the structure shown in Formula I-1 in Example 1; the compound with the structure shown in Formula I-30 is a white solid with a melting point >200℃.

[0330]

[0331] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.48(s,1H,NH,D2Oexchangeable),8.71(s,1H,Ar-H),8.29(d,J=4.1Hz,1H,Ar-H),8.13*7.93(m,2H,Ar-H ),7.36(dd,J=8.1,4.7Hz,1H,Ar-H),5.44(s,2H,-CH2-),4.63(s,2H,-CH2-),4.18(s,2H,-CH2-),3.83(s,2H,-CH2-),2.76(s,4H,-CH2-). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ193.32,168.38,150.67,144.56,142.08,141.5 3,134.58,126.97,125.42,123.60,52.09,45.46,31.24.HR-MS(ESI),calcd.C 16 H 20 N8O2S2,[M+Na] + m / z:421.1229,found:421.1230.

[0332] Example 31

[0333] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0334] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-18 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(thiazol-2-carbamoyl)acetamide;

[0335]

[0336] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-31 was obtained; the compound with the structure shown in Formula I-31 is a white solid with a melting point >200℃;

[0337]

[0338] The analysis results are as follows: 1H NMR(400MHz,DMSO-d6,δ,ppm)δ8.08(s,1H,Ar-H),7.44(s,1H,Ar-H),7.23(s,1H,Ar-H),5.51(s,2H,-CH2 -),4.62(s,2H,-CH2-),4.18(s,2H,-CH2-),3.83(s,2H,-CH2-),2.77(s,4H,-CH2-).HR-MS(ESI),calcd.C 14 H 18 N8O2S3,[M+Na] + m / z:427.0793,found:427.0794.

[0339] Example 32

[0340] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0341] Using the same preparation method as the compound with the structure shown in Formula III-1 in Example 1, the compound with the structure shown in Formula III-19 was obtained, the only difference being that 2-chloro-N-phenylacetamide was replaced with 2-chloro-N-(4-methyldihydrocoumarin-7-carbamoyl)acetamide;

[0342]

[0343] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-32 was obtained; the compound with the structure shown in Formula I-32 is a white solid with a melting point of 190-191°C;

[0344]

[0345] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.30(s,1H,NH,D2Oexchangeable),8.10(s,1H,NH,D2O exchangeable),7.83-7.61(m,2H,Ar-H),7.48(d,J=8.2Hz,1H,Ar-H),6.25(s,1H,Ar-H),5.47(s, 2H,-CH2-),4.63(s,2H,-CH2-),4.38-3.27(m,8H,-CH2-),2.76(s,2H,-CH2-),2.39(s,3H,-CH3). 13C NMR(100MHz,DMSO-d6,δ,ppm)δ193.32,168.44,159.98,153.63,153.07,150.91,141.94,125.85,125.41 ,115.50,114.93,112.18,105.85,52.90,52.40,51.69,45.44,43.18,31.28,17.95.HR-MS(ESI),calcd.C 21 H 25 N7O4S2,[M+Na] + m / z:502.1331,found:502.1336.

[0346] Example 33

[0347] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0348] The compound adopts the structure shown in Formula III-17 of Example 31;

[0349] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-33 were obtained; the compounds with the structures shown in Formula I-34 were yellow solids with melting points >200℃;

[0350]

[0351] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.15(s,1H,NH,D2Oexchangeable),10.09(s,1H,NH,D2O exchangeable),8.69(d,J=2.4Hz,1H,Ar-H),8.30(dd,J=4.6,1.2Hz,1H,Ar-H),8.15-7.88(m,2H),Ar-H,7.37(dd,J=8.3,4.7Hz,1H,A r-H),5.43(s,2H,-CH2-),4.63(s,2H,-CH2-),4.25(s,2H,-CH2-),3.92(s,2H,-CH2-),3.54-3.43(m,4H,-CH2-),1.41(s,9H,-OCH3). 13C NMR(100MHz,DMSO-d6,δ,ppm)δ194.52,168.50,153.65,150.48,144.78,141.93,141. 63,134.25,127.15,125.45,123.63,79.38,51.95,31.37,27.99.HR-MS(ESI),calcd.C 21 H 28 N8O4S2,[M+Na] + m / z:521.1753,found:521.1754.

[0352] Example 34

[0353] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0354] The compound adopts the structure shown in Formula III-18 in Example 32;

[0355] Using the same preparation method as the compounds with the structures shown in Formula I-9 in Example 9, compounds with the structures shown in Formula I-34 were obtained; the compounds with the structures shown in Formula I-34 are yellow solids with melting points >200℃;

[0356]

[0357] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ12.62(s,1H,NH,D2Oexchangeable),11.28(s,1H,NH,D2O exchangeable),8.12(d,J=13.3Hz,1H,Ar-H),7.49(dd,J=16.9,3.5Hz,1H,Ar-H),7.27(d,J=3.5Hz,1H,Ar-H),5.47(d,J =21.9Hz,2H,-CH2-),4.63(s,2H,-CH2-),4.25(s,2H,-CH2-),3.93(s,2H,-CH2-),3.47(s,4H,-CH2-),1.41(s,9H,-CH3). 13 C NMR(100MHz,DMSO-d6,δ,ppm)δ194.54,168.89,164.59,157.39,153.64,141.89,137.78,125.4 2,114.04,79.37,55.99,52.25,51.38,50.58,49.18,31.39,27.99,18.53.HR-MS(ESI),calcd.C19 H 26 N8O4S3,[M+H] + m / z:527.1317,found:527.1319.

[0358] Example 35

[0359] The compound with the structure shown in Formula II-1 in Example 1 was used;

[0360] The compound with the structure shown in Formula III-19 in Example 33;

[0361] Using the same preparation method as the compound with the structure shown in Formula I-1 in Example 1, the compound with the structure shown in Formula I-35 was obtained; the compound with the structure shown in Formula I-35 is a white solid with a melting point of 193-194°C.

[0362]

[0363] The analysis results are as follows: 1 H NMR(400MHz,DMSO-d6,δ,ppm)δ11.16(s,1H,NH,D2O exchangeable),10.31(s,1H,NH,D2O ( s,2H,-CH2-),4.64(s,2H,-CH2-),4.26(s,2H,-CH2-),3.92(s,2H,-CH2-),3.49-3.44(m,4H,-CH2-),2.40(s,3H,-CH3),1.42(s,9H,-CH3). 13 C NMR (100MHz, DMSO-d6, δ, ppm) 13 C NMR (101MHz, DMSO) δ194.57 (s), 168.61 (s), 159.86 (s), 153.63 (d, J = 5.9Hz), 152.99, 150.19, 141.94, 140.86, 126. 00,125.43,115.75,115.43,112.54,106.30,79.38,59.71,52.01,31.39,27.99,17.95,14.05.HR-MS(ESI),calcd.C 26 H 33N7O6S2,[M+Na] + m / z:602.1855, found:602.1857.

[0364] Example 36

[0365] The inhibitory activity of the compounds obtained in Examples 1-35 on LSD1 was determined:

[0366] The compounds obtained in Examples 1-35 were incubated with 5 nmol / L recombinant LSD1 and 25 mmol / L LSD1 substrate H3K4me2 in the presence of FAD (50 nmol / L), Amplex Red (20 nmol / L) and horseradish peroxidase (5.5 U / mL) for 30 minutes.

[0367] Fluorescence was measured at an excitation wavelength of 530 nm and an emission wavelength of 590 nm to evaluate the inhibition rate of Examples 1–35, and IC50 was calculated using SPSS. 50 The values ​​are shown in Table 1.

[0368] Table 1. Inhibitory activity data of the compounds prepared in Examples 1-35 against LSD1.

[0369]

[0370]

[0371] As shown in Table 1, the amino dithioester derivatives containing amide structural units provided by this invention all exhibit certain LSD1 inhibitory effects. Among them, the amino dithioester derivatives containing amide structural units in Examples 6, 9, 12, 13, 16, 17, 19, 21, 22, 26, and 29 show particularly prominent inhibitory effects on LSD1, significantly superior to ZYC-1. The amino dithioester derivatives containing amide structural units provided by this invention all have excellent application prospects in the preparation of drugs for treating tumors.

[0372] Example 37

[0373] Press 5×10 6 MGC-803 cells were inoculated into immunocompetent 615 line mice, and measurements were taken. When the xenograft reached 100 mm, the cells were counted. 3 Mice were divided into three groups: ① control group (0 mg / kg / day, intraperitoneal injection of saline); ② group (25 mg / kg / day, oral gavage); ③ group (50 mg / kg / day, oral gavage). During the 21-day continuous administration, the weight and tumor volume of the nude mice were measured and recorded every 3 days. On the last day after administration, the mice were sacrificed, and the transplanted tumors were removed, weighed, and recorded.

[0374] Test results showed that the mouse body weight did not change significantly throughout the test, indicating that the amino dithioester derivative containing the amide structural unit provided by this invention is non-toxic to nude mice. Tumor volume growth was significantly slower in the high-concentration group than in the control and low-concentration groups. Tumor weight data showed that the tumor weight in the low-concentration group did not change significantly compared to the control group, while the tumor weight in the high-concentration group decreased significantly compared to the control group. Therefore, the amino dithioester derivative containing the amide structural unit provided by this invention can inhibit tumor proliferation with minimal toxic side effects at high concentrations.

[0375] As can be seen from the above embodiments, the amino dithioester derivatives containing amide structural units provided by the present invention have low toxicity, high selectivity, and high activity, and can be used to prepare anti-tumor drugs or for combination immunotherapy, especially suitable for LSD1 small molecule inhibitors.

[0376] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An amino dithioester derivative containing an amide structural unit, the structure of which is shown below: Formula I-34.

2. The use of the amino dithioester derivative containing amide structural units as described in claim 1 in the preparation of LSD1-targeted inhibitors.

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