Aminothiazole heterocyclic compound containing pyridone as well as synthesis and application thereof

Abstract

The invention provides a pyridone-containing aminothiazole heterocyclic compound as well as synthesis and application thereof. The aminothiazole heterocyclic compound has a structure as shown in a general formula I or a general formula II or a pharmaceutically acceptable salt or an isotope labeled compound thereof. The invention also discloses a preparation method and the like of the derivative. Experiments prove that the aminothiazole heterocyclic compound containing pyridone can effectively inhibit replication of herpes simplex virus in Vero cells, the compound is of a non-nucleoside structure, the inhibitory activity of the compound is superior to that of a clinical first-line drug acyclovir, and the compound can be used for preparing active drugs for resisting the herpes simplex virus. The general formula I or the general formula II is shown in the specification.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to aminothiazole heterocyclic compounds containing pyridone and their synthesis and application. Background Technology

[0002] Herpes simplex virus (HSV) is widespread in the global population, and the diseases it causes mainly include cold sores, gingivostomatitis, keratitis, pharyngitis, and HSV-related infectious encephalitis. Currently, the first-line anti-HSV drugs used in clinical practice are mainly nucleoside DNA polymerase inhibitors, represented by acyclovir (ACV). However, these drugs have the following problems: (1) long-term and excessive use has led to herpes simplex virus developing resistance to ACV; (2) ACV has serious side effects, including neurotoxicity and kidney damage. Based on the structural modification of acyclovir, the side effects of the parent nucleus itself cannot be solved, and the problem of drug resistance is also difficult to avoid. Therefore, the development of anti-herpes simplex virus drugs with new structural types is expected to solve the above problems. Summary of the Invention

[0003] One object of this invention is to provide a pyridone-containing aminothiazole heterocyclic compound, specifically a structure represented by general formula I or general formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable isotopically labeled compound thereof. in R1 is selected from halogens, benzene rings, substituted benzene rings, unsubstituted aromatic heterocycles, or substituted aromatic heterocycles. R2 is selected from C1~C4 alkanes or aromatic alkanes; The pyridinone-containing aminothiazole heterocyclic compound, wherein R1 is preferably from one of the following structures: ; The pyridone-containing aminothiazole heterocyclic compound, wherein R2 is preferably derived from methyl or benzyl.

[0004] The pyridinone-containing aminothiazole heterocyclic compound is selected from any of the following compounds: 2-(4-bromo-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-1) N -Methyl-2-(2-oxo-4-p-tolyl-1,2-dihydropyridin-1-yl)- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-2) 2-(4-(2,5-difluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-3) 2-(4-(3-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-4) 2-(4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-5) 2-(4-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-6) N -Methyl-2-(2-oxo-4-phenyl-1,2-dihydropyridin-1-yl)- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-7) 2-(4-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-8) 2-(2-methoxy-2'-oxo-[3,4'-bipyridine]-1'(2'H)-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-9) 2-(4-(benzo[d][1,3]dioxolane-5-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-10) 2-(4-(4-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-11) N-Methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridin-1-yl)- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-I-12) 2-(4-(3-methoxyphenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-13) 2-(4-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-14) 2-(4-(furan-3-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-15) 2-(4-(furan-2-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-16) 2-(4-(3-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-17) 2-(4-(2-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-Methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-18) N -Methyl-2-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)- N -(4-Methyl-5-aminosulfonylthiazo-2-yl)acetamide (L-II-1) 2-(4-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-II-2).

[0005] The present invention relates to pharmaceutically acceptable salts of compounds, wherein the pharmaceutically acceptable salts are formed by the reaction of the compounds with inorganic or organic acids. These pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurine, citrate, or succinate.

[0006] The present invention relates to pharmaceutically acceptable isotopic labels for compounds, wherein the pharmaceutically acceptable isotopic label is a form in which one or more atoms in the compound are replaced by isotopic atoms, including but not limited to: deuterium (…). 2 H) or tritium ( 3 H).

[0007] A second objective of this invention is to provide a method for synthesizing compounds of general formula I and general formula II, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, the method comprising the following steps: Compound I-1 was reacted with H2SO4 and NaNO2 to give intermediate I-2, and intermediate I-2 was reacted with ethyl bromoacetate in the presence of K2CO3 to give intermediate I-3. Compound II-1 undergoes a Suzuki coupling reaction with pinacol diboronic acid in the presence of KOAc and PdCl2 (dppf) to give intermediate II-2; Intermediate I-3 undergoes Suzuki coupling reactions with boric acid compounds or borate ester compounds of different structures in the presence of K2CO3 and PdCl2(dppf) to give intermediates I-2-1 to I-18-1. Intermediate I-3 or intermediates I-2-1 to I-18-1 undergo alkaline hydrolysis in the presence of LiOH·H2O to give intermediates I-1-1 or I-2-2 to I-18-2, respectively. Intermediate I-1-1 or I-2-2 to I-18-2 undergo amide condensation reactions with intermediates 1-4 in the presence of HOBt and EDCI to give L-I-1 to L-I-18. Alternatively, intermediate I-2, in the presence of bases such as NaH or K2CO3, undergoes substitution reactions with haloalkanes of different structures to obtain intermediates II-1-1 or II-2-1. Intermediate II-1-1 or II-2-1, in the presence of KOAc and PdCl2 (dppf), undergoes Suzuki coupling reactions with intermediate II-2 to obtain intermediates II-1-2 or II-2-2. Intermediate II-1-2 or II-2-2 undergoes alkaline hydrolysis in the presence of LiOH·H2O to obtain intermediates II-1-3 or II-2-3. Intermediate II-1-3 or II-2-3, in the presence of HOBt and EDCI, undergoes amide condensation reactions with intermediates 1-4 to obtain L-II-1 or L-II-2. .

[0008] A third objective of this invention is to provide the application of the pyridone compounds in the preparation of drugs against herpes simplex virus.

[0009] The significant advantages of this invention are that the pyridone-containing aminothiazole heterocyclic compounds described herein effectively inhibit the replication of herpes simplex virus in vitro. Specifically, the compounds of this invention exhibit significantly higher inhibition rates against HSV-1 than the positive control drug acyclovir in in vitro inhibition experiments, with some compounds showing better inhibition at IC50. 50 It showed a lower IC50 than acyclovir in the test. 50 The values ​​indicate that the compounds exhibit superior anti-HSV-1 activity compared to acyclovir. This invention also discloses the toxicity evaluation results of the pyridone-containing aminothiazole heterocyclic compounds on Vero E6 cells, showing that most compounds exhibit low cytotoxicity, high selectivity, and a broad therapeutic window. The novel pyridone-containing aminothiazole heterocyclic compounds disclosed in this invention show promising application prospects in the clinical treatment of herpes simplex virus.

[0010] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0011] The present invention will be further described in detail below with reference to embodiments. However, the embodiments of the present invention are not limited thereto. Various substitutions and modifications can be made based on ordinary technical knowledge and common practices in the art without departing from the above-described technical concept of the present invention, and all such substitutions and modifications should be included within the scope of the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified can be purchased from legitimate channels as conventional products.

[0012] The structure of the compound was determined by nuclear magnetic resonance and high-resolution mass spectrometry. 1 H-NMR and 13 C-NMR was performed using a Bruker 500 MHz NMR spectrometer with TMS as an internal standard. LC-HRMS was performed using an Agilent 1290-HPLC 6224 system. Melting points were determined using a Büchi B-540 melting point apparatus. Column chromatography was performed using 200-300 mesh silica gel.

[0013] Example 1. Synthesis of L-I-1 .

[0014] Step 1: Synthesis of Compounds 1-2 SOCl2 (820 μL, 11.3 mmol) and HSO3Cl (1.5 mL, 22.6 mmol) were added to a sealed tube. 2-Chloro-4-methylthiazole (0.286 g, 2.2 mmol) was added dropwise to the system at room temperature. The system was heated to 120 °C. After the reaction was completed by TLC monitoring, the system was quenched in ice water. The mixture was extracted twice with DCM, and the organic phase was dried over anhydrous Na2SO4. The resulting yellow liquid was directly added to the next step.

[0015] Step 2: Synthesis of compounds 1-3 The products 1-2 obtained in the previous step were dissolved in THF, and 20% NH3(aq) (310 μL, 3.3 mmol) was added dropwise under ice bath conditions. The system was slowly raised to room temperature, and the reaction was allowed to proceed overnight. After the reaction was completed by TLC monitoring (PE:EA = 4:1), the solvent was evaporated, and the crude product was purified by column chromatography (PE:EA = 4:1) to give 0.224 g of a white solid, with a yield of 48%. mp 139.2–139.9 ℃. 1 H NMR (500MHz, DMSO- d 6 ) δ 8.03 (s, 2H), 2.50 (s, 3H). HRMS(ESI): m / z calcd forC4H6ClN2O2S2 + [M+H] + : 212.9554, found 212.9556.

[0016] Step 3: Synthesis of compounds 1-4 Dissolve 1-3 (0.361 g, 1.70 mmol) in acetonitrile, and add dropwise 750 μL (8.55 mmol) of 40% methylamine aqueous solution at room temperature. The mixture is then heated to 50 °C and reacted overnight. After the reaction is complete (PE:EA = 1:1) as monitored by TLC, the solvent is evaporated, and the mixture is purified by column chromatography (PE:EA = 1:2) to give 0.312 g of a white solid, yield 87%. mp 186.7–187.5 °C. 1 H NMR (500MHz, DMSO- d 6 ) δ 7.99 (q, J = 5.0 Hz, 1H), 7.33 (s, 2H), 2.79 (d, J = 5.0 Hz,3H), 2.29 (s, 3H). HRMS(ESI): m / z calcd for C5H 10 N3O2S2 + [M+H] + : 208.0209, found208.0200.

[0017] Step 4: Synthesis of Compound I-2 2-Amino-4-bromopyridine (0.17 g, 1 mmol) was dissolved in 2M sulfuric acid solution. A saturated aqueous solution of NaNO2 (90 mg, 1.3 mmol) was added dropwise to the system under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete (PE:EA = 5:3) as monitored by TLC, the mixture was filtered, and the filter cake was washed with water and a small amount of acetone to give 0.116 g of a white solid, yield 67%. mp 209.5–210.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.86 (s, 1H), 7.35 (d, J = 7.0 Hz, 1H), 6.63(d, J = 2.0 Hz, 1H), 6.37 (dd, J = 7.0, 2.0 Hz, 1H). HRMS(ESI): m / z calcd forC5H5BrNO + [M+H] + : 173.9550, found 173.9542.

[0018] Step 5: Synthesis of Compound I-3 I-2 (0.2 g, 1.16 mmol), K2CO3 (0.58 g, 4.20 mmol), were dissolved in acetone, and ethyl bromoacetate (342 μL, 3.10 mmol) was added dropwise. The mixture was heated to reflux overnight. The reaction was monitored by TLC (PE:EA = 5:2). The mixture was filtered, the filter cake was washed with acetone, the filtrates were combined and evaporated to dryness, and purified by column chromatography (PE:EA = 5:2) to give 0.252 g of white solid, 84% yield. mp 112.4–113.3 ℃. 1 H NMR (500 MHz, CDCl3) δ 7.08 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.35 (dd, J = 7.5, 2.0 Hz, 1H), 4.58 (s, 2H), 4.23(q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd forC9H 11 BrNO3 + [M+H] + : 259.9917, found 259.9915.

[0019] Step Six: Synthesis of Compound I-1-1 I-3 (0.2 g, 0.772 mmol) and LiOH·H2O (97 mg, 2.316 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux and reacted for 3 h. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 0.141 g of a white solid, with a yield of 79%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 13.08 (s, 1H), 7.65 (d, J = 7.0 Hz, 1H), 6.75 (d, J =2.0 Hz, 1H), 6.50 (dd, J = 7.5, 2.0 Hz, 1H), 4.59 (s, 2H). HRMS(ESI): m / zcalcd for C7H7BrNO3 + [M+H]+ :231.9604, found 231.9603.

[0020] Step 7: Synthesis of compound L-I-1 I-1-1 (0.131 g, 0.570 mmol), 1-4 (0.118 g, 0.570 mmol), HOBT (0.115 g, 0.854 mmol), EDCI (0.164 g, 0.854 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 0.199 g of white solid, yield 83%. mp 235.4–236.1 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.70 (s, 2H), 7.63 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.58 (dd, J = 7.0, 2.5Hz, 1H), 5.21 (s, 2H), 3.72 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 )δ 167.7, 160.3, 158.1, 148.2, 140.3, 135.8, 128.6, 121.2, 109.4, 50.4, 33.4,16.1. HRMS(ESI): m / z calcd for C 12 H 14 BrN4O4S2 + [M+H] + :420.9635, found 420.9635.

[0021] Example 2. Synthesis of L-I-2.

[0022] .

[0023] Step 1: Synthesis of Compound I-2-1 I-3 (0.2 g, 0.772 mmol), 4-tolueneboronic acid (0.116 g, 0.849 mmol), potassium carbonate (0.32 g, 2.32 mmol), and PdCl2(dppf) (56 mg, 0.0772 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the system was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.188 g of a white solid, 90% yield. mp 122.8–123.4 °C. 1 H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.5 Hz, 2H), 7.25 (m, 3H), 6.79 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 7.0, 2.0 Hz, 1H), 4.67 (s, 2H), 4.25(q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / zcalcd for C 16 H 18 NO3 + [M+H] + : 272.1282, found 272.1276.

[0024] Step 2: Synthesis of Compound I-2-2 I-2-1 (0.2 g, 0.772 mmol) and LiOH·H2O (97 mg, 2.316 mmol) were added to a THF / H2O mixture. The mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered. The filter cake was washed with water, dried, and used to obtain 0.163 g of a white solid, with a yield of 87%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 7.71 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.30(d, J = 8.0 Hz, 2H), 6.66 (d,J = 2.0 Hz, 1H), 6.60 (dd, J = 7.5 Hz, 2.0 Hz,1H), 4.63 (s, 2H), 2.35 (s, 3H). HRMS(ESI): m / z calcd for C 14 H 14 NO3 + [M+H] + :244.0969, found 244.0971.

[0025] Step 3: Synthesis of compound L-I-2 I-2-2 (98 mg, 0.4 mmol), 1-4 (83 mg, 0.4 mmol), HOBT (81 mg, 0.6 mmol), EDCI (115 mg, 0.6 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 96 mg of white solid, yield 55%. mp 237.9–238.5 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.70 (m, 3H), 7.66 (d, J =7.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.72 (s, 1H), 6.67 (dd, J = 7.5 Hz, 2.0 Hz, 1H), 5.23 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H), 2.37 (s, 3H). 13 C NMR (125 MHz, DMSO-) d 6 ) δ 168.1, 161.6, 158.1, 151.3, 148.2, 139.6, 139.4, 133.7,129.7, 126.6, 114.5, 104.3, 50.2, 33.4, 20.8, 16.1. HRMS(ESI): m / z calcd forC 19 H 21 N4O4S2 + [M+H] +: 433.0999, found 433.0981.

[0026] Example 3. Synthesis of L-I-3 Referring to Example 2, 4-tolueneboronic acid was replaced with 2,5-difluorophenylboronic acid.

[0027] Step 1: Synthesis of I-3-1 I-3 (0.354 g, 1.36 mmol), 2,5-difluorophenylboronic acid (0.237 g, 1.50 mmol), potassium carbonate (0.565 g, 4.10 mmol), and PdCl2(dppf) (99 mg, 0.136 mmol) were placed in a three-necked flask, evacuated, and then N2 was introduced. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 0.32 g of a colorless oil, with a yield of 80%. 1 H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 7.0 Hz, 1H), 7.15 – 7.04 (m, 3H), 6.75 – 6.72(m, 1H), 6.40 (dt, J = 7.5, 2.0 Hz, 1H), 4.67 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). HRMS(ESI): m / z calcd for C 15 H 14 F2NO3 + [M+H] + :294.0937, found 294.0938.

[0028] Step 2: Synthesis of I-3-2 I-3-1 (0.3 g, 1.03 mmol) and LiOH·H2O (0.13 g, 3.10 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux for 3 h. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 0.167 g of a white solid, with a yield of 61%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-)d 6 ) δ 13.07 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.50 (m, 1H),7.45 – 7.30 (m, 2H), 6.61 (s, 1H), 6.47 (d, J = 7.0 Hz, 1H), 4.65 (s, 2H).HRMS(ESI): m / z calcd for C 13 H 10 F2NO3 + [M+H] + : 266.0623, found 266.0630.

[0029] Step 3: Synthesis of L-I-3 I-3-2 (0.166 g, 0.626 mmol), 1-4 (0.13 g, 0.626 mmol), HOBT (0.127 g, 0.940 mmol), EDCI (0.180 g, 0.940 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, the solid was recrystallized by heating with acetonitrile, filtered, and washed to give 222 mg of white solid, yield 78%. mp 216.0–216.6 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.74 (d, J =7.0 Hz, 1H), 7.70 (s, 2H), 7.55 (ddd, J = 9.0, 6.0, 3.5 Hz, 1H), 7.46 – 7.35(m, 2H), 6.67 (t, J = 1.5 Hz, 1H), 6.54 (dt, J = 7.0, 2.0 Hz, 1H), 5.26 (s,2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.0, 161.1,158.3 (d, J = 238.8 Hz), 158.1, 155.4 (d, J= 243.8 Hz), 148.2, 145.9, 139.6,128.6, 126.6 (dd, J = 15.0 Hz, 7.5 Hz), 118.7 (d, J = 3.8 Hz), 117.9 (m), 116.5 (dd, J = 25.0 Hz, 3.8 Hz), 105.9 (d, J = 3.8 Hz), 50.4, 33.4, 16.1.HRMS(ESI): m / z calcd for C 18 H 17 F2N4O4S2 + [M+H] + : 455.0654, found 455.0652.

[0030] Example 4. Synthesis of L-I-4 Referring to Example 2, 4-tolueneboronic acid was replaced with 3-chlorophenylboronic acid.

[0031] Step 1: Synthesis of I-4-1 I-3 (0.2 g, 0.772 mmol), 3-chlorophenylboronic acid (0.132 g, 0.849 mmol), potassium carbonate (0.32 g, 2.32 mmol), and PdCl2(dppf) (0.057 g, 0.077 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 0.189 g of a white solid, in 85% yield. mp 108.8–109.4 °C. 1 H NMR (500 MHz, CDCl3) δ 7.55 – 7.53 (m, 1H), 7.44 (dt, J = 7.0,1.5 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.29 (d, J = 7.0 Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 6.43 (dd, J = 7.0, 2.0 Hz, 1H), 4.67 (s, 2H), 4.26 (q, J= 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H). HRMS(ESI): m / z calcd for C 15 H 15 ClNO3 + [M+H] + :292.0735, found 292.0736.

[0032] Step 2: Synthesis of I-4-2 I-4-1 (0.139 g, 0.478 mmol) and LiOH·H₂O (0.060 g, 1.43 mmol) were added to a THF / H₂O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 0.122 g of a white solid, with a yield of 97%. mp >250℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 13.04 (s, 1H), 7.80 (s, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.70 (dt, J = 6.5, 2.0 Hz, 1H), 7.52 (m, 2H), 6.75 (d, J = 2.5 Hz, 1H), 6.64(dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H). HRMS(ESI): m / z calcd for C 13 H 11 ClNO3 + [M+H] + : 264.0422, found 264.0416.

[0033] Step 3: Synthesis of L-I-4 I-4-2 (0.1 g, 0.38 mmol), 1-4 (0.079 g, 0.38 mmol), HOBT (0.056 g, 0.42 mmol), EDCI (0.080 g, 0.42 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was complete, water was added dropwise to the system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 53 mg of white solid, yield 31%. mp 239.6–240.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.84 (s, 1H), 7.74 (d, J = 7.0 Hz, 2H), 7.70 (s, 2H), 7.58 – 7.51 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 7.0, 2.0 Hz, 1H), 5.25 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 CNMR (125 MHz, DMSO- d 6 ) δ 168.1, 161.4, 158.1, 149.9, 148.2, 140.0, 138.9,133.9, 130.9, 129.5, 128.6, 126.6, 125.5, 115.8, 104.3, 50.3, 33.4, 16.2.HRMS(ESI): m / z calcd for C 18 H 18 ClN4O4S2 + [M+H] + : 453.0453, found 453.0453.

[0034] Example 5. Synthesis of L-I-5 Referring to Example 2, 4-tolueneboronic acid was replaced with 4-methoxyphenylboronic acid.

[0035] Step 1: Synthesis of I-5-1 I-3 (0.126 g, 0.485 mmol), 4-methoxyphenylboronic acid (81 mg, 0.534 mmol), potassium carbonate (0.201 g, 1.455 mmol), and PdCl2(dppf) (35 mg, 0.0485 mmol) were placed in a three-necked flask, evacuated, and purged with N2. After dissolving 1,4-dioxane in the solution, the reaction mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 110 mg of a white solid, with a yield of 79%. mp 101.4–102.3 °C. 1 H NMR (500 MHz, CDCl3) δ 7.56 – 7.51 (m, 2H), 7.24 (d, J =7.0 Hz, 1H), 6.99 – 6.94 (m, 2H), 6.76 (d, J = 2.0 Hz, 1H), 6.46 (dd, J =7.0, 2.0 Hz, 1H), 4.66 (s, 2H), 4.25 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 1.30(t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd for C 16 H 18 NO4 + [M+H] + : 288.1231,found288.1222.

[0036] Step 2: Synthesis of I-5-2 I-5-1 (98 mg, 0.343 mmol) and LiOH·H2O (43 mg, 1.029 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 75 mg of a white solid, with a yield of 85%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 13.00 (s, 1H), 7.70 (m, 3H), 7.04 (d, J = 9.0 Hz, 2H), 6.64 (d, J= 2.0 Hz, 1H), 6.60 (dd, J = 7.0, 2.0 Hz, 1H), 4.62 (s, 2H), 3.81(s, 3H). HRMS(ESI): m / z calcd for C 14 H 14 NO4 + [M+H] + : 260.0918, found 260.0925.

[0037] Step 3: Synthesis of L-I-5 I-5-2 (75 mg, 0.291 mmol), 1-4 (60 mg, 0.291 mmol), HOBT (59 mg, 0.437 mmol), EDCI (84 mg, 0.437 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 77 mg of white solid, yield 59%. mp 242.6–243.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.74 (d, J = 8.5 Hz, 2H),7.71-7.69 (m, 3H), 7.06 (d, J = 8.5 Hz, 2H), 6.70(d, J =2.0Hz, 1H), 6.68 (dd, J = 7.0, 2.0 Hz, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6 ) δ 168.2, 161.6, 160.6, 158.1, 150.8, 148.2, 139.5,128.6, 128.5, 128.2, 114.5, 113.8, 104.2, 55.3, 50.1, 33.4, 16.1. HRMS(ESI):m / z calcd for C 19 H 21 N4O5S2 + [M+H]+ : 449.0948, found 449.0955.

[0038] Example 6. Synthesis of L-I-6 Referring to Example 2, 4-tolueneboric acid was replaced with 4-biphenylboric acid.

[0039] Step 1: Synthesis of I-6-1 I-3 (0.2 g, 0.772 mmol), 4-biphenylboronic acid (0.168 g, 0.849 mmol), potassium carbonate (0.32 g, 2.32 mmol), and PdCl2(dppf) (57 mg, 0.077 mmol) were placed in a three-necked flask, evacuated, and purged with N2. After dissolving 1,4-dioxane in the solution, the reaction mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 1:1) to give 0.21 g of a white solid, in 82% yield. mp 188.3–188.9 °C. 1 H NMR (500 MHz, CDCl3) δ 7.71 – 7.64 (m, 4H), 7.64 – 7.60 (m, 2H), 7.49 – 7.44 (m, 2H), 7.40 – 7.36 (m, 1H), 7.30 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 7.0, 2.0 Hz, 1H), 4.69 (s, 2H), 4.27 (q, J =7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd for C 21 H 20 NO3 + [M+H] + : 334.1438, found 334.1437.

[0040] Step 2: Synthesis of I-6-2 I-6-1 (0.21 g, 0.631 mmol) and LiOH·H₂O (0.08 g, 1.890 mmol) were added to a THF / H₂O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered, and the filter cake was washed with water, dried, and used to obtain 0.181 g of a white solid, with a yield of 94%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 7.84 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.77– 7.72 (m, 3H), 7.50 (t, J = 8.0 Hz, 2H), 7.43 – 7.38 (m, 1H), 6.76 (d, J =2.0 Hz, 1H), 6.68 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H). HRMS(ESI): m / zcalcd for C 19 H 16 NO3 + [M+H] + : 306.1125, found 306.1114.

[0041] Step 3: Synthesis of L-I-6 I-6-2 (0.1 g, 0.328 mmol), 1-4 (0.068 g, 0.328 mmol), HOBT (0.049 g, 0.361 mmol), EDCI (0.069 g, 0.361 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 80 mg of white solid, yield 49%. mp >250℃. HRMS(ESI): m / z calcd for C 24 H 22 N4NaO4S2 + [M+Na] + :517.0975, found 517.0970.

[0042] Example 7. Synthesis of L-I-7 Referring to Example 2, 4-tolueneboronic acid was replaced with phenylboronic acid.

[0043] Step 1: Synthesis of I-7-1 I-3 (0.540 g, 2.09 mmol), phenylboronic acid (0.280 g, 2.3 mmol), potassium carbonate (0.864 g, 6.26 mmol), and PdCl2(dppf) (0.15 g, 0.209 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.508 g of a white solid, 95% yield. mp 80.9–82.0 °C. 1 HNMR (500 MHz, CDCl3) δ 7.59 – 7.55 (m, 2H), 7.45 (m, 3H), 7.28 (d, J = 7.0Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 7.0, 2.0 Hz, 1H), 4.68 (s,2H), 4.26 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcdfor C 15 H 16 NO3 + [M+H] + : 258.1125, found 258.1124.

[0044] Step 2: Synthesis of I-7-2 I-7-1 (0.127 g, 0.496 mmol) and LiOH·H2O (62.5 mg, 1.489 mmol) were added to a THF / H2O mixture. The mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered. The filter cake was washed with water, dried, and used to obtain 100 mg of white solid, with a yield of 88%. mp >250℃. 1 H NMR (600 MHz, DMSO-) d 6) δ 13.02 (s, 1H), 7.76 – 7.73 (m, 2H), 7.72 (d, J = 1.2 Hz,1H), 7.52 – 7.45 (m, 3H), 6.69 (d, J = 1.8 Hz, 1H), 6.61 (dd, J = 6.6, 1.8Hz, 1H), 4.64 (s, 2H). HRMS(ESI): m / z calcd for C 13 H 12 NO3 + [M+H] + : 230.0812, found 230.0821.

[0045] Step 3: Synthesis of L-I-7 I-7-2 (84.5 mg, 0.369 mmol), 1-4 (76 mg, 0.369 mmol), HOBT (75 mg, 0.554 mmol), EDCI (106 mg, 0.554 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 108 mg of white solid, yield 70%. mp 237.7–238.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.76 (dd, J = 8.0, 2.0 Hz, 2H), 7.72 (d, J = 7.0 Hz, 1H), 7.70 (s, 2H), 7.54 – 7.47 (m, 3H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 7.0, 2.0 Hz, 1H), 5.25 (s, 2H), 3.75(s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ 168.1, 161.5, 158.1,151.4, 148.2, 139.8, 136.7, 129.7, 129.1, 128.5, 126.7, 115.2, 104.5, 50.2,33.4, 16.1. HRMS(ESI): m / z calcd for C 18 H 19 N4O4S2 + [M+H] + : 419.0843, found419.0834.

[0046] Example 8. Synthesis of L-I-8 Referring to Example 2, 4-tolueneboronic acid was replaced with 4-fluorophenylboronic acid.

[0047] Step 1: Synthesis of I-8-1 I-3 (0.224 g, 0.863 mmol), 4-fluorophenylboronic acid (0.133 g, 0.950 mmol), potassium carbonate (0.358 g, 2.59 mmol), and PdCl2(dppf) (0.063 g, 0.086 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.19 g of a white solid, in 80% yield. mp 139.3–140.0 °C. 1 H NMR (500 MHz, CDCl3) δ 7.59 – 7.55 (m, 2H), 7.45 (m, 3H), 7.28 (d, J =7.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 7.0, 2.0 Hz, 1H), 4.68(s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / zcalcd for C 15 H 15 FNO3 + [M+H] + : 276.1031, found 276.1033.

[0048] Step 2: Synthesis of I-8-2 I-8-1 (0.188 g, 0.683 mmol) and LiOH·H2O (86 mg, 2.050 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered, and the filter cake was washed with water, dried, and used to obtain 0.135 g of a white solid, with a yield of 80%. mp 225.3-226.1 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.03 (s, 1H), 7.86 – 7.77 (m, 2H), 7.74 (d, J =7.5 Hz, 1H), 7.32 (t, J = 8.5 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 6.61 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H). HRMS(ESI): m / z calcd for C 13 H 11 FNO3 + [M+H] + :248.0718, found 248.0719.

[0049] Step 3: Synthesis of L-I-8 I-8-2 (0.129 g, 0.524 mmol), 1-4 (0.108 g, 0.524 mmol), HOBT (0.106 g, 0.786 mmol), EDCI (0.151 g, 0.786 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 112 mg of white solid, yield 49%. mp >250 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.84 (dd, J = 8.5, 5.5 Hz, 2H), 7.72 (d, J= 7.0 Hz, 1H), 7.70 (s, 2H), 7.34 (t, J = 8.5 Hz, 2H), 6.75 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 7.0, 2.0 Hz, 1H), 5.24 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125MHz, DMSO- d 6 ) δ 168.1, 163.0 (d, J =246.2 Hz), 161.5, 158.1, 150.3, 148.2, 139.8, 133.1 (d, J = 3.8 Hz), 129.1(d, J = 8.8 Hz), 128.5, 116.0 (d, J = 22.5 Hz), 115.1, 104.3, 50.2, 33.4,16.1. HRMS(ESI): m / z calcd for C 18 H 18 FN4O4S2 + [M+H] + : 437.0748, found 437.0738.

[0050] Example 9. Synthesis of L-I-9 Referring to Example 2, 4-tolueneboronic acid was replaced with (2-methoxy-3-pyridyl)boronic acid.

[0051] Step 1: Synthesis of I-9-1 I-3 (0.217 g, 0.839 mmol), (2-methoxy-3-pyridyl)boronic acid (0.141 g, 0.923 mmol), potassium carbonate (0.348 g, 2.518 mmol), and PdCl2(dppf) (61 mg, 0.084 mmol) were placed in a three-necked flask, evacuated, and purged with nitrogen. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 4:3) to give 191 mg of an orange oil, with a yield of 79%. 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, J = 5.0, 2.0 Hz, 1H), 7.63 (dd, J =7.5, 2.0 Hz, 1H), 7.22 (dd, J = 7.0, 0.5 Hz, 1H), 6.97 (dd, J = 7.5, 5.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 7.0, 2.0 Hz, 1H), 4.66 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.97 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI):m / z calcd for C 15 H 17 N2O4 + [M+H] + :289.1183, found 289.1188.

[0052] Step 2: Synthesis of I-9-2 I-9-1 (175 mg, 0.607 mmol) and LiOH·H2O (76.5 mg, 1.82 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, the pH was adjusted to 1-2 with hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water, dried, and used to obtain 101 mg of brown solid, with a yield of 64%. mp 229.7-230.6 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.04 (s, 1H), 8.24 (dd, J = 5.0, 2.0 Hz, 1H), 7.84 (dd, J = 7.5, 2.0 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.11 (dd, J = 7.5, 5.0 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.47 (dd,J = 7.0, 2.0 Hz, 1H), 4.63(s, 2H), 3.91 (s, 3H). HRMS(ESI): m / z calcd for C 13 H 13 N2O4 + [M+H] + : 261.0870 ,found 261.0865.

[0053] Step 3: Synthesis of L-I-9 I-9-2 (85.5 mg, 0.329 mmol), 1-4 (68 mg, 0.329 mmol), HOBT (67 mg, 0.493 mmol), and EDCI (95 mg, 0.493 mmol) were dissolved in anhydrous DMF and reacted overnight at room temperature. After the reaction was complete, water was added dropwise to the reaction system, and a solid precipitated. The solid was filtered, dried, recrystallized from acetonitrile, and washed to give 44.3 mg of a light brown solid (30% yield). mp 243.0–244.0 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.29 – 8.23(dd, J =5.0, 1.5Hz, 1H), 7.91 – 7.85 (dd, J =7.5, 2.0Hz, 1H), 7.70 (s, 2H),7.66 (d, J = 7.5 Hz, 1H), 7.13 (dd, J = 7.5, 5.0 Hz, 1H), 6.68 – 6.63 (d, J =2.0Hz, 1H), 6.57 – 6.51 (dd, J =7.5, 2.0Hz, 1H), 5.24 (s, 2H), 3.93 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ 168.1, 161.3, 160.1,158.1, 148.4, 148.2, 147.6, 138.8, 138.7, 128.5, 120.6, 118.4, 117.5, 106.6,53.5, 50.3, 33.4, 16.1. HRMS(ESI): m / z calcd for C 18 H 20 N5O5S2 + [M+H] + : 450.0901,found 450.0901.

[0054] Example 10. Synthesis of L-I-10 Referring to Example 2, 4-tolueneboronic acid was replaced with 3,4-methylenephenylboronic acid.

[0055] Step 1: Synthesis of I-10-1 I-3 (0.2 g, 0.772 mmol), 3,4-methylenephenylboronic acid (0.142 g, 0.850 mmol), potassium carbonate (0.32 g, 3.32 mmol), and PdCl2(dppf) (0.056 g, 0.077 mmol) were placed in a three-necked flask, evacuated, and purged with nitrogen. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was complete as monitored by TLC, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:3) to give 0.196 g of a white solid, in 84% yield. mp 146.6–147.3 °C. 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 7.5 Hz, 1H), 7.09 (dd, J = 8.1, 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 7.0, 2.0 Hz, 1H), 6.02 (s, 2H), 4.66(s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.30 (t, J= 7.1 Hz, 3H). HRMS(ESI): m / zcalcd for C 16 H 16 NO5 + [M+H] + : 302.1023, found 302.1020.

[0056] Step 2: Synthesis of I-10-2 I-10-1 (0.196 g, 0.651 mmol) and LiOH·H2O (82 mg, 1.95 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, the pH was adjusted to 1-2 with hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water, dried, and used to obtain 0.145 g of a white solid, with a yield of 81%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 13.00 (s, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.34 (d, J =2.0 Hz, 1H), 7.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.63(d, J = 2.0 Hz, 1H), 6.57 (dd, J = 7.0, 2.0 Hz, 1H), 6.09 (s, 2H), 4.62 (s,2H). HRMS(ESI): m / z calcd for C 14 H 12 NO5 + [M+H] + : 274.0710, found 274.0707.

[0057] Step 3: Synthesis of L-I-10 I-10-2 (85 mg, 0.311 mmol), I-4 (64.5 mg, 0.311 mmol), HOBT (63 mg, 0.467 mmol), EDCI (90 mg, 0.467 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 91 mg of white solid, yield 63%. mp 244.4–245.2 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.70 (s, 2H), 7.67 (d, J = 7.0 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 7.0,2.0 Hz, 1H), 6.11 (s, 2H), 5.22 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO-) d 6 ) δ 168.1, 161.6, 158.1, 150.9, 148.6, 148.2, 148.1, 139.4,130.6, 128.5, 121.1, 114.3, 108.7, 106.9, 104.3, 101.6, 50.1, 33.4, 16.1.HRMS(ESI): m / z calcd for C 19 H 19 N4O6S2 + [M+H] + : 463.0741, found 463.0740.

[0058] Example 11. Synthesis of L-I-11 Referring to Example 2, 4-tolueneboronic acid was replaced with 4-chlorophenylboronic acid.

[0059] Step 1: Synthesis of I-11-1 I-3 (0.201 g, 0.776 mmol), 4-chlorophenylboronic acid (0.133 g, 0.854 mmol), potassium carbonate (0.321 g, 2.33 mmol), and PdCl2(dppf) (57 mg, 0.0776 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 0.201 g of a white solid, in 89% yield. mp 164.9–165.5 °C. 1 H NMR (500 MHz, CDCl3) δ 7.51 (dt, J = 8.5, 2.0 Hz, 2H), 7.42(dt, J = 8.5, 2.0 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.42(dd, J = 7.5, 2.0 Hz, 1H), 4.67 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd for C 15 H 15 ClNO3 + [M+H] + : 292.0735, found292.0735.

[0060] Step 2: Synthesis of I-11-2 I-11-1 (0.164 g, 0.563 mmol) and LiOH·H2O (71 mg, 1.69 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered. The filter cake was washed with water, dried, and used to obtain 0.123 g of a white solid, with a yield of 83%. mp >250 ℃. 1 HNMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 7.77-7.74 (m, 3H), 7.54 (d, J = 8.5Hz, 2H), 6.71 (d, J = 2.0 Hz, 1H), 6.61 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s,2H). HRMS(ESI): m / z calcd for C 13 H 11 ClNO3 + [M+H] + : 264.0422, found 264.0416.

[0061] Step 3: Synthesis of L-I-11 I-11-2 (89.5 mg, 0.340 mmol), 1-4 (70.5 mg, 0.340 mmol), HOBT (69 mg, 0.510 mmol), EDCI (98 mg, 0.510 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 60 mg of white solid, yield 39%. mp 249.4–250.0 °C. 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.80 (dt, J = 8.4, 2.4 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.69 (s, 2H), 7.57 (dt, J = 8.4, 2.4Hz, 2H), 6.77 (d, J = 1.8 Hz, 1H), 6.68 (dd, J = 7.2, 1.8 Hz, 1H), 5.24 (s, 2H), 3.74 (s, 3H), 2.49 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) δ 168.1, 161.5,158.1, 150.1, 148.2, 139.9, 135.5, 134.5, 129.1, 128.6, 128.5, 115.4, 104.2,50.3, 33.4, 16.1. HRMS(ESI): m / z calcd for C 18 H 18 ClN4O4S2 + [M+H] + : 453.0453,found 453.0459.

[0062] Example 12. Synthesis of L-I-12 Referring to Example 2, 4-tolueneboronic acid was replaced with 4-trifluoromethylphenylboronic acid.

[0063] Step 1: Synthesis of I-12-1 I-3 (0.229 g, 0.885 mmol), 4-trifluoromethylphenylboronic acid (0.185 g, 0.974 mmol), potassium carbonate (0.366 g, 2.66 mmol), and PdCl2(dppf) (65 mg, 0.0885 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was complete as monitored by TLC, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 0.282 g of a white solid, 98% yield. mp 211.3–211.8 ℃. 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 7.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.45 (dd, J = 7.0, 2.0 Hz, 1H), 4.69 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 1.31 (t, J =7.0 Hz, 3H). HRMS(ESI): m / z calcd for C 16 H 15 F3NO3+ [M+H] + : 326.0999, found326.1006.

[0064] Step 2: Synthesis of I-12-2 I-12-1 (0.224 g, 0.689 mmol) and LiOH·H2O (87 mg, 2.07 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered, and the filter cake was washed with water, dried, and used to obtain 0.171 g of a light brown solid, with a yield of 83%. mp 210.4-211.0℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.95 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 7.0 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 7.0,2.0 Hz, 1H), 4.65 (s, 2H). HRMS(ESI): m / z calcd for C 14 H 11 F3NO3 + [M+H] + :298.0686, found 298.0686.

[0065] Step 3: Synthesis of L-I-12 I-12-2 (60 mg, 0.202 mmol), 1-4 (42 mg, 0.202 mmol), HOBT (41 mg, 0.303 mmol), EDCI (58 mg, 0.303 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 28 mg of a white solid, yield 28%. mp 243.1–243.7 °C. 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.98 (d, J= 7.8 Hz, 2H), 7.87 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.2 Hz, 1H), 7.69 (s, 2H), 6.84(d, J = 2.4 Hz, 1H), 6.73 (dd, J = 7.2, 2.4 Hz, 1H), 5.26 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.0, 161.4, 158.1, 150.0,148.2, 140.8, 140.2, 129.7 (d, J = 31.2 Hz), 128.6, 127.7, 125.9 (q, J = 3.8Hz), 124.1 (d, J = 271.2 Hz), 116.3, 104.3, 50.3, 33.4, 16.1. HRMS(ESI): m / zcalcd for C 19 H 18 F3N4O4S2 + [M+H] + :487.0717, found 487.0713.

[0066] Example 13. Synthesis of L-I-13 Referring to Example 2, 4-tolueneboronic acid was replaced with 3-methoxyphenylboronic acid.

[0067] Step 1: Synthesis of I-13-1 I-3 (0.2 g, 0.772 mmol), 3-methoxyphenylboronic acid (0.129 g, 0.849 mmol), potassium carbonate (0.32 g, 2.32 mmol), and PdCl2(dppf) (56 mg, 0.0772 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to obtain 0.144 g of a reddish-brown oily substance, with a yield of 65%. 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.15(ddd, J = 7.5, 1.5, 1.0 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.97 (ddd, J =8.5, 2.5, 1.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 7.0, 2.0 Hz,1H), 4.67 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 1.30 (t, J = 7.0Hz, 3H). HRMS(ESI): m / z calcd for C 16 H 18 NO4 + [M+H] + : 288.1231, found 288.1239.

[0068] Step 2: Synthesis of I-13-2 I-13-1 (0.135 g, 0.522 mmol) and LiOH·H2O (66 mg, 1.56 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 0.1 g of a light brown solid, with a yield of 74%. mp 240.5-241.5 ℃. 1 H NMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.33 – 7.19 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 6.71 (s, 1H), 6.61 (d, J= 7.0 Hz, 1H), 4.64 (s, 2H), 3.83 (s, 3H). HRMS(ESI): m / z calcdfor C 14 H 14 NO4 + [M+H] + : 260.0918, found 260.0910.

[0069] Step 3: Synthesis of L-I-13 I-13-2 (66 mg, 0.255 mmol), 1-4 (52 mg, 0.255 mmol), HOBT (52 mg, 0.382 mmol), EDCI (73 mg, 0.382 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 24.5 mg of white solid, yield 21%. mp 239.6–240.7 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.72 (s, 1H),7.69 (s, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.28 -7.22 (m,1H), 7.05 (d, J = 8.5 Hz, 1H), 6.77 (s, 1H), 6.69 (d, J = 7.0 Hz, 1H), 5.24(s, 2H), 3.84 (s, 3H), 3.75 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.1,161.5, 159.7, 151.3, 148.2, 139.7, 138.2, 130.2, 128.5, 119.0, 115.5, 115.4,112.0, 104.6, 55.3, 50.2, 33.4, 16.1. HRMS(ESI): m / z calcd for C 19 H 21 N4O5S2 + [M+H] + : 449.0948, found 449.0944.

[0070] Example 14. Synthesis of L-I-14 Referring to Example 2, 4-tolueneboronic acid was replaced with 2-chlorophenylboronic acid.

[0071] Step 1: Synthesis of I-14-1 I-3 (0.2 g, 0.774 mmol), 2-chlorophenylboronic acid (0.133 g, 0.852 mmol), potassium carbonate (0.32 g, 2.32 mmol), and PdCl2(dppf) (57 mg, 0.0774 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.187 g of a white solid, in 83% yield. mp 82.3–83.0 °C. 1 H NMR (500 MHz, CDCl3) δ 7.48 – 7.44 (m, 1H), 7.36 – 7.31 (m, 3H), 7.25 (d, J = 7.0 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H), 6.35 (dd, J = 7.0, 2.0 Hz, 1H), 4.69(s, 2H), 4.27 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / zcalcd for C 15 H 15 ClNO3 + [M+H] + : 292.0735, found 292.0741.

[0072] Step 2: Synthesis of I-14-2 I-14-1 (0.108 g, 0.370 mmol) and LiOH·H2O (47 mg, 1.11 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, the pH was adjusted to 1-2 with hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water, dried, and used to give 76 mg of white solid, with a yield of 78%. mp 218.8-219.8 ℃.1 H NMR (500 MHz, DMSO- d 6 ) δ 13.06 (s, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.61 –7.54 (m, 1H), 7.48-7.45 (m, 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.33 (dd, J = 7.0,2.0 Hz, 1H), 4.66 (s, 2H). HRMS(ESI): m / z calcd for C 13 H 11 ClNO3 + [M+H] + :264.0422, found 264.0413.

[0073] Step 3: Synthesis of L-I-14 I-14-2 (43 mg, 0.163 mmol), 1-4 (34 mg, 0.163 mmol), EDCI (47 mg, 0.245 mmol), HOBT (33 mg, 0.245 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. The crude product was filtered and recrystallized from acetonitrile upon heating to give 47.5 mg of a white solid, yield 64%. mp 222.0–223.0 °C. 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.71 (s, 1H), 7.70 (s, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.48-7.45 (m, 3H), 6.47 (s, 1H), 6.40 (d, J = 6.6 Hz, 1H), 5.26 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) δ 168.0, 161.1, 158.1, 150.8, 148.2, 139.2, 137.0, 130.7, 130.5,130.1, 128.6, 127.7, 118.9, 118.1, 107.0, 50.4, 33.4, 16.1. HRMS(ESI): m / zcalcd for C 18 H 18 ClN4O4S2 + [M+H] + : 453.0453, found 453.0446.

[0074] Example 15. Synthesis of L-I-15 Referring to Example 2, 4-tolueneboronic acid was replaced with 3-furanboronic acid.

[0075] Step 1: Synthesis of I-15-1 I-3 (0.122 g, 0.471 mmol), 3-furanboronic acid (58 mg, 0.518 mmol), potassium carbonate (0.195 g, 1.41 mmol), and PdCl2(dppf) (34 mg, 0.047 mmol) were placed in a three-necked flask, evacuated, and purged with nitrogen. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 57 mg of a white solid, in 49% yield. mp 119.7–120.4 °C. 1 H NMR (500 MHz, CDCl3) δ 7.80 (t, J = 1.5 Hz, 1H), 7.49 (t, J = 1.5 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.66 (q, J = 1.0 Hz, 1H), 6.33 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd for C13 H 14 NO4 + [M+H] + : 248.0918, found 248.0911.

[0076] Step 2: Synthesis of I-15-2 I-15-1 (51 mg, 0.206 mmol) and LiOH·H2O (26 mg, 0.619 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 30 mg of a white solid, with a yield of 67%. mp >250 ℃. 1 H NMR (600 MHz, DMSO-) d 6 ) δ 12.97 (s, 1H), 8.37 (s, 1H), 7.79 (t, J = 1.8Hz, 1H), 7.65 (d, J = 6.6 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.55 (dd, J = 7.2, 1.8 Hz, 1H), 4.59 (s, 2H). HRMS(ESI): m / z calcd forC 11 H 10 NO4 + [M+H] + : 220.0605, found 220.0609.

[0077] Step 3: Synthesis of L-I-15 I-15-2 (18 mg, 0.082 mmol), 1-4 (18 mg, 0.082 mmol), EDCI (24 mg, 0.123 mmol), HOBT (17 mg, 0.123 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. The crude product was filtered and recrystallized from acetonitrile upon heating to give 9.1 mg of a white solid, yield 27%. mp 237.3–237.8 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 8.40 (t, J = 1.2 Hz, 1H), 7.81 (t, J = 1.8 Hz, 1H), 7.69 (s, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.06 (dd, J = 1.8, 0.6 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.62 (dd, J = 7.2, 1.8Hz, 1H), 5.19 (s, 2H), 3.73 (s, 3H), 2.49 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6 )δ 168.6, 162.1, 158.6, 148.7, 145.5, 144.0, 143.1, 140.0, 129.0, 123.9,113.9, 108.9, 104.2, 50.6, 33.8, 16.6. HRMS(ESI): m / z calcd for C 16 H 17 N4O5S2 + [M+H] + : 409.0635, found 409.0626.

[0078] Example 16. Synthesis of L-I-16 Referring to Example 2, 4-tolueneboronic acid was replaced with 2-furanboronic acid.

[0079] Step 1: Synthesis of I-16-1 I-3 (0.119 g, 0.461 mmol), 2-furanboronic acid (57 mg, 0.507 mmol), potassium carbonate (0.191 g, 1.38 mmol), and PdCl2(dppf) (34 mg, 0.046 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 61.5 mg of a white solid, in 54% yield. mp 145.6–146.3 °C. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 1.5 Hz, 1H), 7.21 (d, J = 7.0Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 6.51 (dd, J =3.5, 1.5 Hz, 1H), 6.49 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H), 4.24 (q, J =7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd for C 13 H 14 NO4 + [M+H] + : 248.0918, found 248.0918.

[0080] Step 2: Synthesis of I-16-2 I-16-1 (54 mg, 0.219 mmol) and LiOH·H2O (28 mg, 0.658 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to obtain 36 mg of a pale yellow solid, with a yield of 75%. mp >250 ℃. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 12.98 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.69 (d, J =7.0 Hz, 1H), 7.25 (d, J = 3.5 Hz, 1H), 6.68 (dd, J = 3.5, 1.5 Hz, 1H), 6.63(d, J = 2.0 Hz, 1H), 6.61 (dd, J= 7.0, 2.0 Hz, 1H), 4.60 (s, 2H). HRMS(ESI):m / z calcd for C 11 H 10 NO4 + [M+H] + : 220.0604, found 220.0604.

[0081] Step 3: Synthesis of L-I-16 I-16-2 (31 mg, 0.142 mmol), 1-4 (29 mg, 0.142 mmol), HOBT (29 mg, 0.213 mmol), EDCI (41 mg, 0.213 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 37.6 mg of a pale yellow solid, yield 65%. mp 242.4–243.1 °C. 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.91 (d, J =1.8 Hz, 1H), 7.69 (s, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 3.6, 1.8 Hz, 1H), 6.68-6.66 (m, 3H), 5.20 (s, 2H), 3.73(s, 3H), 2.49 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6 ) δ 168.1, 161.4, 158.1,149.9, 148.2, 145.5, 140.5, 140.1, 128.5, 112.7, 111.5, 110.5, 101.4, 50.2,33.4, 16.1. HRMS(ESI): m / z calcd for C 16 H 17 N4O5S2 + [M+H] + : 409.0635, found409.0630.

[0082] Example 17. Synthesis of L-I-17 Referring to Example 2, 4-tolueneboronic acid was replaced with 3-fluorophenylboronic acid.

[0083] Step 1: Synthesis of I-17-1 I-3 (0.2 g, 0.770 mmol), 3-fluorophenylboronic acid (0.119 g, 0.847 mmol), potassium carbonate (0.319 g, 2.31 mmol), and PdCl2(dppf) (56 mg, 0.077 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to give 0.125 g of a colorless oil, with a yield of 59%. 1 H NMR (500MHz, CDCl3) δ 7.44 - 7.40 (m, 1H), 7.35 (dt, J = 8.0, 1.5 Hz, 1H), 7.29 (d, J = 7.0 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.12 (tdd, J = 8.5, 2.5, 1.0 Hz, 1H),6.78 (d, J = 2.5 Hz, 1H), 6.43 (dd, J = 7.0, 2.0 Hz, 1H), 4.68 (s, 2H), 4.26(q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / z calcd forC 15 H 15 FNO3 + [M+H] + : 276.1031, found 276.1035.

[0084] Step 2: Synthesis of I-17-2 I-17-1 (0.125 g, 0.455 mmol) and LiOH·H2O (57 mg, 1.36 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, the mixture was dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, which was filtered, and the filter cake was washed with water, dried, and used to obtain 0.1 g of a white solid, with a yield of 89%. mp 250.5-250.9 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.05 (s, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.65 –7.57 (m, 2H), 7.53 (td, J = 8.0, 6.0 Hz, 1H), 7.31 (td, J = 8.0, 2.5 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 7.0, 2.0 Hz, 1H), 4.64 (s, 2H). HRMS(ESI): m / z calcd for C 13 H 11 FNO3 + [M+H] + : 248.0718, found 248.0723.

[0085] Step 3: Synthesis of L-I-17 I-17-2 (82 mg, 0.331 mmol), 1-4 (68.5 mg, 0.331 mmol), HOBT (67 mg, 0.496 mmol), EDCI (95 mg, 0.496 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 101 mg of white solid, yield 70%. mp 245.9–246.5 °C. 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.74 (d, J =7.2 Hz, 1H), 7.70 (s, 2H), 7.67 – 7.62 (m, 2H), 7.56 (td, J= 7.8, 1.8 Hz, 1H), 7.33 (td, J = 8.4, 2.4 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H)(15), 6.72 (dd, J = 7.2, 1.8 Hz, 1H)(17), 5.25 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (150 MHz, DMSO-) d 6 ) δ 168.0, 162.6 (d, J = 243 Hz), 161.5, 158.1, 150.0,148.2, 139.9, 139.1(d, J = 7.5 Hz), 131.1 (d, J = 9.0 Hz), 128.6, 122.9 (d, J = 3.0 Hz), 116.4 (d, J = 21.0 Hz), 115.7, 113.7 (d, J = 22.5 Hz), 104.3, 50.3,33.4, 16.1. HRMS(ESI): m / z calcd for C 18 H 18 FN4O4S2 + [M+H] + : 437.0748, found437.0752.

[0086] Example 18. Synthesis of L-I-18 Referring to Example 2, 4-tolueneboronic acid was replaced with 2-fluorophenylboronic acid.

[0087] Step 1: Synthesis of I-18-1 I-3 (0.2 g, 0.769 mmol), 2-fluorophenylboronic acid (0.118 g, 0.846 mmol), potassium carbonate (0.318 g, 2.31 mmol), and PdCl2(dppf) (56 mg, 0.077 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the precipitate, and the system was heated to reflux. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.203 g of a colorless oil, with a yield of 96%. 1 H NMR (500MHz, CDCl3) δ 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.22 (td, J = 7.5, 1.5 Hz, 1H), 7.15 (ddd, J = 11.0, 8.5, 1.0Hz, 1H), 6.78 – 6.73 (t, J = 1.0Hz, 1H), 6.45 (dt, J = 7.5, 2.0 Hz, 1H), 4.67(s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). HRMS(ESI): m / zcalcd for C 15 H 15 FNO3 + [M+H] + : 276.1030, found 276.1034.

[0088] Step 2: Synthesis of I-18-2 I-18-1 (0.181 g, 0.658 mmol) and LiOH·H2O (83 mg, 1.97 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the solvent was evaporated, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with water, dried, and used to give 0.132 g of a white solid, with a yield of 82%. mp 235.4-236.2 ℃. 1 H NMR (600 MHz, DMSO- d 6) δ 13.05 (s, 1H), 7.74 (d, J = 6.6 Hz, 1H), 7.60 (td, J = 7.8, 1.8 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.37 – 7.31 (m, 2H), 6.57 (t, J =1.8 Hz, 1H), 6.45 (dt, J = 7.2, 1.8 Hz, 1H), 4.65 (s, 2H). HRMS(ESI): m / zcalcd for C 13 H 10 FNO3 + [M+H] + : 248.0718, found 248.0720.

[0089] Step 3: Synthesis of L-I-18 I-18-2 (0.12 g, 0.486 mmol), 1-4 (0.1 g, 0.486 mmol), HOBT (0.098 g, 0.729 mmol), EDCI (0.14 g, 0.729 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 0.167 g of white solid, yield 79%. mp 201.3–202.2 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.72 (d, J =7.0 Hz, 1H), 7.70 (s, 2H), 7.63 (td, J = 8.0, 2.0 Hz, 1H), 7.55 – 7.50 (m,1H), 7.40 – 7.32 (m, 2H), 6.63 (s, 1H), 6.53 (dt, J = 7.0, 2.0Hz, 1H), 5.26(s, 2H), 3.75 (s, 3H), 2.50 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.0,161.2, 159.2 (d, J= 246.2 Hz), 158.1, 148.2, 147.1, 139.5, 131.5(d, J = 7.5Hz), 130.2(d, J = 2.5 Hz), 128.6, 125.2 (q, J = 3.8 Hz), 118.3, 116.4 (d, J =21.2 Hz), 106.2, 50.4, 33.4 16.1. HRMS(ESI): m / z calcd for C 18 H 18 FN4O4S2 + [M+H] + : 437.0748, found 437.0738.

[0090] Example 19. Synthesis of L-II-1 .

[0091] Step 1: Synthesis of II-2 Ethyl p-bromophenylacetate (60 mg, 0.248 mmol), pinacol diboronate (77 mg, 0.303 mmol), potassium acetate (70 mg, 0.714 mmol), and PdCl2 (dppf) (6 mg, 0.008 mmol) were placed in a three-necked flask, evacuated, and purged with nitrogen. Anhydrous 1,4-dioxane was added to dissolve the ester, and the system was heated to 85 °C. The reaction was monitored by TLC and LC-MS until completion. The reaction system was then allowed to return to room temperature, filtered through diatomaceous earth, and evaporated to dryness. The crude product was subjected to rapid column chromatography (PE:EA = 20:1), and the two solutions were combined and evaporated to dryness to obtain a colorless, transparent liquid, II-2, which was used directly in the next step.

[0092] Step 2: Synthesis of II-1-1 I-2 (50 mg, 0.289 mmol) and 60% NaH (20 mg, 0.5 mmol) were dissolved in THF. CH3I (80 μL, 1.28 mmol) was added dropwise to the reaction system under ice bath conditions, and the reaction was slowly brought to room temperature. After the reaction was completed by TLC monitoring, water was added dropwise to quench the reaction under ice bath conditions. The mixture was extracted twice with EA, and the combined organic phases were evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 45 mg of a white solid, with a yield of 82%. mp 91.8–92.4 ℃. 1 H NMR (500 MHz, CDCl3) δ 7.13(d, J = 7.0 Hz, 1H), 6.81 (d,J = 2.0 Hz, 1H), 6.31 (dd, J = 7.0, 2.0 Hz,1H), 3.49 (s, 3H). HRMS(ESI): m / z calcd for C6H7BrNO + [M+H] + :187.9706, found187.9715.

[0093] Step 3: Synthesis of II-1-2 II-2 (75 mg, 0.259 mmol), II-1-1 (45 mg, 0.285 mmol), PdCl2(dppf) (9 mg, 0.012 mmol), and potassium carbonate (105 mg, 0.761 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the solids, and the mixture was heated to reflux. After the reaction was completed by TLC and LC-MS monitoring, the reaction system was cooled to room temperature, and the insoluble solids were removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 2:5) to give 51 mg of a brown oily substance, with a yield of 65%. 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33(d, J = 7.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.42 (dd, J = 7.0, 2.0 Hz, 1H), 4.16 (q, J = 7.5 Hz, 2H), 3.65 (s, 2H), 3.57 (s, 3H), 1.26 (t, J = 7.5Hz, 3H). HRMS(ESI): m / z calcd for C 16 H 18 NO3 + [M+H] + : 272.1281, found 272.1273.

[0094] Step 4: Synthesis of II-1-3 II-1-2 (51 mg, 0.188 mmol) and LiOH·H2O (24 mg, 0.565 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the mixture was evaporated to dryness, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with a small amount of water and dried to give 35 mg of a white solid, with a yield of 76%. mp 232.7-233.3℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.40 (s, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.66(d, J = 7.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H), 6.66 (s, 1H), 6.56 (d, J = 7.0Hz, 1H), 3.63 (s, 2H), 3.44 (s, 3H). HRMS(ESI): m / z calcd for C 14 H 14 NO3 + [M+H] + :244.0969, found 244.0978.

[0095] Step 5: Synthesis of L-II-1 II-1-3 (35 mg, 0.144 mmol), 1-4 (30 mg, 0.144 mmol), HOBT (21 mg, 0.158 mmol), EDCI (30 mg, 0.158 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 43.2 mg of white solid, yield 70%. mp 249.7–250.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.77 (d, J =7.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.65 (s, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.68 (d, J= 2.0 Hz, 1H), 6.58 (dd, J = 7.0, 2.0 Hz, 1H), 4.22 (s, 2H), 3.70 (s, 3H), 3.45 (s, 3H), 2.47 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ 171.7,162.0, 158.4, 150.3, 148.1, 139.9, 135.6, 135.3, 130.4, 128.3, 126.6, 114.7,103.8, 36.4, 34.2, 16.1. HRMS(ESI): m / z calcd for C 19 H 21 N4O4S2 + [M+H] + : 433.0999, found 433.1005.

[0096] Example 20. Synthesis of L-II-2 .

[0097] Step 1: Synthesis of II-2-1 4-Bromopyridine-2(1 H 0.415 g (2.4 mmol) of ketone, 0.787 g (4.6 mmol) of benzyl bromide, and 0.988 g (7.2 mmol) of potassium carbonate were dissolved in acetonitrile. The reaction mixture was heated under reflux for 6 h. After the reaction was completed, the mixture was cooled to room temperature by TLC and LC-MS, filtered, and the filter cake was washed with acetonitrile. The filtrates were combined, evaporated to dryness, and purified by column chromatography (PE:EA = 3:1) to give 0.41 g of white solid, with a yield of 65%. mp 111.6–112.2 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.81(d, J = 7.2 Hz, 1H), 7.48-7.16 (m, 5H), 6.76 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 5.07 (s, 2H). HRMS(ESI): m / z calcd for C 12 H 11 BrNO +[M+H]+: 264.0024, found :264.0026.

[0098] Step 2: Synthesis of II-2-2 II-2 (0.354 g, 1.22 mmol), II-2-1 (0.352 g, 1.34 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), and potassium carbonate (0.5 g, 3.66 mmol) were placed in a three-necked flask, evacuated, and purged with N2. 1,4-dioxane was added to dissolve the solid, and the mixture was heated to reflux. The reaction was monitored by TLC and LC-MS until completion. The reaction system was cooled to room temperature, and the insoluble solids were removed by filtration. The filtrate was evaporated to dryness and purified by column chromatography (PE:EA = 5:2) to give 0.36 g of a white solid, in 85% yield. mp 82.2–82.7 °C. 1 H NMR (500 MHz, CDCl3) δ 7.55 – 7.51 (m, 2H), 7.39 – 7.35 (m, 3H), 7.35 –7.28 (m, 5H), 6.83 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 7.5, 2.0 Hz, 1H), 5.18(s, 2H), 4.16 (q, J = 7.0 Hz, 2H), 3.65 (s, 2H), 1.26 (t, J = 7.0 Hz, 3H).HRMS(ESI): m / z calcd for C 22 H 22 NO3 + [M+H] + : 348.1594, found 348.1593.

[0099] Step 3: Synthesis of II-2-3 II-2-2 (0.355 g, 1.02 mmol) and LiOH·H2O (0.129 g, 3.07 mmol) were added to a THF / H2O mixture, and the mixture was heated to reflux. After the reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness, dissolved in water, and the pH was adjusted to 1-2 with hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed with a small amount of water and dried to give 0.15 g of a white solid, with a yield of 46%. mp 172.3-173.2 ℃. 1 H NMR (500 MHz, DMSO- d 6) δ 12.41 (s, 1H), 7.86 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.35 – 7.26 (m, 5H), 6.71(d, J = 2.5 Hz, 1H), 6.61 (dd, J = 7.0, 2.5 Hz, 1H), 5.13 (s, 2H), 3.63 (s,2H). HRMS(ESI): m / z calcd for C 20 H 18 NO3 + [M+H] + : 320.1282, found 320.1278.

[0100] Step 4: Synthesis of L-II-2 II-2-3 (0.13 g, 0.407 mmol), 1-4 (84 mg, 0.407 mmol), HOBT (82 mg, 0.610 mmol), EDCI (0.117 g, 0.610 mmol), dissolved in anhydrous DMF, reacted overnight at room temperature. After the reaction was completed, water was added dropwise to the reaction system, and a solid precipitated. After filtration and drying, it was recrystallized from acetonitrile, filtered, and washed to give 0.124 g of white solid, yield 60%. mp 238.8-239.2 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.87 (d, J =7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.65 (s, 2H), 7.42 – 7.32 (m, 6H), 7.29 (s, 1H), 6.73 (s, 1H), 6.63 (d, J = 7.0 Hz, 1H), 5.13 (s, 2H), 4.22 (s, 2H), 3.70 (s, 3H), 2.48 (s, 3H). 13 C NMR (125 MHz, DMSO- d6) δ 171.7, 161.5,158.4, 150.5, 148.1, 139.1, 137.4, 135.8, 135.2, 130.4, 128.6, 128.3, 127.7,127.5, 126.7, 115.4, 104.4, 50.8, 34.3, 16.1. HRMS(ESI): m / z calcd forC 25 H 25 N4O4S2 + [M+H] + :509.1312, found 509.1302.

[0101] Example 21. Evaluation of the inhibitory effect of the compounds disclosed in this invention on HSV-1. 3×10 4 Vero E6 cells were seeded into 96-well plates with 100 μL of cell suspension in each well, and the plates were pre-cultured for 24 h (37 ℃, 5% CO2). 2 μM and 6 μM of the test compounds were added to the plates, with three replicates for each compound. A DMSO negative control and an ACV positive control were also included. Vero cells were infected with HSV-1-Luciferase virus at MOI=0.01. Luciferase activity of infected cells was measured 36 h after infection (37 ℃, 5% CO2) using a firefly luciferase assay kit (Yeasen Biotech 11401ES), and biofluorescence intensity was read using a ThermoScientific full-wavelength scanning multifunction reader. Data analysis was performed using GraphPad Prism 10 software. IC50 50 The method for determining the IC50 is the same as above, requiring at least five compound concentrations. Data were fitted with dose-dependent curves using GraphPad Prism 10 software to determine the IC50 value. 50 .

[0102] Table 1. Inhibition rate of some compounds of the present invention on Luc-HSV-1 The results showed that in the in vitro screening model of full-length Luc-HSV-1 virus, the pyridone-containing aminothiazole heterocyclic compounds of the present invention inhibited Luc-HSV-1 at a concentration of 6 μM with an inhibition rate of 73%-99%. Among them, compounds L-I-3, L-I-4, L-I-10, L-I-14, L-I-17, and L-I-18 achieved an inhibition rate of 81%-98% at a low concentration of 2 μM, which was superior to the positive control drug acyclovir (78%).

[0103] Table 2. Inhibition of Luc-HSV-1 IC50 by the pyridone-containing aminothiazole heterocyclic compound of the present invention 50 The IC50 of the pyridone-containing aminothiazole heterocyclic compounds LI-3, L-I-13, and L-I-14 described in this invention 50 Numerical values ​​and ACV IC 50 The values ​​are similar, but L-I-17 and L-I-18 are significantly better than ACV.

[0104] Example 22. Cytotoxicity evaluation of the compounds disclosed in this invention. 3×10 4 Vero E6 cells were seeded into 96-well plates with 100 μL of cell suspension in each well and cultured for 24 h (37 ℃, 5% CO2). The test compound was serially diluted to five concentrations: 100, 30, 10, 3, and 1 μM, with three replicates for each concentration. Each well contained DMEM medium with 10% fetal bovine serum and 1% (v / v) penicillin-streptomycin solution. After incubation for a period, 10 μL of CCK-8 (SolarbioCA1210) solution was added to each well, and the cells were incubated in the dark for another 1 h (37 ℃, 5% CO2). Cell viability was determined by reading the absorbance at 450 nm using a Thermo Scientific full-wavelength scanning multifunction reader.

[0105] Table 3. Toxicity of the compounds of the present invention against Vero E6 cells Examples 1-10, 13-20, and the results of acyclovir's cytotoxicity on Vero E6 cells are shown in Table 3. The cytotoxicity test results indicate that most of the compounds described in this invention have no significant cytotoxicity in Vero cells. 50 With a value greater than 100 μM, the target compounds have a wider therapeutic window compared to their antiviral activity. Among them, compounds L-I-3, L-I-10, L-I-13, L-I-14, L-I-17, and L-I-18 all have a selectivity index (SI) of over 100.

[0106] In summary, the pyridone-containing aminothiazole heterocyclic compounds of this invention can effectively inhibit the replication of herpes simplex virus in vitro, exhibiting a higher inhibition rate against HSV-1 than the positive control drug acyclovir, and some compounds show better inhibition at IC50. 50 It showed a lower IC50 than acyclovir in the test. 50The values ​​indicate that the compound's anti-HSV-1 activity is superior to acyclovir; simultaneously, most of the pyridone compounds described in this invention did not exhibit significant cytotoxicity at high concentrations (100 μM), indicating that the compounds have high selectivity and a wide therapeutic window. The novel pyridone-containing aminothiazole heterocyclic compounds disclosed in this invention show promising application prospects in the clinical treatment of herpes simplex virus.

[0107] For those skilled in the art, the apparatus and methods of the present invention are not limited to the details of the exemplary embodiments described above, and the technical solutions of the present invention can be implemented in other specific forms without departing from the purpose or essential characteristics of the present invention. Therefore, the embodiments should be considered as exemplary and non-limiting in all respects, and the scope of the present invention is defined by the appended claims rather than the foregoing description.

Claims

1. A pyridone-containing aminothiazole heterocyclic compound, characterized in that, Compounds having the structure shown in general formula I or general formula II, or a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof. in R1 is selected from halogens, benzene rings, substituted benzene rings, unsubstituted aromatic heterocycles, or substituted aromatic heterocycles; R2 is selected from C1~C4 alkanes or aromatic alkanes.

2. The pyridone-containing aminothiazole heterocyclic compound according to claim 1, characterized in that, R1 is preferably selected from one of the following structures: 。 3. The pyridone-containing aminothiazole heterocyclic compound according to claim 1, characterized in that, R2 is preferably derived from methyl or benzyl groups.

4. The pyridone-containing aminothiazole heterocyclic compound according to claim 1, characterized in that, The pharmaceutically acceptable isotope label is a form in which one or more atoms in the compound are replaced by its isotopic atom, wherein the isotopic atom is: deuterium ( 2 H) or tritium ( 3 H).

5. The pyridone-containing aminothiazole heterocyclic compound according to any one of claims 1 to 4, characterized in that, Selected from any of the following compounds: 2-(4-bromo-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-1). N -Methyl-2-(2-oxo-4-p-tolyl-1,2-dihydropyridin-1-yl)- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-2). 2-(4-(2,5-difluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-3). 2-(4-(3-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-4). 2-(4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-5). 2-(4-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-6). N -Methyl-2-(2-oxo-4-phenyl-1,2-dihydropyridin-1-yl)- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-7). 2-(4-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-8). 2-(2-methoxy-2'-oxo-[3,4'-bipyridine]-1'(2'H)-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-9). 2-(4-(benzo[d][1,3]dioxolane-5-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-10). 2-(4-(4-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-11). N -Methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridin-1-yl)- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-12). 2-(4-(3-methoxyphenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-13). 2-(4-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-14). 2-(4-(furan-3-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-15). 2-(4-(furan-2-yl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-16). 2-(4-(3-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-17). 2-(4-(2-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-I-18). N -Methyl-2-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-II-1). 2-(4-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)- N -methyl- N -(4-methyl-5-aminosulfonylthiazolyl-2-yl)acetamide (L-II-2).

6. The method for synthesizing the pyridone-containing aminothiazole heterocyclic compound according to any one of claims 1 to 5, characterized in that, This can be achieved through the following steps: Compound I-1 reacts with H₂SO₄ and NaNO₂ to give intermediate I-2. Intermediate I-2 then undergoes a substitution reaction with ethyl bromoacetate in the presence of K₂CO₃ to give intermediate I-3. ； Compound II-1 undergoes a Suzuki coupling reaction with pinacol diboronic acid ester in the presence of KOAc and PdCl2(dppf) to give intermediate II-2. ； Intermediate I-3, in the presence of K₂CO₃ and PdCl₂(dppf), undergoes Suzuki coupling reactions with boric acid compounds or borate esters of different structures to give intermediates I-2-1 to I-18-1. Intermediates I-3 or I-2-1 to I-18-1 undergo alkaline hydrolysis in the presence of LiOH·H₂O to give intermediates I-1-1 or I-2-2 to I-18-2, respectively. Intermediates I-1-1 or I-2-2 to I-18-2 then undergo amide condensation reactions with intermediates 1-4 in the presence of HOBt and EDCI to give L-I-1 to L-I-18. ； Alternatively, intermediate I-2, in the presence of bases such as NaH or K₂CO₃, undergoes substitution reactions with haloalkanes of different structures to yield intermediates II-1-1 or II-2-1. Intermediates II-1-1 or II-2-1, in the presence of KOAc and PdCl₂(dppf), undergo Suzuki coupling reactions with intermediate II-2 to yield intermediates II-1-2 or II-2-2. Intermediates II-1-2 or II-2-2 undergo alkaline hydrolysis in the presence of LiOH·H₂O to yield intermediates II-1-3 or II-2-3. Intermediates II-1-3 or II-2-3, in the presence of HOBt and EDCI, undergo amide condensation reactions with intermediates 1-4 to yield L-II-1 or L-II-2. 。 7. The use of the pyridone-containing aminothiazole heterocyclic compound or its pharmaceutically acceptable salt or its isotopically labeled compound according to any one of claims 1 to 5 in the preparation of a medicament with antiherpesvirus activity.

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