An als inhibitor sulfonylurea herbicide, and a preparation method and application thereof

Abstract

The application discloses an ALS inhibitor sulfonylurea herbicide and a preparation method and application thereof, relates to the technical field of herbicides, and comprises 22 compounds with structures as shown in general formula I or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates of each of the compounds and a preparation method and application thereof. After reasonable collocation, the medicine has good prevention and control effects on gramineous plants or broad-leaved plants. The herbicide does not cause harm to soil and environment.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticides, in particular to an ALS inhibitor sulfonylurea herbicide and a preparation method and application thereof. BACKGROUND

[0002] Bensulfuron-methyl has been registered for use in China since 1986, and is a commonly used ALS inhibitor sulfonylurea herbicide in rice fields, which can effectively control most broadleaf weeds and sedge in rice fields, and is safe to rice and subsequent crops. Bensulfuron-methyl is a highly effective, broad-spectrum, low-toxicity and low-dose selective internal conductive sulfonylurea herbicide, and is one of the main herbicides widely used for weed control in rice fields at present. However, since the first bensulfuron-methyl-resistant Cyperus difformis was found in rice fields in the United States in 1993, the resistance of weeds to bensulfuron-methyl has rapidly evolved.

[0003] At present, the most reported bensulfuron-methyl-resistant weeds in rice fields are of different species, and the number of reports at home and abroad exceeds 60 times, and a total of 26 species of weeds in 12 genera in rice fields have developed resistance to bensulfuron-methyl. SUMMARY

[0004] The present application aims to provide an ALS inhibitor sulfonylurea herbicide and a preparation method and application thereof, which has high herbicidal activity, good stability and low resistance.

[0005] In order to solve the above technical problems, the technical scheme adopted by the present application is:

[0006] An ALS inhibitor sulfonylurea herbicide, a compound as shown in general formula I or each optical isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

[0007]

[0008] In the formula, R is selected from Y is selected from S, S=O, O=S=O, Z1, Z2, Z3 are independently selected from C and N; R1 is selected from hydrogen, C1-C4 alkyl and C1-C4 alkoxy.

[0009] The herbicide includes water emulsifiable concentrate, dispersible oil suspension concentrate, dispersible oil, microemulsion, emulsifiable concentrate, soluble concentrate, water, suspension, suspended emulsion, ultra-low volume agent, powder, wettable powder, granule, water dispersible granule, dry suspension, microcapsule suspension, emulsifiable powder, effervescent granule, effervescent tablet, water dispersible tablet and the like herbicide types of the compound as shown in general formula I as an active ingredient.

[0010] Further, R2 is selected from O-R3, halogen, O=C-R4; R3 is selected from hydrogen, C1-C10 alkyl, C1-C4 haloalkane; R4 is selected from C1-C4 alkoxy, C1-C4 alkyl, substituted amine; R1 is selected from hydrogen, methyl, methoxy. Further, halogen is chlorine; R3 is selected from hydrogen, methyl, ethyl, n-butyl, chloroethane; R4 is selected from methoxy, ethoxy, isopropyl, methylamine, dimethylamine.

[0011] Further, the herbicide is selected from the following compounds:

[0012]

[0013] A method for preparing sulfonylurea herbicide, comprising the following steps:

[0014] Firstly, an intermediate A is generated by substitution reaction of bromoacetyl bromide or chloroacetic anhydride with an amine compound, then the intermediate A reacts with a mercapto compound in the presence of triethylamine to generate a thioether, and finally the thioether is oxidized to generate a target product.

[0015] Further, the amine compound is selected from 2-amino-4,6-dimethoxy pyrimidine, 2-amino-4-methyl-6-methoxy-1,3,5-triazine.

[0016] Further, the mercapto compound is selected from N,N-dimethyl-2-mercapto nicotinamide, methyl thiosalicylate, 2-thiophenol, 4,6-dimethyl-2-mercapto pyrimidine, 2-methoxy thiophenol, o-chlorothiophenol, ethyl o-mercaptobenzoate. Further, the oxidant of the oxidation reaction is meta-chloroperoxybenzoic acid.

[0017] Use of sulfonylurea herbicide, the use of the herbicide in inhibiting growth of grass or broadleaf herbaceous plants.

[0018] Further, the use of the herbicide in inhibiting growth of barnyard grass, dogtail grass, zinnia, morning glory, okra, cyperus, cyperus alternifolius.

[0019] "Substitution" refers to replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0020] "Alkyl", refers to aliphatic hydrocarbon group, refers to saturated hydrocarbon group. The alkyl moiety can be straight chain alkyl, or branched chain alkyl. Typical alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

[0021] C1~Cn used in the present application includes C1~C2, C1~C3,..., C1~Cn, n is an integer greater than one; the prefix of the substituent group indicates the minimum and maximum number of carbon atoms in the substituent group, for example, "C1~C6 alkyl" refers to a straight chain or branched chain alkyl group containing one to six carbon atoms.

[0022] IC50 refers to the concentration of an inhibitor when the "cell activity" is inhibited by half, in terms of apoptosis, it can be understood that a certain drug induces 50% of tumor cell apoptosis at a certain concentration, which is called 50% inhibition concentration, that is, the concentration corresponding to the ratio of apoptotic cells to the total number of cells is equal to 50%, IC50 value can be used to measure the ability of a drug to induce apoptosis, that is, the stronger the induction ability, the lower the value, which can also be used to indicate the degree of tolerance of a certain cell to a drug.

[0023] The beneficial effects of the present application are:

[0024] The drug of the present application has good prevention and control effect on gramineous or broad-leaved plants after reasonable collocation, and has faster effect, high herbicidal efficiency and more thorough herbicidal effect. The herbicide of the present application will not cause harm to soil and environment. DETAILED DESCRIPTION

[0025] The technical solutions of the present application are described below in detail and completely. Obviously, the examples described herein are only a part of the examples in the present application, but not all the examples. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0026] Example 1

[0027] Synthesis of GA-SM-4, the synthesis route is as follows:

[0028]

[0029] Specific synthesis steps:

[0030] Synthesis of intermediate 1

[0031] Thiourea (10.0 g, 131.4 mmol, 1.0 eq.) and acetylacetone (6.6 g, 131.4 mmol, 1.0 eq.) were dissolved in methanol (84.2 g, 2627.4 mmol, 20.0 eq.), and refluxed at 65℃ for 2h. After slight cooling, concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) was slowly added dropwise, and refluxed at 70℃ for 1h. After cooling, the reaction solution was removed under reduced pressure, dissolved in water, the pH was adjusted to about 7 with 10% sodium hydroxide solution, and the solvent was removed under reduced pressure again. After column chromatography, 5.3g of product (yellow solid, yield 58%) was obtained.

[0032] Synthesis of intermediate 2

[0033] Dissolve intermediate 1 (1.3 g, 7.1 mmol, 1.0 eq.) in dry dichloromethane (30 mL) and add triethylamine (2.8 g, 21.4 mmol, 3.0 eq.) at 0 °C. After activation for 30 min, add intermediate 1 (2.2 g, 7.1 mmol, 1.0 eq.) and allow to react at room temperature overnight. After the end of the reaction, adjust the pH to acidic with 2N HC1, extract with water and dichloromethane, dry the organic phase with anhydrous sodium sulfate and remove the solvent under reduced pressure. Column chromatography gives the product 1.6 g (white solid, yield 51%).

[0034] Synthesis of intermediate 3

[0035] Dissolve intermediate 1 (1.3 g, 7.1 mmol, 1.0 eq.) in dry dichloromethane (30 mL) and add triethylamine (2.8 g, 21.4 mmol, 3.0 eq.) at 0 °C. After activation for 30 min, add intermediate 1 (2.2 g, 7.1 mmol, 1.0 eq.) and allow to react at room temperature overnight. After the end of the reaction, adjust the pH to acidic with 2N HC1, extract with water and dichloromethane, dry the organic phase with anhydrous sodium sulfate and remove the solvent under reduced pressure. Column chromatography gives the product 1.6 g (white solid, yield 51%).

[0036] Synthesis of GA-SM-4

[0037] Dissolve intermediate 3 (1.6 g, 4.7 mmol, 1.0 eq.) in dry dichloromethane (30 mL) and add meta-chloroperoxybenzoic acid (2.4 g, 9.4 mmol, 5.0 eq.) and allow to react at room temperature for 4 h. After the end of the reaction, quench with saturated sodium carbonate solution (10 mL) and extract with dichloromethane and water. Wash the organic phase with saturated brine, dry the combined organic phases with anhydrous sodium sulfate and remove the solvent under reduced pressure. Recrystallize the crude product in acetonitrile to obtain the product 660 mg (white solid, yield: 38%).

[0038] The structural formula of GA-SM-4 is as follows:

[0039]

[0040] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.58 (s, 1H), 5.95 (s, 1H), 5.12 (s, 2H), 3.86 (s, 6H), 2.54 (s, 6H).13 C NMR (101 MHz, DMSO-d6) δ 172.0, 169.3, 164.6, 156.4, 123.7, 85.1, 57.6, 54.7, 23.8. HRMS (ESI): calcd for C 14 H 18 N5O5S + (M+H) + : 368.1023, found 368.1031.

[0041] Example 2

[0042] Synthesis of GA-SM-5, the synthetic route is as follows:

[0043]

[0044] Specific synthesis steps:

[0045] Synthesis of intermediate 1

[0046] Dissolve 2-amino-4,6-dimethoxy-pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.4 g (white solid, yield 34%).

[0047] Synthesis of intermediate 2

[0048] Dissolve methyl thiosalicylate (5.5 g, 32.6 mmol, 2.0 eq.) with dry dichloromethane (100 mL), add triethylamine (6.6 g, 65.3 mmol, 4.0 eq.) at 0 °C. After activation for 30 min, add intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 4.1 g (white solid, yield 48%).

[0049] Synthesis of GA-SM-5

[0050] Intermediate 2 (4.1 g, 15.6 mmol, 1.0 eq.) was dissolved in dry dichloromethane (100 mL), m-chloroperoxybenzoic acid (9.8 g, 57.1 mmol, 5.0 eq.) was added and the reaction was allowed to proceed at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench the reaction and the reaction mixture was extracted with dichloromethane and water. The organic layer was washed with saturated brine solution and the combined organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was recrystallized in acetonitrile to obtain 2.5 g of the product (white solid, yield: 55%).

[0051] The structure of GA-SM-5 is as follows:

[0052]

[0053] 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.99 (dd, J = 7.7, 1.4 Hz, 1H), 7.85 (td, J = 1.4 Hz, 1H), 7.82 (dd, 1H), 7.78 (td, J = 7.2, 1.7 Hz, 1H), 5.95 (s, 1H), 5.03 (s, 2H), 3.88 (s, 3H), 3.85 (s, 6H).13C NMR (101 MHz, DMSO-d6) δ 172.05, 167.67, 156.39, 137.99, 134.72, 133.03, 131.74, 131.50, 129.91, 85.13, 62.79, 54.65, 53.54. HRMS (ESI): calcd for C16H18N3O7S+(M+H)+: 396.0860, found 396.0859.

[0054] Example 3

[0055] Synthesis of GA-SM-7, the synthetic route is as follows:

[0056]

[0057] Specific synthesis steps:

[0058] Synthesis of Intermediate 1

[0059] To a solution of mercaptoacetic acid (4.9 g, 54.0 mmol, 1.0 eq.) in a mixture of DCM (32.4 mL) and glacial acetic acid (32.4 mL), triphenylmethyl chloride (15.1 mmol, 54.0 mmol, 1.0 eq.) and boron trifluoride etherate solution (10.8 mL) were added and the reaction was stirred at room temperature for 1 h. The reaction was distilled under reduced pressure and extracted with water and EA. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain the product 5.0 g (yellow liquid, yield 28%).

[0060] Synthesis of intermediate 2

[0061] Intermediate 1 (5.0 g, 15.0 mol, 1.0 eq.) was dissolved in dry DCM under argon protection. DMF (54 mg, 0.7 mmol, 0.05 eq.) and oxalyl chloride (7.6 g, 59.8 mmol, 4.0 eq.) were added dropwise at 0 °C. The temperature was raised to room temperature and the reaction was continued for 3 h. Distillation was carried out under reduced pressure. Dry DCM was added. Triethylamine (6.1 g, 59.8 mmol, 4.0 eq.) was added at 0 °C and stirred for 30 min. 2-amino-4,6-dimethoxypyrimidine (4.6 g, 29.9 mmol, 2.0 eq.) was added and the reaction was stirred at room temperature for 1 h. The reaction was extracted with saturated sodium bicarbonate solution. The pH of the organic layer was adjusted to be acidic. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. Column chromatography was performed to obtain the product 2.3 g (white solid, yield 33%).

[0062] Synthesis of intermediate 4

[0063] Intermediate 2 (2.3 g, 4.9 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL). Trifluoroacetic acid (5.5 g, 48.8 mmol, 10.0 eq.) and triethylsilane (2.3 g, 19.5 mmol, 4.0 eq.) were added at 0 °C. The reaction was stirred at room temperature for 6 h. Triethylamine was added to adjust the pH to 10. Activation was carried out at 0 °C for 30 min. Methyl 2-bromomethylbenzoate (1.5 g, 6.6 mml, 1.5 eq.) was added and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was washed with saturated sodium bicarbonate solution and adjusted to be acidic with 2N HCl. The reaction was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Column chromatography was performed to obtain the product 500 mg (white solid, yield 30%).

[0064] Synthesis of GA-SM-7

[0065] Intermediate 4 (500 mg, 1.3 mmol, 1.0 eq.) was dissolved in dry dichloromethane (20 mL), m-chloroperoxybenzoic acid (1.1 g, 6.6 mmol, 5.0 eq.) was added and the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (10 mL) was added to quench the reaction, which was then extracted with dichloromethane and water. The organic layer was washed with saturated brine water, combined organic layers were dried over anhydrous sodium sulfate and distilled under reduced pressure. The product was obtained by column chromatography as 100 mg (white solid, yield: 18%).

[0066] The structural formula of GA-SM-7 is as follows:

[0067]

[0068] 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.50 - 7.42 (m, 1H), 5.78 (s, 1H), 5.24 (s, 2H), 3.93 (s, 3H), 3.88 (s, 6H).13C NMR (101 MHz, Chloroform-d) δ 172.0, 171.3, 167.8, 155.3, 133.4, 132.4, 131.8, 131.5, 129.3, 128.5, 86.0, 60.5, 57.2, 54.7, 52.6. HRMS (ESI): calcd for C17H20N3O7S+(M+H)+: 410.1016, found 410.1006.

[0069] Example 4

[0070] The synthesis of GA-SM-9 is shown in the following synthetic route:

[0071]

[0072]

[0073] Specific synthesis steps:

[0074] Synthesis of Intermediate 1

[0075] Dissolve 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HC1, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 mL), dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.38 g (white solid, yield 34%).

[0076] Synthesis of intermediate 2

[0077] Dissolve 2-mercapto-N-methyl benzamide (4.0 g, 12.0 mmol, 2.0 eq.) in dry dichloromethane (50 mL), add triethylamine (2.4 g, 13.9 mmol, 4.0 eq.) at 0 °C. After activation for 30 min, add intermediate 1 (1.7 g, 6.0 mmol, 1.0 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HC1, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 1.1 g (white solid, yield 51%).

[0078] Synthesis of GA-SM-9

[0079] Dissolve intermediate 2 (1.1 g, 3.0 mmol, 1.0 eq.) in dry dichloromethane (30 mL), add meta-chloro peroxibenzoic acid (2.6 g, 15.3 mmol, 5.0 eq.), react for 4 h at room temperature, after the reaction is completed, quench with saturated sodium carbonate solution (10 mL), extract with dichloromethane and water, wash the organic layer with saturated brine, dry the combined organic layer with anhydrous sodium sulfate, distill under reduced pressure, column chromatography to obtain the product 2.5 g (white solid, yield: 55%).

[0080] The structural formula of GA-SM-9 is as follows:

[0081]

[0082] 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82-7.76 (m, 1H), 7.73-7.66 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 5.95 (s, 1H), 5.14 (s, 2H), 3.86 (s, 6H), 2.78 (d, J = 4.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 171.5, 168.1, 155.9, 137.5, 137.0, 134.0, 130.7, 129.6, 128.7, 84.6, 63.1, 54.2, 26.2. HRMS (ESI): calcd for C 16 H 19 N4O6S + (M+H) + :395.1020, found 395.1009.

[0083] Example 5

[0084] Synthesis of GA-SM-10, the synthetic route is as follows:

[0085]

[0086] Specific synthesis steps:

[0087] Synthesis of intermediate 1

[0088] Dithiosalicylic acid (2.0 g, 6.5 mmol, 1.0 eq.) was dissolved in dry tetrahydrofuran (30 mL), and then DMF (0.05 eq.) was added dropwise. Under stirring conditions, oxalyl chloride (3.0 g, 19.6 mmol, 3.0 eq.) was slowly added dropwise, and the reaction was carried out at 30°C for 4 h. The reaction solution was distilled under reduced pressure, dissolved in dry tetrahydrofuran (30 mL), DIEA (2.53 g, 19.6 mmol, 3.0 eq.) was added, dimethylamine tetrahydrofuran solution (2.94 g, 2 mol / L in THF, 10.0 eq.) was added dropwise with a syringe, and the reaction was carried out at room temperature for 3 h. The reaction solution was distilled under reduced pressure, extracted with water and dichloromethane, and the organic layer was washed with saturated sodium bicarbonate solution (1*30 mL) and then saturated brine (1*30 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was obtained as 2.1 g (yellow solid, yield 89%).

[0089] Synthesis of intermediate 2

[0090] Take intermediate 1 (2.0 g, 5.5 mmol, 1.0 eq.) and dissolve in methanol (20 mL), add dichloromethane (15 mL), add tris (2-carboxyethyl) phosphine hydrochloride (7.95 g, 27.7 mmol, 5.0 eq.), react at room temperature, monitor by TLC, reaction is complete in 1.5 h. Distill the reaction under reduced pressure, extract with dichloromethane and water, wash the organic layer with saturated brine (1*20 mL), dry the organic layer over anhydrous sodium sulfate, distill off the solvent under reduced pressure. Get product 1.9 g (yellow oil, yield 95%).

[0091] Synthesis of intermediate 3

[0092] Dissolve 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop in bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust the pH to acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 ml), then dry the organic layer over anhydrous sodium sulfate, distill off the solvent under reduced pressure. Column chromatography to get product 2.38 g (white solid, yield 34%).

[0093] Synthesis of intermediate 4

[0094] Dissolve intermediate 2 (1.9 g, 10.7 mmol, 1.5 eq.) in dry dichloromethane (30 mL), then add triethylamine (2.9 g, 28.6 mmol, 4.0 eq.) at 0 °C. After activation for 30 min, add intermediate 3 (2.0 g, 7.1 mmol, 1.0 eq.), react at room temperature overnight, after the reaction is completed, adjust the pH to acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer over anhydrous sodium sulfate, distill off the solvent under reduced pressure. Column chromatography to get product 1.9 g (pale yellow solid, yield 71%).

[0095] Synthesis of GA-SM-10

[0096] Dissolve intermediate 4 (1.9 g, 5.0 mmol, 1.0 eq.) in dry dichloromethane (30 mL), add m-chloroperoxybenzoic acid (4.4 g, 25.2 mmol, 5.0 eq.), react at room temperature for 4 h, after the reaction is completed, quench with saturated sodium carbonate solution (10 mL), then extract with dichloromethane and water, wash the organic layer with saturated brine, combine the organic layers, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, recrystallize in acetonitrile to get the crude product, column chromatography to get product 800 mg (white solid, yield: 39%).

[0097] The structural formula of GA-SM-10 is as follows:

[0098]

[0099] 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82-7.76 (m, 1H), 7.73-7.66 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 5.95 (s, 1H), 5.14 (s, 2H), 3.86 (s, 6H), 2.78 (d, J = 4.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 171.5, 168.1, 155.9, 137.5, 137.0, 134.0, 130.7, 129.6, 128.7, 84.6, 63.1, 54.2, 26.2. HRMS (ESI): calcd for C 16 H 19 N4O6S + (M+H) + :395.1020, found 395.1009.

[0100] Example 6

[0101] Synthesis of GA-SM-11, the synthetic route is as follows:

[0102]

[0103] Specific synthesis steps:

[0104] Synthesis of intermediate 1

[0105] 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly dropped at 0°C, and the reaction was carried out for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and extracted with water and dichloromethane, and the organic layer was washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. Column chromatography gave the product 2.4 g (white solid, yield 34%).

[0106] Synthesis of intermediate 2

[0107] Methyl thiosalicylate (5.5 g, 32.6 mmol, 2.0 eq.) was dissolved in dry dichloromethane (100 mL) and triethylamine (6.6 g, 65.3 mmol, 4.0 eq.) was added at 0 °C. After 30 min of activation, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and the reaction was allowed to proceed at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and the reaction mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The product was obtained by column chromatography as 4.1 g (white solid, yield 48%).

[0108] Synthesis of intermediate 3

[0109] Intermediate 3 (2.5 g, 5.1 mmol, 1.0 eq.), N, O-dimethylhydroxylamine hydrochloride (1.2 g, 10.1 mmol, 2.0 eq.) were taken in a dry round bottom flask under argon atmosphere and dry tetrahydrofuran (10 mL) was added. Isopropyl magnesium bromide (11.38 mL, 18.2 mmol, 3.6 eq.) was added slowly at 0 °C using a syringe. The reaction was allowed to proceed at room temperature for 2 h. Isopropyl magnesium bromide (8.22 mL, 13.2 mmol, 2.6 eq.) was added slowly at room temperature using a syringe. The reaction was allowed to proceed at room temperature for 2 h. TLC monitoring showed completion of the reaction. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The product was obtained by column chromatography (DCM: MeOH = 100: 1) as 210 mg (yellow solid, yield 15%).

[0110] Synthesis and characterization of GA-SM-11

[0111] Intermediate 3 (2.5 g, 5.1 mmol, 1.0 eq.), N, O-dimethylhydroxylamine hydrochloride (1.2 g, 10.1 mmol, 2.0 eq.) were taken in a dry round bottom flask under argon atmosphere and dry tetrahydrofuran (10 mL) was added. Isopropyl magnesium bromide (11.38 mL, 18.2 mmol, 3.6 eq.) was added slowly at 0 °C using a syringe. The reaction was allowed to proceed at room temperature for 2 h. Isopropyl magnesium bromide (8.22 mL, 13.2 mmol, 2.6 eq.) was added slowly at room temperature using a syringe. The reaction was allowed to proceed at room temperature for 2 h. TLC monitoring showed completion of the reaction. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The product was obtained by column chromatography (DCM: MeOH = 100: 1) as 210 mg (yellow solid, yield 15%).

[0112] The structure of GA-SM-11 is as follows:

[0113]

[0114] 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.81 - 7.74 (m, 2H), 7.69 - 7.60 (m, 2H), 5.99 (s, 1H), 3.88 (s, 6H), 3.34 (s, 2H), 2.27 - 2.14 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.06, 166.1, 155.2, 144.6, 138.1, 133.6, 129.9, 125.8, 121.3, 86.6, 81.6, 70.8, 54.8, 37.4, 18.1, 16.9. HRMS (ESI): calcd for C 18 H 22 N3O6S + (M+H) + : 408.1224, found 408.1223.

[0115] Example 7

[0116] Synthesis of GA-SM-12, the synthetic route is as follows:

[0117]

[0118] Specific synthesis steps:

[0119] Synthesis of Intermediate 1

[0120] 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, slowly droped into bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, and the reaction was allowed to proceed for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HC1, extracted with water and dichloromethane, and the organic layer was washed with saturated brine (3*50 mL), and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave the product 2.38 g (white solid, yield 34%).

[0121] Synthesis of Intermediate 2

[0122] To a solution of intermediate 2 (5.0 g, 55.6 mmol, 1.0 eq.) and 1-bromo-2- chloroethane (2.7 g, 18.7 mmol, 1.2 eq.) in acetone (20 mL) was added anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) and the reaction mixture was refluxed at 65 °C for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to acidic using 2N HCI and the reaction mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*10 mL) and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 2.9 g (white solid, yield 49%).

[0123] Synthesis of intermediate 3

[0124] To a solution of intermediate 2 (5.0 g, 55.6 mmol, 1.0 eq.) and 1-bromo-2- chloroethane (2.7 g, 18.7 mmol, 1.2 eq.) in acetone (20 mL) was added anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) and the reaction mixture was refluxed at 65 °C for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to acidic using 2N HCI and the reaction mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*10 mL) and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 2.9 g (white solid, yield 49%).

[0125] Synthesis of GA-SM-12

[0126] To a solution of intermediate 3 (2.9 g, 7.6 mmol, 1.0 eq.) in dry dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (6.5 g, 37.8 mmol, 5.0 eq.) and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was quenched with saturated sodium carbonate solution (10 mL) and extracted with dichloromethane and water. The organic layer was washed with saturated brine and combined organic layer was dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 700 mg (white solid, yield: 22%).

[0127] Structure of GA-SM-12

[0128]

[0129] 1H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.99-7.93 (m, 1H), 7.62-7.55 (m, 1H), 7.17-7.10 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.77 (s, 1H), 5.23 (s, 2H), 4.43-4.38 (m, 2H), 3.95-3.91 (m, 2H), 3.90 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 171.8, 155.7, 155.3, 135.9, 130.7, 121.5, 113.3, 85.7, 69.2, 60.4, 54.5, 41.8. HRMS (ESI): calcd for C 16 H 19 ClN3O6S + (M+H) + : 416.0678, found 416.0674.

[0130] Example 8

[0131] Synthesis of GA-SM-13, the synthetic route is as follows:

[0132]

[0133] Specific synthesis steps:

[0134] Synthesis of Intermediate 1

[0135] 2-Amino-4,6-dimethoxy-pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, slowly droped into bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, and the reaction was allowed to proceed for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was washed with saturated brine (3*50 mL), and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. Column chromatography gave the product 2.38 g (white solid, yield 34%).

[0136] Synthesis of Intermediate 2

[0137] To a solution of intermediate 2 (5.0 g, 15.5 mmol, 1.0 eq.) and iodoethane (3.9 g, 24.9 mmol, 1.6 eq.) in acetone (20 mL) was added anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) and the reaction mixture was refluxed at 50 °C for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to acidic using 2N HCI and the reaction mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*10 mL) and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 3.1 g (white solid, 57% yield).

[0138] Synthesis of intermediate 3

[0139] To a solution of intermediate 2 (5.0 g, 15.5 mmol, 1.0 eq.) and iodoethane (3.9 g, 24.9 mmol, 1.6 eq.) in acetone (20 mL) was added anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) and the reaction mixture was refluxed at 50 °C for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to acidic using 2N HCI and the reaction mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*10 mL) and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 3.1 g (white solid, 57% yield).

[0140] Synthesis of GA-SM-13

[0141] To a solution of intermediate 4 (3.1 g, 8.9 mmol, 1.0 eq.) in dry dichloromethane (50 mL) was added m-chloroperoxybenzoic acid (7.7 g, 44.4 mmol, 5.0 eq.) and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was quenched with saturated sodium carbonate solution (10 mL) and extracted with dichloromethane and water. The organic layer was washed with saturated brine and combined organic layer was dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 1.3 g (white solid, 38% yield).

[0142] Structure of GA-SM-13

[0143]

[0144] 1H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.94 (dd, J = 8.0, 1.8 Hz, 1H), 7.58 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.11 - 7.00 (m, 2H), 5.79 (s, 1H), 5.10 (s, 2H), 4.24 (q, J = 6.8 Hz, 2H), 3.91 (s, 6H), 1.51 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 156.7, 155.3, 136.0, 130.4, 120.6, 113.3, 85.8, 65.2, 60.2, 54.5, 14.6. HRMS (ESI): calcd for C 16 H 20 N3O6S + (M+H) + : 382.1067, found 382.2.1055.

[0145] Example 9

[0146] Synthesis of GA-SM-14, the synthetic route is as follows:

[0147]

[0148] Specific synthesis steps:

[0149] Synthesis of Intermediate 1

[0150] Compound chloroacetic anhydride (4.0 g, 23.4 mmol, 1.0 eq.) was weighed, 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 28.5 mmol, 3.0 eq.) was added and mixed, refluxed at 90°C for 1 h, saturated sodium bicarbonate solution was added to adjust pH to 8, extracted with DCM, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. The layer was column chromatographed to obtain the product 1.2 g (white solid, yield 19%).

[0151] Synthesis of Intermediate 2

[0152] To a solution of intermediate 2 (1.0 g, 2.9 mmol, 1.0 eq.) in dry dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.5 g, 14.3 mmol, 5.0 eq.) and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench the reaction and the reaction mixture was extracted with dichloromethane and water. The organic layer was washed with saturated brine solution and the combined organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The product was obtained as a white solid (600 mg, 71% yield) after column chromatography.

[0153] Synthesis of GA-SM-14

[0154] To a solution of intermediate 2 (1.0 g, 2.9 mmol, 1.0 eq.) in dry dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (2.5 g, 14.3 mmol, 5.0 eq.) and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench the reaction and the reaction mixture was extracted with dichloromethane and water. The organic layer was washed with saturated brine solution and the combined organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The product was obtained as a white solid (600 mg, 71% yield) after column chromatography.

[0155] Structure of GA-SM-14

[0156]

[0157] 1 H NMR (400 MHz, Chloroform-d) δ 9.26 (s, 1H), 8.25 (dd, J = 8.0, 1.2 Hz, 1H), 8.10 (dd, J = 7.6, 1.2 Hz, 1H), 7.82-7.73 (m, 1H), 7.63-7.55 (m, 1H), 4.44 (d, J = 14.0 Hz, 1H), 4.17 (d, J = 14.0 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.49 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 179.9, 171.4, 165.8, 164.1, 163.5, 146.0, 134.1, 131.1, 131.0, 126.9, 125.3, 59.7, 55.1, 52.9, 25.5. HRMS (ESI): calcd for C 15 H 17 N4O6S + (M+H) + : 381.0863, found 381.0853.

[0158] Example 10

[0159] Synthesis of GA-SM-15, the synthetic route is as follows:

[0160]

[0161] Specific synthesis steps:

[0162] Synthesis of Intermediate 1

[0163] Dissolve 2-amino-6-dimethoxy-pyridine (2.0 g, 16.1 mmol, 1.0 eq.) and cesium carbonate (6.3 g, 19.3 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.0 g (white solid, yield 76%).

[0164] Synthesis of Intermediate 2

[0165] Dissolve methyl thiosalicylate (2.8 g, 16.3 mmol, 2.0 eq.) in dry dichloromethane (40 mL), add triethylamine (3.3 g, 32.7 mmol, 4.0 eq.) at 0 °C. After activation for 30 min, add Intermediate 1 (2.0 g, 8.2 mmol, 1.0 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.0 g (white solid, yield 74%).

[0166] Synthesis of GA-SM-15

[0167] Dissolve Intermediate 2 (2.0 g, 6.0 mmol, 1.0 eq.) in dry dichloromethane (50 mL), add m-chloroperoxybenzoic acid (5.2 g, 30.1 mmol, 5.0 eq.), react for 4 h at room temperature, after the reaction is completed, quench with saturated sodium carbonate solution (20 mL), extract with dichloromethane and water, wash the organic layer with saturated brine, combine the organic layers, dry with anhydrous sodium sulfate, distill under reduced pressure, recrystallize in acetonitrile to obtain the crude product, column chromatography to obtain the product 800 mg (white solid, yield: 37%).

[0168] Structural formula of GA-SM-15

[0169]

[0170] 1 H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.70-7.64 (m, 1H), 7.64-7.54 (m, 2H), 6.53 (dd, J = 7.6, 1.2 Hz, 1H), 4.69 (s, 2H), 4.04 (s, 3H), 3.88 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 166.4, 161.8, 157.8, 147.2, 139.8, 136.4, 133.2, 131.9, 130.5, 130.1, 129.2, 105.8, 104.8, 62.6, 52.5, 52.5. HRMS (ESI): calcd for C 16 H 17 N2O6S + (M+H) + : 365.0802, found 365.0804.

[0171] Example 11

[0172] Synthesis of GA-SM-16, the synthetic route is as follows:

[0173]

[0174] Specific synthesis steps:

[0175] Synthesis of Intermediate 1

[0176] 4-amino-2,6-dimethoxy-pyrimidine (2.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, slowly droped into bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) at 0 °C, and the reaction was carried out for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, the organic layer was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave the product 2.4 g (white solid, yield 34%).

[0177] Synthesis of Intermediate 2

[0178] Methyl thiosalicylate (1.9 g, 11.3 mmol, 2.0 eq.) was dissolved in dry dichloromethane (20 mL) and triethylamine (2.3 g, 22.5 mmol, 4.0 eq.) was added at 0 °C. After activation for 30 min, intermediate 1 (1.6 g, 5.6 mmol, 1.0 eq.) was added and the reaction was allowed to proceed at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic with 2N HCI and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Column chromatography gave the product 1.5 g (white solid, yield 44%).

[0179] Synthesis of GA-SM-16

[0180] Intermediate 2 (1.3 g, 3.6 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (40 mL). m-Chloroperoxybenzoic acid (3.1 g, 17.9 mmol, 5.0 eq.) was added and the reaction was allowed to proceed at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (15 mL) was added to quench the reaction and then extracted with dichloromethane and water. The organic layer was washed with saturated brine and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from acetonitrile. Column chromatography gave the product 512 mg (white solid, yield: 38%).

[0181] Structure of GA-SM-16

[0182]

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.91 - 7.74 (m, 3H), 6.95 (s, 1H), 4.79 (s, 2H), 3.88 (s, 3H), 3.87 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 173.0, 167.6, 164.9, 162.1, 159.5, 137.6, 135.0, 133.1, 131.9, 131.5, 130.0, 88.4, 62.8, 54.9, 54.5, 53.6. HRMS (ESI): calcd for C 16 H 18 N3O7S + (M+H) + : 396.0860, found 396.0853.

[0184] Example 12

[0185] Synthesis of GA-SM-17, the synthetic route is as follows:

[0186]

[0187] Specific synthesis steps:

[0188] Synthesis of intermediate 1

[0189] Weigh 2-mercapto nicotinic acid (4.0 g, 25.8 mmol, 1.0 eq.) and HATU (11.8 g, 30.9 mmol, 1.2 eq.), dissolve in dry tetrahydrofuran (30 mL), add DIEA (6.7 g, 51.6 mmol, 2.0 eq), drop in dimethylamine tetrahydrofuran solution (64 mL, 2 mol / L in THF, 5.0 eq.) with a syringe, react at room temperature for 5 h, reduce pressure to distill the reaction solution, extract with water and dichloromethane, reduce pressure to distill the water layer, and obtain the product 2.0 g (yellow liquid, yield 43%).

[0190] Synthesis of intermediate 2

[0191] Dissolve 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop in bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) at 0°C, and react for 3 h. After the reaction is completed, adjust the pH to be acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 mL), and then dry the organic layer with anhydrous sodium sulfate, and remove the solvent by reducing pressure. Column chromatography obtains the product 2.38 g (white solid, yield 34%).

[0192] Synthesis of intermediate 3

[0193] Dissolve intermediate 1 (1.1 g, 5.8 mmol, 2.0 eq.) in dry dichloromethane (30 mL), and then add triethylamine (1.2 g, 11.6 mmol, 4.0 eq.) at 0°C. After activation for 30 min, add intermediate 1 (800 mg, 2.9 mmol, 1.0 eq.), and react at room temperature overnight. After the reaction is completed, adjust the pH to be acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, and remove the solvent by reducing pressure. Column chromatography obtains the product 1.0 g (white solid, yield 46%).

[0194] Synthesis of GA-SM-17

[0195] Intermediate 3 (1.3 g, 3.3 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL), m-chloroperoxybenzoic acid (2.9 g, 16.6 mmol, 5.0 eq.) was added and the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (10 mL) was added to quench the reaction and dichloromethane and water were used to extract the reaction mixture. The organic layer was washed with saturated brine and the combined organic layer was dried over anhydrous sodium sulfate. The product was obtained by column chromatography (300 mg, white solid, yield: 22%).

[0196] GA-SM-17 has the following structural formula:

[0197]

[0198] 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.46 (s, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H), 5.18 (s, 2H), 4.00 (s, 6H), 3.13 (s, 3H), 2.88 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 167.2, 166.6, 153.3, 152.6, 149.6, 136.8, 132.9, 127.6, 82.7, 59.5, 55.6, 39.0, 35.0. HRMS (ESI): calcd for C 16 H 20 N5O6S + (M+H) + : 410.1129, found 410.1130.

[0199] Example 13

[0200] GA-SM-19 was synthesized according to the following synthetic route:

[0201]

[0202] Specific synthesis steps:

[0203] Synthesis of Intermediate 1

[0204] Take thiourea (10.0 g, 131.4 mmol, 1.0 eq.) and acetylacetone (6.6 g, 131.4 mmol, 1.0 eq.) dissolved in methanol (84.2 g, 2627.4 mmol, 20.0 eq.), 65 °C reflux for 2 h. After slightly cooling, add concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) dropwise, 70 °C reflux for 1 h. After cooling, spin dry the reaction solution, then dissolve in water, adjust the pH to about 7 with 10% sodium hydroxide solution, and spin dry again. After column chromatography, 5.3 g of product (yellow solid, yield 58%) is obtained.

[0205] Synthesis of intermediate 2

[0206] Take compound chloroacetic anhydride (4.0 g, 23.4 mmol, 1.0 eq.), add 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 28.5 mmol, 3.0 eq.), mix well, 90 °C reflux for 1 h, add saturated sodium bicarbonate solution to adjust the pH to 8, extract with DCM, then dry the organic layer with anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. After column chromatography, 1.2 g of product (white solid, yield 19%) is obtained.

[0207] Synthesis of intermediate 3

[0208] Dissolve intermediate 1 (777 mg, 5.5 mmol, 1.0 eq.) in dry dichloromethane (30 mL), then add triethylamine (1.1 g, 11.1 mmol, 4.0 eq.) at 0 °C. After activation for 30 min, add intermediate 2 (600 mg, 2.8 mmol, 1.0 eq.), and react at room temperature overnight. After the reaction is completed, adjust the pH to be acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. After column chromatography, 745 mg of product (white solid, yield 84%) is obtained.

[0209] Synthesis of GA-SM-19

[0210] Dissolve intermediate 3 (745 mg, 2.3 mmol, 1.0 eq.) in dry dichloromethane (30 mL), then add m-chloroperoxybenzoic acid (2.0 g, 11.6 mmol, 5.0 eq.) and react at room temperature for 4 h. After the reaction is completed, quench with saturated sodium carbonate solution (10 mL), then extract with dichloromethane and water, wash the organic layer with saturated brine, combine the organic layers, dry with anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. Recrystallize the crude product in acetonitrile, and obtain 100 mg of product (white solid, yield: 12%) after column chromatography.

[0211] The structural formula of GA-SM-19 is as follows:

[0212]

[0213] 1 H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.23 (s, 1H), 5.21 (s, 2H), 4.02 (s, 3H), 2.61 (s, 6H), 2.51 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 180.1, 171.4, 169.5, 164.7, 164.0, 161.5, 123.2, 57.9, 55.4, 25.5, 23.9. HRMS (ESI): calcd for C 13 H 17 N6O4S + (M+H) + : 353.1027, found 353.1023.

[0214] Example 14

[0215] Synthesis of GA-SM-20, the synthetic route is as follows:

[0216]

[0217] Specific synthesis steps:

[0218] Synthesis of Intermediate 1

[0219] Thiourea (10.0 g, 131.4 mmol, 1.0 eq.) and acetylacetone (6.6 g, 131.4 mmol, 1.0 eq.) were dissolved in methanol (84.2 g, 2627.4 mmol, 20.0 eq.) and refluxed at 65 °C for 2 h. After slightly cooling, concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) was added dropwise and refluxed at 70 °C for 1 h. After cooling, the reaction solution was spin-dried, then dissolved in water, and the pH was adjusted to about 7 with 10% sodium hydroxide solution, and spin-dried again. After column chromatography, 5.3 g of product (yellow solid, yield 58%) was obtained.

[0220] Synthesis of Intermediate 2

[0221] Intermediate 3 was synthesized under argon atmosphere by dissolving 2-amino-6- dimethoxy pyridine (2.0 g, 16.1 mmol, 1.0 eq.) and cesium carbonate (6.3 g, 19.3 mmol, 1.2 eq.) in acetonitrile (150 mL) and slowly adding bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) drop wise at 0 °C and allowing the reaction to proceed for 3 h. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was obtained by column chromatography as 2.0 g (white solid, 76% yield).

[0222] Synthesis of intermediate 3

[0223] Intermediate 1 (2.3 g, 16.3 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and triethylamine (3.3 g, 32.6 mmol, 3.0 eq.) was added at 0 °C. After activation for 30 min, intermediate 2 (2.0 g, 8.2 mmol, 1.0 eq.) was added and allowed to react at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The product was obtained by column chromatography as 1.5 g (white solid, 60% yield).

[0224] Synthesis of GA-SM-20

[0225] Intermediate 3 (1.5 g, 4.9 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and m-chloroperoxybenzoic acid (4.2 g, 24.5 mmol, 5.0 eq.) was added and allowed to react at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench and extracted with dichloromethane and water. The organic layer was washed with saturated brine and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was obtained by column chromatography as 590 mg (white solid, 36% yield).

[0226] The structure of GA-SM-20 is as follows:

[0227]

[0228] 1 H NMR (400 MHz, Chloroform-d) δ 9.20 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.57-7.52 (m, 1H), 7.26 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 2.63 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 169.6, 164.7, 162.9, 158.7, 148.3, 140.7, 123.4, 106.9, 105.8, 58.4, 53.5, 23.9. HRMS (ESI): calcd for C 14 H 17 N4O4S + (M+H) + : 337.0965, found 337.0961.

[0229] Example 15

[0230] Synthesis of GA-SM-21, the synthetic route is as follows:

[0231]

[0232] Specific synthesis steps:

[0233] Synthesis of Intermediate 1

[0234] Dissolve 2-amino-4,6-dimethoxy-pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop in bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 mL), then dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.38 g (white solid, yield 34%).

[0235] Synthesis of Intermediate 2

[0236] Dissolve 2-mercaptophenol (5.0 g, 39.6 mmol, 1.0 eq.) with dry dichloromethane (50 mL), add triethylamine (12.0 g, 118.9 mmol, 3.0 eq.) at 0 °C, activate for 30 min, then add Intermediate 1 (9.8 g, 47.6 mmol, 1.2 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 5.9 g (white solid, yield 46%).

[0237] Synthesis of Intermediate 3

[0238] Intermediate 2 (3.0 g, 9.3 mmol, 1.0 eq.) and bromobutane (2.0 g, 14.9 mmol, 1.6 eq.) were dissolved in acetone (20 mL) and anhydrous potassium carbonate (2.6 g, 18.7 mmol, 2.0 eq.) was added. The reaction was refluxed at 55 °C for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*10 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The product was purified by column chromatography to obtain 600 mg (white solid, yield 17%).

[0239] Synthesis of GA-SM-21

[0240] Intermediate 4 (400 mg, 1.1 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and m-chloroperoxybenzoic acid (919 mg, 5.3 mmol, 5.0 eq.) was added. The reaction was carried out at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench the reaction and extracted with dichloromethane and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the product was purified by column chromatography to obtain 103 mg (white solid, yield: 24%).

[0241] The structure of GA-SM-21 is as follows:

[0242]

[0243] 1 H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.61-7.52 (m, 1H), 7.14-6.97 (m, 2H), 5.79 (s, 1H), 5.08 (s, 2H), 4.16 (t, J = 6.8 Hz, 2H), 3.91 (s, 6H), 1.86 (p, J = 7.2, 6.8 Hz, 2H), 1.53 (h, J = 7.6 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 156.9, 155.4, 136.0, 130.5, 126.7, 120.6, 113.2, 85.8, 69.2, 60.2, 54.5, 31.0, 19.2, 13.8. HRMS (ESI): calcd for C 18 H 24 N3O6S + (M+H) +:410.1380, found 410.1379.

[0244] Example 16

[0245] Synthesis of GA-SM-22, the synthetic route is as follows:

[0246]

[0247] Specific synthesis steps:

[0248] Synthesis of Intermediate 1

[0249] Dissolve 2-amino-4,6-dimethoxy-pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 mL), dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.38 g (white solid, yield 34%).

[0250] Synthesis of Intermediate 2

[0251] Dissolve 2-methoxythiophenol (761 mg, 5.4 mmol, 1.5 eq.) in dry dichloromethane (20 mL), add triethylamine (1.1 g, 10.9 mmol, 3.0 eq.) at 0 °C. After activation for 30 min, add Intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HCl, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 730 mg (white solid, yield 60%).

[0252] Synthesis of GA-SM-22

[0253] Dissolve Intermediate 4 (730 mg, 2.2 mmol, 1.0 eq.) in dry dichloromethane (30 mL), add meta-chloroperoxybenzoic acid (1.9 g, 10.9 mmol, 5.0 eq.), react for 4 h at room temperature, after the reaction is completed, quench with saturated sodium carbonate solution (10 mL), extract with dichloromethane and water, wash the organic layer with saturated brine, dry the combined organic layer with anhydrous sodium sulfate, distill under reduced pressure, recrystallize in acetonitrile to obtain the crude product, column chromatography to obtain the product 384 mg (white solid, yield: 48%).

[0254] The structural formula of GA-SM-22 is as follows:

[0255]

[0256] 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.14 - 7.03 (m, 2H), 5.79 (s, 1H), 5.09 (s, 2H), 3.99 (s, 3H), 3.92 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 157.3, 155.3, 136.1, 130.6, 126.7, 120.8, 112.4, 85.8, 60.2, 56.4, 54.5. HRMS (ESI): calcd for C 15 H 18 N3O6S + (M+H) + : 368.0911, found 368.0903.

[0257] Example 17

[0258] Synthesis of GA-SM-23, the synthetic route is as follows:

[0259]

[0260] Specific synthesis steps:

[0261] Synthesis of intermediate 1

[0262] 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly dropped at 0°C, and the reaction was carried out for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and extracted with water and dichloromethane, and the organic layer was washed with saturated brine (3*50 mL), and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. Column chromatography gave the product 2.38 g (white solid, yield 34%).

[0263] Synthesis of intermediate 2

[0264] Intermediate 2 (800 mg, 2.5 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL), m-chloroperoxybenzoic acid (2.5 g, 12.5 mmol, 5.0 eq.) was added and the reaction was carried out at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (10 mL) was added to quench the reaction, and then dichloromethane and water were used to extract the reaction mixture. The organic layer was washed with saturated brine water, and the combined organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was used to obtain the product 200 mg (white solid, yield: 23%).

[0265] Synthesis of GA-SM-23

[0266] Intermediate 2 (800 mg, 2.5 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL), m-chloroperoxybenzoic acid (2.5 g, 12.5 mmol, 5.0 eq.) was added and the reaction was carried out at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (10 mL) was added to quench the reaction, and then dichloromethane and water were used to extract the reaction mixture. The organic layer was washed with saturated brine water, and the combined organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was used to obtain the product 200 mg (white solid, yield: 23%).

[0267] The structural formula of GA-SM-23 is as follows:

[0268]

[0269] 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.53-7.41 (m, 1H), 7.02-6.94 (m, 2H), 5.78 (s, 1H), 3.90 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 156.5, 155.1, 136.9, 129.7, 121.9, 120.5, 119.0, 85.8, 62.0, 54.6. HRMS (ESI): calcd for C 14 H 16 N3O6S + (M+H) + : 354.0754, found 354.0741.

[0270] Example 18

[0271] Synthesis of GA-SM-24, the synthesis route is as follows:

[0272]

[0273] Specific synthesis steps:

[0274] Synthesis of intermediate 1

[0275] Dissolve 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) in acetonitrile (150 mL) under argon protection, slowly drop bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) at 0 °C, react for 3 h. After the reaction is completed, adjust pH to acidic with 2N HC1, extract with water and dichloromethane, wash the organic layer with saturated brine (3*50 mL), dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 2.38 g (white solid, yield 34%).

[0276] Synthesis of intermediate 2

[0277] Dissolve o-chlorothiophenol (662 mg, 4.4 mmol, 1.2 eq.) in dry dichloromethane (50 mL), add triethylamine (1.1 g, 10.8 mmol, 3.0 eq.) at 0 °C, activate for 30 min, add intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.), react overnight at room temperature, after the reaction is completed, adjust pH to acidic with 2N HC1, extract with water and dichloromethane, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure. Column chromatography to obtain the product 400 mg (white solid, yield 66%).

[0278] Synthesis of GA-SM-24

[0279] Dissolve intermediate 4 (400 mg, 1.2 mmol, 1.0 eq.) in dry dichloromethane (20 mL), add meta-chloroperoxybenzoic acid (1.1 g, 6.0 mmol, 5.0 eq.), react for 4 h at room temperature, after the reaction is completed, quench with saturated sodium carbonate solution (8 mL), extract with dichloromethane and water, wash the organic layer with saturated brine, dry the combined organic layer with anhydrous sodium sulfate, distill under reduced pressure, column chromatography to obtain the product 100 mg (white solid, yield: 23%).

[0280] The structural formula of GA-SM-24 is as follows:

[0281]

[0282] 1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.02-7.92 (m, 1H), 7.54-7.34 (m, 3H), 5.74 (s, 1H), 4.58-4.25 (m, 2H), 3.82 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 155.4, 132.6, 130.2, 129.9, 128.1, 126.4, 85.6, 54.6, 54.3, 29.7. HRMS (ESI): calcd for C 14 H 15 ClN3O6S + (M+H) + : 372.0415, found 372.0409.

[0283] Example 19

[0284] Synthesis of GA-SM-25, the synthetic route is as follows:

[0285]

[0286] Specific synthesis steps:

[0287] Synthesis of Intermediate 1

[0288] Dithiosalicylic acid (2.0 g, 6.5 mmol, 1.0 eq.) and cesium carbonate (4.1 g, 26.1 mmol, 4.0 eq.) were weighed, dissolved with DMF (10 mL), and reacted at 70 °C for 5 h. The reaction solution was distilled under reduced pressure, extracted with water and dichloromethane, washed with water solution (3*10 mL) and saturated brine (1*30 mL), dried with anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The product 1.5 g (yellow liquid, yield 63%) was obtained.

[0289] Synthesis of Intermediate 2

[0290] Intermediate 1 (1.5 g, 4.1 mmol, 1.0 eq.) was dissolved in methanol (20 mL) and dichloromethane (20 mL), and tris(2-carboxyethyl)phosphine hydrochloride (5.9 g, 20.7 mmol, 5.0 eq.) was added. The reaction was carried out at room temperature, and TLC was used for monitoring. The reaction was completed after 1.5 h. The reaction solution was distilled under reduced pressure, extracted with dichloromethane and water, washed with saturated brine (1*20 mL), dried with anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The product 1.1 g (yellow oil, yield 70%) was obtained.

[0291] Synthesis of Intermediate 3

[0292] Intermediate 2 (1.1 g, 6.0 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and triethylamine (1.8 g, 18.1 mmol, 3.0 eq.) was added at 0 °C. After activation for 30 min, intermediate 3 (1.8 g, 6.6 mmol, 1.1 eq.) was added and the reaction was allowed to proceed at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Column chromatography gave the product 1.1 g (yellowish solid, yield 52%).

[0293] Synthesis of GA-SM-25

[0294] Intermediate 3 (1.1 g, 2.5 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and m-chloroperoxybenzoic acid (2.5 g, 14.6 mmol, 5.0 eq.) was added and the reaction was allowed to proceed at room temperature for 4 h. After completion of the reaction, saturated sodium carbonate solution (10 mL) was added to quench and extracted with dichloromethane and water. The organic layer was washed with saturated brine and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from acetonitrile. Column chromatography gave the product 200 mg (white solid, yield: 17%).

[0295] The structure of GA-SM-25 is as follows:

[0296]

[0297] 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 8.03 - 7.96 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.24 - 7.18 (m, 1H), 5.77 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.21 (s, 2H), 3.91 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 171.9, 170.1, 167.1, 155.3, 138.1, 133.8, 133.1, 131.8, 131.1, 129.9, 85.8, 62.6, 54.5, 53.2, 14.0. HRMS (ESI): calcd for C 17 H 22 N3O7S + (M+H) + : 410.1016, found 410.1012.

[0298] Example 20

[0299] Synthesis of GA-SM-28, the synthetic route is as follows:

[0300]

[0301] Specific synthesis steps:

[0302] Synthesis of Intermediate 1

[0303] Chloroacetic anhydride (4.0 g, 28.5 mmol, 1.0 eq.) and 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 85.6 mmol, 3.0 eq.) were weighed into a bottle and reacted at 90°C for 1 h. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 8, extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The product was purified by column chromatography to obtain 1.2 g (white solid, yield 69%).

[0304] Synthesis of Intermediate 2

[0305] Chloroacetic anhydride (4.0 g, 28.5 mmol, 1.0 eq.) and 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 85.6 mmol, 3.0 eq.) were weighed into a bottle and reacted at 90°C for 1 h. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 8, extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The product was purified by column chromatography to obtain 1.2 g (white solid, yield 69%).

[0306] Synthesis of GA-SM-28

[0307] Intermediate 2 (1.1 g, 3.4 mmol, 1.0 eq.) was weighed into dry dichloromethane (30 mL) and dissolved. M-chloroperbenzoic acid (2.9 g, 16.9 mmol, 5.0 eq.) was added and reacted at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (10 mL) was added to quench, and then extracted with dichloromethane and water. The organic layer was washed with saturated brine, combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The product was obtained by column chromatography, 300 mg (white solid, yield: 25%).

[0308] The structural formula of GA-SM-28 is as follows:

[0309]

[0310] 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 4.49 (d, J = 14.0 Hz, 1H), 4.27 (d, J = 14.0 Hz, 1H), 3.96 (s, 3H), 2.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 180.0, 171.3, 164.0, 163.2, 139.6, 132.8, 130.3, 130.0, 128.2, 126.4, 58.2, 55.2, 25.5. HRMS (ESI): calcd for C 13 H 14 ClN4O4S + (M+H) + : 357.0419, found 357.0418.

[0311] Example 21

[0312] Synthesis of GA-SM-29, the synthetic route is as follows:

[0313]

[0314] Specific synthesis steps:

[0315] Synthesis of Intermediate 1

[0316] 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL) under argon protection, slowly droped into bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) at 0 °C, and reacted for 3 h. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave the product 2.4 g (white solid, yield 34%).

[0317] Synthesis of GA-SM-29

[0318] Methyl thiosalicylate (5.5 g, 32.6 mmol, 2.0 eq.) was dissolved in dry dichloromethane (100 mL) and triethylamine (6.6 g, 65.3 mmol, 4.0 eq.) was added at 0 °C. After activation for 30 min, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and the reaction was allowed to proceed at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic with 2N HCI and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Column chromatography gave the product 4.1 g (white solid, yield 48%).

[0319] The structure of GA-SM-29 is as follows:

[0320]

[0321] 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.23 - 7.15 (m, 1H), 5.76 (s, 1H), 4.21 (s, 2H), 3.91 (s, 3H), 3.90 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 172.0, 168.4, 166.8, 155.6, 140.1, 133.0, 131.5, 127.6, 126.4, 124.9, 85.4, 54.4, 52.2, 37.7. HRMS (ESI): calcd for C 16 H 18 N3O5S + (M+H) + : 364.0962, found 364.0951.

[0322] Example 22

[0323] Synthesis of GA-SM-30, the synthetic route is as follows:

[0324]

[0325] Specific synthesis steps:

[0326] Synthesis of intermediate 1

[0327] To a solution of 2-amino-4,6-dimethoxy pyrimidine (4.0 g, 25.8 mmol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) in acetonitrile (150 mL) was added bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) drop wise at 0 °C under argon atmosphere. The reaction was stirred for 3 h. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was obtained by column chromatography as 2.4 g (white solid, 34% yield).

[0328] Synthesis of intermediate 2

[0329] To a solution of methyl thiosalicylate (5.5 g, 32.6 mmol, 2.0 eq.) in dry dichloromethane (100 mL) was added triethylamine (6.6 g, 65.3 mmol, 4.0 eq.) at 0 °C. After 30 min of activation, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to acidic using 2N HCI and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was obtained by column chromatography as 4.1 g (white solid, 48% yield).

[0330] Synthesis of GA-SM-30

[0331] To a solution of intermediate 2 (1.0 g, 2.7 mmol, 1.0 eq.) in glacial acetic acid (4 mL) and 30% hydrogen peroxide solution (1 mL) was stirred at room temperature for 24 h. After completion of the reaction, the pH was adjusted to 8 using saturated sodium bicarbonate solution and extracted with dichloromethane and water. The organic layer was washed with saturated brine and combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was obtained by column chromatography as 300 mg (white solid, 29% yield).

[0332] The structure of GA-SM-30 is as follows:

[0333]

[0334] 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.30 (dd, J = 8.0, 1.2 Hz, 1H), 8.09 (dd, J = 7.6, 1.2 Hz, 1H), 7.82-7.74 (m, 1H), 7.63-7.53 (m, 1H), 5.74 (s, 1H), 4.48 (d, J = 14.0 Hz, 1H), 4.22 (d, J = 14.0 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 6H).13 C NMR (101 MHz, Chloroform-d) δ 171.9, 165.8, 155.5, 134.0, 131.0, 130.8, 126.9, 125.3, 85.5, 54.2, 53.7, 52.8. HRMS (ESI): calcd for C 16 H 18 N3O6S + (M+H) + : 380.0911, found 380.0901.

[0335] Example 23

[0336] ALS enzyme activity experiment

[0337] (1) Sample preparation

[0338] Take 0.3 g of tobacco leaves, add 1 mL of extraction solution, homogenize in ice bath, centrifuge at 4°C x 12000 rpm for 15 min, take the supernatant for use.

[0339] (2) Sample preparation

[0340] Weigh the medicine and configure it into a 10 mmol / L and 1 mmol / L DMSO solution, and then take 5 μL of each and add it to 500 μL of tobacco protein extract (i.e. the detection concentrations are: 100 μM and 10 μM, respectively), mix well and test.

[0341] (3) Machine detection

[0342] First, preheat the enzyme marker for 30 min, adjust the wavelength to 525 nm. Preheat all reagents in the kit at 25°C for 10 min, set the sample tube and control tube, and set three parallel samples in each group. Add reagent one (20 μL for the sample tube and 0 for the control tube) to a 1 mL centrifuge tube, reagent two (100 μL for the sample tube and 120 μL for the control tube), sample solution (80 μL for the sample tube and 80 μL for the control tube), and react in the dark at 35°C for 1 h. Then add reagent three (20 μL for the sample tube and 20 μL for the control tube), and decarboxylate at 60°C for 15 min, add reagent four (100 μL for the sample tube and 100 μL for the control tube), and reagent five (100 μL for the sample tube and 100 μL for the control tube), continue to develop color at 60°C for 15 min. Finally, centrifuge at 12000 rpm for 5 min, and take 200 μL of clear liquid to a 96-well plate, and read the value at 525 nm to obtain ΔA, ΔA = A sample tube - A control tube.

[0343] (4) Inhibition rate calculation

[0344] Formula: Enzyme activity inhibition rate = 1 - (ΔA sample / ΔA blank control)

[0345] The results are shown in Table 1.

[0346] Table 1 Inhibition rate of synthesized compounds and control compounds on enzyme at different concentrations, IC50 value list

[0347]

[0348]

[0349] From Table 1, it can be seen that the compounds of the present application have good inhibitory effect on ALS enzyme at 100 μM and 10 μM concentrations, especially at 10 μM concentration, the inhibition rates of compounds GA-SM-5, compound GA-SM-12, compound GA-SM-13, compound GA-SM-21, compound GA-SM-22, etc. on enzyme are quite or better than that of bensulfuron as a chemical control.

[0350] Example 24

[0351] Weed pot experiment

[0352] 1) Preparation of liquid medicine

[0353] 30 mg of medicine was weighed, 500 μL of DMSO solution was added, 2 drops of Tween 80 were added, mixed, and sterilized water was added to make up to 30 mL (the final concentration was 1 mg / mL).

[0354] 2) Seedling culture

[0355] The seeds of morning glory, abutilon, wild oat and barnyard grass were evenly planted in nutrient soil, the temperature was set to 25℃, 16h light + 8h darkness, and water was regularly poured. After the seeds germinated and rooted, when they grew to two-leaf stage, they could be used for the following experiments.

[0356] 3) Spraying

[0357] The liquid medicine was evenly sprayed on the weeds to be tested by using a handheld spray bottle, the temperature was set to 25℃, 16h light + 8h darkness, and the growth was continued, four parallel groups were set for each group. After one week, the growth of weeds was observed.

[0358] 4) Test statistics: 7d, 14d after treatment, the number of surviving weeds was investigated, and the control formula was:

[0359]

[0360] In the formula: C is the number of surviving weeds in the blank control group, and T is the number of surviving weeds in the herbicide group.

[0361] The experimental results are shown in Table 2.

[0362] Table 2 Experimental results of Example 24

[0363]

[0364] As shown in Table 2, the herbicides of the present application are superior to the control bensulfuron-methyl in terms of the herbicidal activity on grasses, broadleaf weeds and sedge weeds. The control effects of the herbicides at 14 days after treatment are 71.6% to 100%, which are higher than the herbicidal activity of bensulfuron-methyl (63.4% to 95.8%), especially the control effects on resistant weeds such as barnyard grass, morningglory, and cyperus iria are obviously improved. Compared with the control bensulfuron-methyl, the herbicides of the present application have faster onset, higher herbicidal efficiency, and more complete herbicidal effect, and have great application prospects.

Claims

1. An ALS inhibitor sulfonylurea herbicide characterized in that, selected from the following compounds:

2. The method for preparing a sulfonylurea herbicide according to Claim 1, wherein the compound of the formula (2) is prepared by the reaction of the compound of the formula (3) with the compound of the formula (4) in the presence of a base. comprising the following steps: first, an intermediate A is generated by substitution reaction of bromoacetyl bromide or chloroacetic anhydride with an amine compound, then the intermediate A is reacted with a mercapto compound in the presence of triethylamine to generate a thioether, and finally the thioether is oxidized to generate the target product; the amine compound is selected from 2-amino-4,6-dimethoxy pyrimidine, 2-amino-4-methyl-6-methoxy-1,3,5-triazine; the oxidant of the oxidation reaction is meta-chloro-peroxy benzoic acid.

3. The production method according to claim 2, characterized by, the mercapto compound is selected from N,N-dimethyl-2-mercapto nicotinamide, methyl thiosalicylate, 2-sulfenyl phenol, 2-methoxy thiophenol, o-chlorothiophenol, ethyl o-mercaptobenzoate.

4. The use of a sulfonylurea herbicide according to claim 1, wherein the sulfonylurea herbicide is applied to the soil surface of the field. application of the herbicide in inhibiting growth of grass or broadleaf herbaceous plants.

5. The use according to claim 4, wherein the compound is ###0002### application of the herbicide in inhibiting growth of barnyard grass, dogtail grass, zinnia, morning glory, abutilon, cyperus iria, and cyperus alternifolius.

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