ALS inhibitor sulfonylurea herbicide as well as preparation method and application thereof

Abstract

The invention discloses an ALS inhibitor sulfonylurea herbicide as well as a preparation method and application thereof, relates to the technical field of herbicides, and comprises 22 compounds with structures as shown in a general formula I or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as well as a preparation method and application thereof. After the medicines are reasonably matched, the herbicide has a relatively good control effect on gramineae or broad leaf, and the herbicide disclosed by the invention does not cause harm to soil and environment.

Description

Technical Field

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

[0002] Bensulfuron-methyl has been registered for use in my country since 1986. It is a commonly used ALS inhibitor sulfonylurea herbicide in rice fields. It can effectively control most broad-leaved weeds and sedges in rice fields and is very safe for rice and subsequent crops. Bensulfuron-methyl is a highly effective, broad-spectrum, low-toxic and low-dosage selective systemic sulfonylurea herbicide. It is currently one of the main herbicides widely used for weed control in rice fields. However, since the first case of Cyperus difformis resistant to benzsulfuron-methyl was discovered in rice fields in the United States in 1993, weed resistance to benzsulfuron-methyl has evolved rapidly.

[0003] At present, the most reported cases are that weeds of different genera in rice fields are resistant to benzylsulfuron-methyl, with more than 60 reports that can be counted both domestically and internationally. A total of 26 species of rice field weeds from 12 genera are resistant to benzylsulfuron-methyl. Summary of the invention

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

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

[0006] An ALS inhibitor sulfonylurea herbicide, the structure of which is a compound shown in general formula I or its optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0007]

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

[0009] The herbicides include aqueous emulsions, dispersible oil suspensions, dispersible oils, microemulsions, emulsifiable concentrates, soluble solutions, aqueous solutions, suspensions, suspended emulsions, ultra-low volume solutions, powders, wettable powders, granules, water-dispersible granules, dry suspensions, microcapsule suspensions, emulsifiable powders, effervescent granules, effervescent tablets, water-dispersible tablets and other herbicide formulations with the compound represented by general formula I as the active ingredient.

[0010] Further, R2 is selected from O-R3, halogen, O=C-R4; R3 is selected from hydrogen, C1-C10 alkyl, C1-C4 halogenated hydrocarbon; R4 is selected from C1-C4 alkoxy, C1-C4 alkyl, substituted amino; R1 is selected from hydrogen, methyl, methoxy. Further, halogen is chlorine; R3 is selected from hydrogen, methyl, ethyl, n-butyl, ethyl chloride; R4 is selected from methoxy, ethoxy, isopropyl, methylamino, dimethylamino.

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

[0012]

[0013] The preparation method of sulfonylurea herbicide comprises the following steps:

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

[0015] Furthermore, the amine compound is selected from 2-amino-4,6-dimethoxypyrimidine and 2-amino-4-methyl-6-methoxy-1,3,5-triazine.

[0016] Further, the thiol compound is selected from N,N-dimethyl-2-mercaptonicotinamide, methyl thiosalicylate, 2-thiophenol, 4,6-dimethyl-2-mercaptopyrimidine, 2-methoxythiophenol, o-chlorothiophenol, ethyl o-mercaptobenzoate. Further, the oxidant of the oxidation reaction is m-chloroperbenzoic acid.

[0017] Application of sulfonylurea herbicides, and application of the herbicides in inhibiting the growth of grass or broad-leaved herbaceous plants.

[0018] Furthermore, the herbicide is used to inhibit the growth of barnyard grass, foxtail grass, zinnia, morning glory, chrysanthemum, cyperus rotundus, and sedge.

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

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

[0021] C1~Cn used in the present invention include C1~C2, C1~C3...C1~Cn, n is an integer greater than one; the prefix of the substituent represents the minimum and maximum number of carbon atoms in the substituent, for example, "C1~C6 alkyl" refers to a straight chain or branched alkyl containing one to 6 carbon atoms.

[0022] IC50 refers to the concentration of the inhibitor when "cell activity" is inhibited by half. In terms of apoptosis, it can be understood that a certain concentration of a drug induces 50% apoptosis of tumor cells. This concentration is called the 50% inhibitory concentration, that is, the concentration corresponding to the ratio of apoptotic cells to the total number of cells is equal to 50%. The 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. It can also reversely indicate the tolerance of a certain cell to a drug.

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

[0024] After reasonable combination, the drug of the present invention has a good control effect on Gramineae or broad-leaved plants, and takes effect more quickly, has a high weed control efficiency, and has a more thorough weed control effect. The herbicide of the present invention will not cause harm to the soil and the environment. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described here are only a part of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention.

[0026] Example 1

[0027] The synthesis route of GA-SM-4 is as follows:

[0028]

[0029] Specific synthesis steps:

[0030] Synthesis of intermediate 1

[0031] Weigh thiourea (10.0 g, 131.4 mmol, 1.0 eq.) and acetylacetone (6.6 g, 131.4 mmol, 1.0 eq.) and dissolve them in methanol (84.2 g, 2627.4 mmol, 20.0 eq.), and reflux at 65°C for 2 h. Cool slightly, slowly drop concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.), and reflux at 70°C for 1 h. After cooling, remove the solvent from the reaction solution under reduced pressure, dissolve it in water, adjust the pH to about 7 with 10% sodium hydroxide solution, and remove the solvent under reduced pressure again. After column chromatography, 5.3 g of the product (yellow solid, yield 58%) was obtained.

[0032] Synthesis of intermediate 2

[0033] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0034] Synthesis of intermediate 3

[0035] After dissolving the intermediate 1 (1.3 g, 7.1 mmol, 1.0 eq.) in dry dichloromethane (30 mL), triethylamine (2.8 g, 21.4 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, the intermediate 1 (2.2 g, 7.1 mmol, 1.0 eq.) was added and reacted at room temperature overnight. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.6 g of the product (white solid, yield 51%).

[0036] Synthesis of GA-SM-4

[0037] Intermediate 3 (1.6 g, 4.7 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (2.4 g, 9.4 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, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 660 mg of the product was obtained by column chromatography (white solid, yield: 38%).

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

[0039]

[0040] 1 H NMR (400MHz, DMSO-d6) δ10.80(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(101MHz,DMSO-d6)δ172.0,169.3,164.6,156.4,123.7,85.1,57.6,54.7,23.8.HRMS(ESI):calcd for C 14 H 18 N5O5S + (M+H) + :368.1023,found368.1031.

[0041] Example 2

[0042] The synthesis route of GA-SM-5 is as follows:

[0043]

[0044] Specific synthesis steps:

[0045] Synthesis of intermediate 1

[0046] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.4 g of the product (white solid, yield 34%).

[0047] Synthesis of intermediate 2

[0048] 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 overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 4.1 g of the product (white solid, yield 48%).

[0049] Synthesis of GA-SM-5

[0050] Intermediate 2 (4.1 g, 15.6 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (100 mL) to dissolve, and m-chloroperbenzoic acid (9.8 g, 57.1 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, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 2.5 g of the product (white solid, yield: 55%) was obtained by column chromatography (PE:EA:DCM=7:1:1).

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

[0052]

[0053] 1H NMR (400MHz, DMSO-d6) δ10.80(s,1H),7.99(dd,J=7.7,1.4Hz,1H),7.85(td,J=1.4Hz,1H),7.8 2(dd,1H),7.78(td,J=7.2,1.7Hz,1H),5.95(s,1H),5.03(s,2H),3.88(s,3H),3.85(s,6H).13C NMR(101MHz,DMSO-d6)δ172.05,167.67,156.39,137.99,134.72,133.03,131.74,131.50,129.91,85.13,62.79,54.65,53.54.HRMS(ESI):calcd forC16H18N3O7S+(M+H)+:396.0860, found 396.0859.

[0054] Example 3

[0055] The synthesis route of GA-SM-7 is as follows:

[0056]

[0057] Specific synthesis steps:

[0058] Synthesis of intermediate 1

[0059] Weigh thioglycolic acid (4.9 g, 54.0 mmol, 1.0 eq.), dissolve in a mixed solution of DCM (32.4 mL) and glacial acetic acid (32.4 mL), add triphenylmethane (15.1 mmol, 54.0 mmol, 1.0 eq.) and boron trifluoride ether solution (10.8 mL), react at room temperature for 1 h, distill the reaction solution under reduced pressure, extract with water and EA, dry the organic layer over anhydrous sodium sulfate, and distill under reduced pressure to obtain 5.0 g of the product (yellow liquid, yield 28%).

[0060] Synthesis of intermediate 2

[0061] Under argon protection, intermediate 1 (5.0 g, 15.0 mol, 1.0 eq.) was dissolved in dry DCM, and DMF (54 mg, 0.7 mmol, 0.05 eq.) and oxalyl chloride (7.6 g, 59.8 mmol, 4.0 eq.) were slowly added dropwise at 0°C, stirred at 0°C for 10 min, the temperature was raised to room temperature, the reaction was continued for 3 h, and distilled under reduced pressure. Dry DCM was added to dissolve, 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 reacted at room temperature for 1 h. The reaction solution was extracted with saturated sodium bicarbonate, and the organic layer was adjusted to acidic pH, washed with water, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 2.3 g of the product (white solid, yield 33%) by column chromatography.

[0062] Synthesis of intermediate 4

[0063] After dissolving the intermediate 2 (2.3 g, 4.9 mmol, 1.0 eq.) 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, reacted at room temperature for 6 h, triethylamine was added to adjust the pH to 10, activated at 0°C for 30 min, methyl 2-bromomethylbenzoate (1.5 g, 6.6 mml, 1.5 eq.) was added, reacted at room temperature for 2 h, after the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate solution, and then the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 500 mg of the product (white solid, yield 30%).

[0064] Synthesis of GA-SM-7

[0065] Intermediate 4 (500 mg, 1.3 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (20 mL). Meta-chloroperbenzoic acid (1.1 g, 6.6 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 100 mg of the product was obtained by column chromatography (white solid, yield: 18%).

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

[0067]

[0068] 1H NMR(400MHz,Chloroform-d)δ8.22(s,1H),8.00(d,J=7.6Hz,1H),7.64(d,J=7.6Hz,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(101MHz,Chloroform-d)δ172.0,171.3,167.8,155.3,133.4,132.4,131.8,131.5,129.3,128.5,86.0,60.5,57.2,54.7,52.6.HRMS(ESI):calcd forC17H20N3O7S+(M+H)+:410.1016, found 410.1006.

[0069] Example 4

[0070] The synthesis route of GA-SM-9 is as follows:

[0071]

[0072]

[0073] Specific synthesis steps:

[0074] Synthesis of intermediate 1

[0075] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0076] Synthesis of intermediate 2

[0077] 2-Mercapto-N-methylbenzamide (4.0 g, 12.0 mmol, 2.0 eq.) was dissolved in dry dichloromethane (50 mL), and triethylamine (2.4 g, 13.9 mmol, 4.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.7 g, 6.0 mmol, 1.0 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.1 g of the product (white solid, yield 51%).

[0078] Synthesis of GA-SM-9

[0079] Intermediate 2 (1.1 g, 3.0 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-chloroperbenzoic acid (2.6 g, 15.3 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 2.5 g of the product (white solid, yield: 55%) by column chromatography.

[0080] The structural formula of GA-SM-9 is shown below:

[0081]

[0082] 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.60(s,1H),7.94(d,J=8.0Hz,1H),7.82-7.76(m,1H),7.73 -7.66(m,1H),7.56(d,J=7.6Hz,1H),5.95(s,1H),5.14(s,2H),3.86(s,6H),2.78(d,J=4.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.5,168.1,155.9,137.5,137.0,134.0,130.7,129.6,128.7,84.6,63.1,54.2,26.2.HRMS(ESI):calcd forC 16 H 19 N4O6S + (M+H) + :395.1020, found 395.1009.

[0083] Example 5

[0084] The synthesis route of GA-SM-10 is as follows:

[0085]

[0086] Specific synthesis steps:

[0087] Synthesis of intermediate 1

[0088] Weigh dithiosalicylic acid (2.0 g, 6.5 mmol, 1.0 eq.) and dissolve it in dry tetrahydrofuran (30 mL), then drop DMF (0.05 eq). Slowly drop oxalyl chloride (3.0 g, 19.6 mmol, 3.0 eq) under stirring, and react 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, and a tetrahydrofuran solution of dimethylamine (2.94 g, 2 mol / Lin THF, 10.0 eq.) was added dropwise with a syringe, and reacted 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 washed with saturated brine (1*30 mL), and the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 2.1 g of the product was obtained (yellow solid, yield 89%).

[0089] Synthesis of intermediate 2

[0090] Weigh the intermediate 1 (2.0 g, 5.5 mmol, 1.0 eq.), dissolve it in methanol (20 mL), add dichloromethane (15 mL), add tri(2-carboxyethyl)phosphine hydrochloride (7.95 g, 27.7 mmol, 5.0 eq.), react at room temperature, monitor by TLC, and the reaction is complete in 1.5 h. The reaction solution is distilled under reduced pressure, extracted with dichloromethane and water, the organic layer is washed with saturated brine (1*20 mL), the organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. 1.9 g of the product (yellow oil, yield 95%) is obtained.

[0091] Synthesis of intermediate 3

[0092] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 ml), and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0093] Synthesis of intermediate 4

[0094] Weigh the intermediate 2 (1.9 g, 10.7 mmol, 1.5 eq.), dissolve it in dry dichloromethane (30 mL), and add triethylamine (2.9 g, 28.6 mmol, 4.0 eq.) at 0°C. After activation for 30 min, add the intermediate 3 (2.0 g, 7.1 mmol, 1.0 eq.), and react overnight at room temperature. After the reaction is completed, adjust the pH to 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. Column chromatography gives 1.9 g of the product (light yellow solid, yield 71%).

[0095] Synthesis of GA-SM-10

[0096] Intermediate 4 (1.9 g, 5.0 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (4.4 g, 25.2 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, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 800 mg of the product was obtained by column chromatography (white solid, yield: 39%).

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

[0098]

[0099] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.60(s,1H),7.94(d,J=8.0Hz,1H),7.82-7.76(m,1H),7.73 -7.66(m,1H),7.56(d,J=7.6Hz,1H),5.95(s,1H),5.14(s,2H),3.86(s,6H),2.78(d,J=4.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.5,168.1,155.9,137.5,137.0,134.0,130.7,129.6,128.7,84.6,63.1,54.2,26.2.HRMS(ESI):calcd forC 16 H 19 N4O6S + (M+H) + :395.1020, found 395.1009.

[0100] Example 6

[0101] The synthesis route of GA-SM-11 is as follows:

[0102]

[0103] Specific synthesis steps:

[0104] Synthesis of intermediate 1

[0105] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.4 g of the product (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 activation for 30 min, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 4.1 g of the product (white solid, yield 48%).

[0108] Synthesis of intermediate 3

[0109] Intermediate 2 (4.1 g, 15.6 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (100 mL) to dissolve, and m-chloroperbenzoic acid (9.8 g, 57.1 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, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 2.5 g of the product was obtained by column chromatography (white solid, yield: 55%).

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

[0111] Weigh the intermediate 3 (2.5 g, 5.1 mmol, 1.0 eq.), N, O-dimethylhydroxylamine hydrochloride (1.2 g, 10.1 mmol, 2.0 eq.), place in a dry round-bottom bottle, add ultra-dry tetrahydrofuran (10 mL) under argon protection, slowly add isopropylmagnesium bromide (11.38 mL, 18.2 mmol, 3.6 eq.) with a syringe at 0 ° C, react at room temperature for 2 h, slowly add isopropylmagnesium bromide (8.22 mL, 13.2 mmol, 2.6 eq.) with a syringe, continue to react at room temperature for 2 h, and monitor the reaction of the raw materials by TLC. Add saturated ammonium chloride solution to quench, extract with dichloromethane, dry the organic layer with anhydrous magnesium sulfate, distill under reduced pressure, and chromatographic column (DCM: MeOH = 100: 1) to obtain 210 mg of the product (yellow solid, yield 15%).

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

[0113]

[0114] 1H NMR(400MHz,DMSO-d6)δ11.06(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=6.8Hz,3H),0.91(d,J=6.7Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ172.06,166.1,155.2,144.6,138.1,133.6,129.9,125.8,121.3,86.6,81.6,70.8,54.8,37.4,18.1,16.9.HRMS(ESI):calcd forC 18 H 22 N3O6S + (M+H) + :408.1224, found 408.1223.

[0115] Example 7

[0116] The synthesis route of GA-SM-12 is as follows:

[0117]

[0118] Specific synthesis steps:

[0119] Synthesis of intermediate 1

[0120] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After the reaction, 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 dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0121] Synthesis of intermediate 2

[0122] 2-sulfanylphenol (5.0 g, 39.6 mmol, 1.0 eq.) was dissolved in dry dichloromethane (50 mL), and triethylamine (12.0 g, 118.9 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (9.8 g, 47.6 mmol, 1.2 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidity with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. After column chromatography, 5.9 g of the product (white solid, yield 46%) was obtained.

[0123] Synthesis of intermediate 3

[0124] Weigh the 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.) and add acetone (20 mL) to dissolve, anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.), reflux at 65 ° C for 24 h, after the reaction is completed, the solvent is distilled under reduced pressure, the pH is adjusted to acidic with 2N HCl, extracted with water and dichloromethane, the organic layer is washed with saturated brine (3*10 mL), and then the organic layer is dried with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Purification by column chromatography gives 2.9 g of the product (white solid, yield 49%).

[0125] Synthesis of GA-SM-12

[0126] Intermediate 3 (2.9 g, 7.6 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (6.5 g, 37.8 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, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 700 mg of the product (white solid, yield: 22%) by column chromatography.

[0127] The structural formula of GA-SM-12

[0128]

[0129] 1H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.99-7.93(m,1H),7.62-7.55(m,1H),7.17-7.10(m,1H), 7.01(d,J=8.4Hz,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(101MHz,Chloroform-d)δ171.8,155.7,155.3,135.9,130.7,121.5,113.3,85.7,69.2,60.4,54.5,41.8.HRMS(ESI):calcd forC 16 H 19 ClN3O6S + (M+H) + :416.0678,found 416.0674.

[0130] Example 8

[0131] The synthesis route of GA-SM-13 is as follows:

[0132]

[0133] Specific synthesis steps:

[0134] Synthesis of intermediate 1

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

[0136] Synthesis of intermediate 2

[0137] 2-sulfanylphenol (5.0 g, 39.6 mmol, 1.0 eq.) was dissolved in dry dichloromethane (50 mL), and triethylamine (12.0 g, 118.9 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (9.8 g, 47.6 mmol, 1.2 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidity with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. After column chromatography, 5.9 g of the product (white solid, yield 46%) was obtained.

[0138] Synthesis of intermediate 3

[0139] Weigh the intermediate 2 (5.0 g, 15.5 mmol, 1.0 eq.) and iodoethane (3.9 g, 24.9 mmol, 1.6 eq.) and add acetone (20 mL) to dissolve, anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.), reflux at 50 ° C for 24 h, after the reaction is completed, the solvent is distilled under reduced pressure, the pH is adjusted to acidic with 2N HCl, extracted with water and dichloromethane, the organic layer is washed with saturated brine (3*10 mL), and then the organic layer is dried with anhydrous sodium sulfate, and the solvent is distilled under reduced pressure. After column chromatography, 3.1 g of the product (white solid, yield 57%) is obtained.

[0140] Synthesis of GA-SM-13

[0141] Intermediate 4 (3.1 g, 8.9 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (50 mL). Meta-chloroperbenzoic acid (7.7 g, 44.4 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 1.3 g of the product (white solid, yield: 38%) by column chromatography.

[0142] The structural formula of GA-SM-13

[0143]

[0144] 1H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.94(dd,J=8.0,1.8Hz,1H),7.58(ddd,J=8.4,7.4,1.8Hz,1H) ,7.11-7.00(m,2H),5.79(s,1H),5.10(s,2H),4.24(q,J=6.8Hz,2H),3.91(s,6H),1.51(t,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.9,156.7,155.3,136.0,130.4,120.6,113.3,85.8,65.2,60.2,54.5,14.6.HRMS(ESI):calcdfor C 16 H 20 N3O6S + (M+H) + :382.1067, found 382.2.1055.

[0145] Example 9

[0146] The synthesis route of GA-SM-14 is as follows:

[0147]

[0148] Specific synthesis steps:

[0149] Synthesis of intermediate 1

[0150] Weigh the 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.) and mix well, reflux at 90°C for 1 h, add saturated sodium bicarbonate solution to adjust the pH to 8, extract with DCM, and then dry the organic layer with anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. The layer is subjected to column chromatography to obtain 1.2 g of the product (white solid, yield 19%).

[0151] Synthesis of intermediate 2

[0152] Thiosalicylic acid methyl ester (1.8 g, 10.7 mmol, 2.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Triethylamine (2.2 g, 21.4 mmol, 4.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.2 g, 5.4 mmol, 1.0 eq.) was added. The mixture was reacted at room temperature for 2 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 dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. 1.0 g of the product (white solid, yield 52%) was obtained by column chromatography.

[0153] Synthesis of GA-SM-14

[0154] Intermediate 2 (1.0 g, 2.9 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (2.5 g, 14.3 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, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 600 mg of the product was obtained by column chromatography (white solid, yield: 71%).

[0155] The structural formula of GA-SM-14

[0156]

[0157] 1 H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.25(dd,J=8.0,1.2Hz,1H),8.10(dd,J=7.6,1.2Hz,1H),7.82-7.73( m,1H),7.63-7.55(m,1H),4.44(d,J=14.0Hz,1H),4.17(d,J=14.0Hz,1H),3.98(s,3H),3.94(s,3H),2.49(s,3H). 13 C NMR(101MHz,Chloroform-d)δ179.9,171.4,165.8,164.1,163.5,146.0,134.1,131.1,131.0,126.9,125.3,59.7,55.1,52.9,25.5.HRMS(ESI):calcd for C 15 H 17 N4O6S + (M+H) + :381.0863,found381.0853.

[0158] Example 10

[0159] The synthesis route of GA-SM-15 is as follows:

[0160]

[0161] Specific synthesis steps:

[0162] Synthesis of intermediate 1

[0163] Under argon protection, 2-amino-6-dimethoxypyridine (2.0 g, 16.1 mol, 1.0 eq.) and cesium carbonate (6.3 g, 19.3 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.0 g of the product (white solid, yield 76%).

[0164] Synthesis of intermediate 2

[0165] Methyl thiosalicylate (2.8 g, 16.3 mmol, 2.0 eq.) was dissolved in dry dichloromethane (40 mL), and triethylamine (3.3 g, 32.7 mmol, 4.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (2.0 g, 8.2 mmol, 1.0 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.0 g of the product (white solid, yield 74%).

[0166] Synthesis of GA-SM-15

[0167] Intermediate 2 (2.0 g, 6.0 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (50 mL) to dissolve, and m-chloroperbenzoic acid (5.2 g, 30.1 mmol, 5.0 eq.) was added and reacted at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (20 mL) was added to quench, and then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 800 mg of the product was obtained by column chromatography (white solid, yield: 37%).

[0168] The structural formula of GA-SM-15

[0169]

[0170] 1 H NMR(400MHz,Chloroform-d)δ8.70(s,1H),8.15(d,J=8.0Hz,1H),7.80(dd,J=7.6,1.6Hz,1H),7.76-7.71(m,1 H),7.70-7.64(m,1H),7.64-7.54(m,2H),6.53(dd,J=7.6,1.2Hz,1H),4.69(s,2H),4.04(s,3H),3.88(s,3H). 13 C NMR(101MHz,Chloroform-d)δ166.4,161.8,157.8,147.2,139.8,136.4,133.2,131.9,130.5,130.1,129.2,105.8,104.8,62.6,52.5,52.5.HRMS(ESI):calcd for C 16 H 17 N2O6S + (M+H) + :365.0802,found365.0804.

[0171] Embodiment 11

[0172] The synthesis route of GA-SM-16 is as follows:

[0173]

[0174] Specific synthesis steps:

[0175] Synthesis of intermediate 1

[0176] Under argon protection, 4-amino-2,6-dimethoxypyrimidine (2.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.4 g of the product (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 overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.5 g of the product (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 added to dry dichloromethane (40 mL) to dissolve, and m-chloroperbenzoic acid (3.1 g, 17.9 mmol, 5.0 eq.) was added and reacted at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (15 mL) was added to quench, and then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 512 mg of the product was obtained by column chromatography (white solid, yield: 38%).

[0181] The structural formula of GA-SM-16

[0182]

[0183] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),7.96(d,J=7.6Hz,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(101MHz,DMSO-d6)δ173.0,167.6,164.9,162.1,159.5,137.6,135.0,133.1,131.9,131.5,130.0,88.4,62.8,54.9,54.5,53.6.HRMS(ESI):calcd for C 16 H 18 N3O7S + (M+H) + :396.0860, found 396.0853.

[0184] Example 12

[0185] The synthesis route of GA-SM-17 is as follows:

[0186]

[0187] Specific synthesis steps:

[0188] Synthesis of intermediate 1

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

[0190] Synthesis of intermediate 2

[0191] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0192] Synthesis of intermediate 3

[0193] After dissolving the intermediate 1 (1.1 g, 5.8 mmol, 2.0 eq.) in dry dichloromethane (30 mL), triethylamine (1.2 g, 11.6 mmol, 4.0 eq.) was added at 0°C. After activation for 30 min, the intermediate 1 (800 mg, 2.9 mmol, 1.0 eq.) was added and reacted at room temperature overnight. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.0 g of the product (white solid, yield 46%).

[0194] Synthesis of GA-SM-17

[0195] Intermediate 3 (1.3 g, 3.3 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-chloroperbenzoic acid (2.9 g, 16.6 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 300 mg of the product was obtained by column chromatography (white solid, yield: 22%).

[0196] The structural formula of GA-SM-17 is as follows:

[0197]

[0198] 1 H NMR(400MHz,Chloroform-d)δ8.72(dd,J=4.8,1.6Hz,1H),8.46(s,1H),7.78(dd,J=8.0,1. 6Hz, 1H), 7.60 (dd, J = 8.0, 4.8Hz, 1H), 5.18 (s, 2H), 4.00 (s, 6H), 3.13 (s, 3H), 2.88 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ167.2,166.6,153.3,152.6,149.6,136.8,132.9,127.6,82.7,59.5,55.6,39.0,35.0.HRMS(ESI):calcd for C 16 H 20 N5O6S + (M+H) + :410.1129, found 410.1130.

[0199] Embodiment 13

[0200] The synthesis route of GA-SM-19 is as follows:

[0201]

[0202] Specific synthesis steps:

[0203] Synthesis of intermediate 1

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

[0205] Synthesis of intermediate 2

[0206] Weigh the 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.) and mix well, reflux at 90°C for 1 h, add saturated sodium bicarbonate solution to adjust the pH to 8, extract with DCM, and then dry the organic layer with anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. The layer is subjected to column chromatography to obtain 1.2 g of the product (white solid, yield 19%).

[0207] Synthesis of intermediate 3

[0208] After dissolving the intermediate 1 (777 mg, 5.5 mmol, 1.0 eq.) in dry dichloromethane (30 mL), triethylamine (1.1 g, 11.1 mmol, 4.0 eq.) was added at 0°C. After activation for 30 min, the intermediate 2 (600 mg, 2.8 mmol, 1.0 eq.) was added and reacted at room temperature overnight. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 745 mg of the product (white solid, yield 84%).

[0209] Synthesis of GA-SM-19

[0210] Intermediate 3 (745 mg, 2.3 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-chloroperbenzoic acid (2.0 g, 11.6 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 100 mg of the product was obtained by column chromatography (white solid, yield: 12%).

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

[0212]

[0213] 1 H NMR (400MHz, Chloroform-d) δ8.97(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(101MHz,Chloroform-d)δ180.1,171.4,169.5,164.7,164.0,161.5,123.2,57.9,55.4,25.5,23.9.HRMS(ESI):calcd for C 13 H 17 N6O4S + (M+H) + :353.1027, found 353.1023.

[0214] Embodiment 14

[0215] The synthesis route of GA-SM-20 is as follows:

[0216]

[0217] Specific synthesis steps:

[0218] Synthesis of intermediate 1

[0219] Weigh thiourea (10.0 g, 131.4 mmol, 1.0 eq.) and acetylacetone (6.6 g, 131.4 mmol, 1.0 eq.) and dissolve in methanol (84.2 g, 2627.4 mmol, 20.0 eq.), reflux at 65°C for 2 h. Cool slightly, slowly drop concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.), reflux at 70°C for 1 h. After cooling, spin dry the reaction solution, dissolve it in water, adjust the pH to about 7 with 10% sodium hydroxide solution, and spin dry again. After column chromatography, 5.3 g of the product (yellow solid, yield 58%) was obtained.

[0220] Synthesis of intermediate 2

[0221] Under argon protection, 2-amino-6-dimethoxypyridine (2.0 g, 16.1 mol, 1.0 eq.) and cesium carbonate (6.3 g, 19.3 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.0 g of the product (white solid, yield 76%).

[0222] Synthesis of intermediate 3

[0223] After dissolving the intermediate 1 (2.3 g, 16.3 mmol, 1.0 eq.) in dry dichloromethane (30 mL), triethylamine (3.3 g, 32.6 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, the intermediate 2 (2.0 g, 8.2 mmol, 1.0 eq.) was added and reacted at room temperature overnight. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.5 g of the product (white solid, yield 60%).

[0224] Synthesis of GA-SM-20

[0225] Intermediate 3 (1.5 g, 4.9 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-chloroperbenzoic acid (4.2 g, 24.5 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 the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 590 mg of the product was obtained by column chromatography (white solid, yield: 36%).

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

[0227]

[0228] 1 H NMR (400MHz, Chloroform-d) δ9.20 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.57-7.52 (m, 1H),7.26(s,1H),6.49(d,J=8.0Hz,1H),4.59(s,2H),3.83(s,3H),2.63(s,6H). 13C NMR(101MHz,Chloroform-d)δ169.6,164.7,162.9,158.7,148.3,140.7,123.4,106.9,105.8,58.4,53.5,23.9.HRMS(ESI):calcd for C 14 H 17 N4O4S + (M+H) + :337.0965, found 337.0961.

[0229] Embodiment 15

[0230] The synthesis route of GA-SM-21 is as follows:

[0231]

[0232] Specific synthesis steps:

[0233] Synthesis of intermediate 1

[0234] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0235] Synthesis of intermediate 2

[0236] 2-sulfanylphenol (5.0 g, 39.6 mmol, 1.0 eq.) was dissolved in dry dichloromethane (50 mL), and triethylamine (12.0 g, 118.9 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (9.8 g, 47.6 mmol, 1.2 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidity with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. After column chromatography, 5.9 g of the product (white solid, yield 46%) was obtained.

[0237] Synthesis of intermediate 3

[0238] Weigh intermediate 2 (3.0 g, 9.3 mmol, 1.0 eq.) and bromobutyl (2.0 g, 14.9 mmol, 1.6 eq.) and add acetone (20 mL) to dissolve, anhydrous potassium carbonate (2.6 g, 18.7 mmol, 2.0 eq.), reflux at 55 ° C for 24 h, after the reaction is completed, the solvent is distilled under reduced pressure, the pH is adjusted to acidic with 2N HCl, extracted with water and dichloromethane, the organic layer is washed with saturated brine (3*10 mL), and then the organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled under reduced pressure. After column chromatography, 600 mg of the product (white solid, yield 17%) is obtained.

[0239] Synthesis of GA-SM-21

[0240] Intermediate 4 (400 mg, 1.1 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-chloroperbenzoic acid (919 mg, 5.3 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 the reaction. The mixture was extracted with dichloromethane and water. The organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 103 mg of the product was obtained by column chromatography (white solid, yield: 24%).

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

[0242]

[0243] 1 H NMR(400MHz,Chloroform-d)δ8.34(s,1H),7.93(d,J=8.0Hz,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=6.8Hz,2H),3.91(s,6H),1.86(p,J=7.2,6.8Hz,2H),1.53(h,J=7.6Hz,2H),0.97(t,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.9,156.9,155.4,136.0,130.5,126.7,120.6,113.2,85.8,69.2,60.2,54.5,31.0,19.2,13.8.HRMS(ESI):calcd for C 18 H 24 N3O6S + (M+H) +:410.1380, found 410.1379.

[0244] Example 16

[0245] The synthesis route of GA-SM-22 is as follows:

[0246]

[0247] Specific synthesis steps:

[0248] Synthesis of intermediate 1

[0249] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0250] Synthesis of intermediate 2

[0251] 2-Methoxybenzenethiol (761 mg, 5.4 mmol, 1.5 eq.) was dissolved in dry dichloromethane (20 mL), and triethylamine (1.1 g, 10.9 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 730 mg of the product (white solid, yield 60%).

[0252] Synthesis of GA-SM-22

[0253] Intermediate 4 (730 mg, 2.2 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (1.9 g, 10.9 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, and the combined organic layers were dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 384 mg of the product was obtained by column chromatography (white solid, yield: 48%).

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

[0255]

[0256] 1 H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.94(dd,J=8.0,2.0Hz,1H),7.64-7.5 7(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(101MHz,Chloroform-d)δ171.9,157.3,155.3,136.1,130.6,126.7,120.8,112.4,85.8,60.2,56.4,54.5.HRMS(ESI):calcd for C 15 H 18 N3O6S + (M+H) + :368.0911, found 368.0903.

[0257] Embodiment 17

[0258] The synthesis route of GA-SM-23 is as follows:

[0259]

[0260] Specific synthesis steps:

[0261] Synthesis of intermediate 1

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

[0263] Synthesis of intermediate 2

[0264] 2-sulfanylphenol (761 mg, 5.4 mmol, 1.5 eq.) was dissolved in dry dichloromethane (30 mL), and triethylamine (1.1 g, 10.9 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.) was added and reacted overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. After column chromatography, 800 mg of the product (white solid, yield 66%) was obtained.

[0265] Synthesis of GA-SM-23

[0266] Intermediate 2 (800 mg, 2.5 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (2.5 g, 12.5 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, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 200 mg of the product was obtained by column chromatography (white solid, yield: 23%).

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

[0268]

[0269] 1 H NMR (400MHz, Chloroform-d) δ8.24 (s, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.53-7.41 (m, 1H), 7.02-6.94 (m, 2H), 5.78 (s, 1H), 3.90 (s, 6H). 13 C NMR(101MHz,Chloroform-d)δ171.9,156.5,155.1,136.9,129.7,121.9,120.5,119.0,85.8,62.0,54.6.HRMS(ESI):calcd for C 14 H 16 N3O6S + (M+H) + :354.0754, found 354.0741.

[0270] Embodiment 18

[0271] The synthesis route of GA-SM-24 is as follows:

[0272]

[0273] Specific synthesis steps:

[0274] Synthesis of intermediate 1

[0275] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.93 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine (3*50 mL), and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.38 g of the product (white solid, yield 34%).

[0276] Synthesis of intermediate 2

[0277] After dissolving o-chlorobenzenethiol (662 mg, 4.4 mmol, 1.2 eq.) in dry dichloromethane (50 mL), triethylamine (1.1 g, 10.8 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.) was added and reacted overnight at room temperature. After the reaction was completed, the pH was adjusted to acidity with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. After column chromatography, 400 mg of the product (white solid, yield 66%) was obtained.

[0278] Synthesis of GA-SM-24

[0279] Intermediate 4 (400 mg, 1.2 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (20 mL). Meta-chloroperbenzoic acid (1.1 g, 6.0 mmol, 5.0 eq.) was added and reacted at room temperature for 4 h. After the reaction was completed, saturated sodium carbonate solution (8 mL) was added to quench the reaction. The reaction was then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 100 mg of the product was obtained by column chromatography (white solid, yield: 23%).

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

[0281]

[0282] 1H NMR (400MHz, Chloroform-d) δ8.62(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(101MHz,Chloroform-d)δ171.9,155.4,132.6,130.2,129.9,128.1,126.4,85.6,54.6,54.3,29.7.HRMS(ESI):calcd forC 14 H 15 ClN3O6S + (M+H) + :372.0415, found 372.0409.

[0283] Embodiment 19

[0284] The synthesis route of GA-SM-25 is as follows:

[0285]

[0286] Specific synthesis steps:

[0287] Synthesis of intermediate 1

[0288] Weigh dithiosalicylic acid (2.0 g, 6.5 mmol, 1.0 eq.) and cesium carbonate (4.1 g, 26.1 mmol, 4.0 eq.), dissolve in DMF (10 mL), react at 70 ° C for 5 h, distill the reaction solution under reduced pressure, extract with water and dichloromethane, wash the organic layer with aqueous solution (3*10 mL), then wash with saturated brine (1*30 mL), dry the organic layer with anhydrous sodium sulfate, and distill to remove the solvent under reduced pressure. 1.5 g of the product (yellow liquid, yield 63%) was obtained.

[0289] Synthesis of intermediate 2

[0290] Weigh the intermediate 1 (1.5 g, 4.1 mmol, 1.0 eq.), dissolve it in methanol (20 mL), add dichloromethane (20 mL), add tri(2-carboxyethyl)phosphine hydrochloride (5.9 g, 20.7 mmol, 5.0 eq.), react at room temperature, monitor by TLC, and the reaction is complete after 1.5 h. The reaction solution is distilled under reduced pressure, extracted with dichloromethane and water, the organic layer is washed with saturated brine (1*20 mL), the organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. 1.1 g of the product (yellow oil, yield 70%) is obtained.

[0291] Synthesis of intermediate 3

[0292] Weigh the intermediate 2 (1.1 g, 6.0 mmol, 1.0 eq.), dissolve it in dry dichloromethane (30 mL), and add triethylamine (1.8 g, 18.1 mmol, 3.0 eq.) at 0°C. After activation for 30 min, add the intermediate 3 (1.8 g, 6.6 mmol, 1.1 eq.), and react overnight at room temperature. After the reaction is completed, adjust the pH to 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. Column chromatography gives 1.1 g of the product (light yellow solid, yield 52%).

[0293] Synthesis of GA-SM-25

[0294] Intermediate 3 (1.1 g, 2.5 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and m-chloroperbenzoic acid (2.5 g, 14.6 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, and the combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized in acetonitrile to obtain a crude product. 200 mg of the product was obtained by column chromatography (white solid, yield: 17%).

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

[0296]

[0297] 1 H NMR(400MHz,Chloroform-d)δ8.29(s,1H),8.03-7.96(m,1H),7.54(d,J=8.0Hz,1H),7.50-7.42(m,1H), 7.24-7.18(m,1H),5.77(s,1H),4.39(q,J=7.2Hz,2H),4.21(s,2H),3.91(s,6H),1.40(t,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.9,170.1,167.1,155.3,138.1,133.8,133.1,131.8,131.1,129.9,85.8,62.6,54.5,53.2,14.0.HRMS(ESI):calcd for C 17 H 22 N3O7S + (M+H) + :410.1016, found 410.1012.

[0298] Embodiment 20

[0299] The synthesis route of GA-SM-28 is as follows:

[0300]

[0301] Specific synthesis steps:

[0302] Synthesis of intermediate 1

[0303] Weigh 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.) in a bottle, react at 90°C for 1 hour, add saturated sodium bicarbonate solution to adjust the pH to 8 after the reaction, extract with DCM, dry the organic layer with anhydrous sodium sulfate, and remove the solvent by vacuum distillation. Purify by column chromatography to obtain 1.2 g of the product (white solid, yield 69%).

[0304] Synthesis of intermediate 2

[0305] After dissolving o-chlorobenzenethiol (961 mg, 6.6 mmol, 1.2 eq.) in dry dichloromethane (20 mL), triethylamine (1.7 g, 16.6 mmol, 3.0 eq.) was added at 0°C. After activation for 30 min, intermediate 1 (1.2 g, 5.5 mmol, 1.0 eq.) was added and reacted overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, extracted with water and dichloromethane, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 1.1 g of the product (white solid, yield 59%).

[0306] Synthesis of GA-SM-28

[0307] Intermediate 2 (1.1 g, 3.4 mmol, 1.0 eq.) was weighed and added to dry dichloromethane (30 mL) to dissolve, and 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, and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. 300 mg of the product was obtained by column chromatography (white solid, yield: 25%).

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

[0309]

[0310] 1H NMR(400MHz,Chloroform-d)δ9.19(s,1H),7.92(d,J=7.6Hz,1H),7.52-7.42(m,2H),7.39( d,J=7.6Hz,1H),4.49(d,J=14.0Hz,1H),4.27(d,J=14.0Hz,1H),3.96(s,3H),2.48(s,3H). 13 C NMR(101MHz,Chloroform-d)δ180.0,171.3,164.0,163.2,139.6,132.8,130.3,130.0,128.2,126.4,58.2,55.2,25.5.HRMS(ESI):calcd for C 13 H 14 ClN4O4S + (M+H) + :357.0419, found 357.0418.

[0311] Embodiment 21

[0312] The synthesis route of GA-SM-29 is as follows:

[0313]

[0314] Specific synthesis steps:

[0315] Synthesis of intermediate 1

[0316] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.4 g of the product (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 overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 4.1 g of the product (white solid, yield 48%).

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

[0320]

[0321] 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.98(d,J=8.0Hz,1H),7.53(d,J=8.2Hz,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(101MHz,Chloroform-d)δ172.0,168.4,166.8,155.6,140.1,133.0,131.5,127.6,126.4,124.9,85.4,54.4,52.2,37.7.HRMS(ESI):calcd for C 16 H 18 N3O5S + (M+H) + :364.0962, found 364.0951.

[0322] Embodiment 22

[0323] The synthesis route of GA-SM-30 is as follows:

[0324]

[0325] Specific synthesis steps:

[0326] Synthesis of intermediate 1

[0327] Under argon protection, 2-amino-4,6-dimethoxypyrimidine (4.0 g, 25.8 mol, 1.0 eq.) and cesium carbonate (10.1 g, 30.9 mmol, 1.2 eq.) were dissolved in acetonitrile (150 mL), and bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C, and the reaction was continued for 3 h. After the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 2.4 g of the product (white solid, yield 34%).

[0328] Synthesis of intermediate 2

[0329] 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 overnight at room temperature. After the reaction was completed, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography gave 4.1 g of the product (white solid, yield 48%).

[0330] Synthesis of GA-SM-30

[0331] Intermediate 2 (1.0 g, 2.7 mmol, 1.0 eq.) was weighed, glacial acetic acid (4 mL) and 30% hydrogen peroxide solution (1 mL) were added, and the mixture was reacted at room temperature for 24 h. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 8, and then extracted with dichloromethane and water. The organic layer was washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 300 mg of the product (white solid, yield: 29%) by column chromatography.

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

[0333]

[0334] 1 H NMR(400MHz,Chloroform-d)δ8.73(s,1H),8.30(dd,J=8.0,1.2Hz,1H),8.09(dd,J=7.6,1.2Hz,1H),7.82-7.74( m,1H),7.63-7.53(m,1H),5.74(s,1H),4.48(d,J=14.0Hz,1H),4.22(d,J=14.0Hz,1H),3.94(s,3H),3.84(s,6H).13 C NMR(101MHz,Chloroform-d)δ171.9,165.8,155.5,134.0,131.0,130.8,126.9,125.3,85.5,54.2,53.7,52.8.HRMS(ESI):calcd for C 16 H 18 N3O6S + (M+H) + :380.0911,found380.0901.

[0335] Embodiment 23

[0336] ALS enzyme activity test

[0337] (1) Sample preparation

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

[0339] (2) Sample configuration

[0340] Weigh the drug and prepare it into 10mmol / L and 1mmol / L DMSO solutions, then take 5μL of each and add it into 500μL tobacco protein extract (ie, the detection concentrations are 100μM and 10μM, respectively), mix well and test.

[0341] (3) On-machine testing

[0342] Preheat the microplate reader for 30 minutes and adjust the wavelength to 525nm. Preheat all reagents in the kit at 25℃ for 10 minutes, set up sample tubes and control tubes, and set up three parallels for each group. Add reagent one (sample tube 20μL, control tube 0), reagent two (sample tube 100μL, control tube 120μL), sample solution (sample tube 80μL, control tube 80μL) in a 1mL centrifuge tube in sequence, and react in the dark at 35℃ for 1h. Then add reagent three (sample tube 20μL, control tube 20μL), decarboxylate in a water bath at 60℃ for 15min, add reagent four (sample tube 100μL, control tube 100μL), reagent five (sample tube 100μL, control tube 100μL), and continue to color in a water bath at 60℃ for 15min. Finally, centrifuge at 12000 rpm for 5 min, take 200 μL of the clarified liquid into a 96-well plate, read the value at 525 nm, and obtain ΔA, ΔA=A sample tube-A control tube.

[0343] (4) Calculation of inhibition rate

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

[0345] The results are shown in Table 1.

[0346] Table 1. The inhibition rate and IC50 value of the synthetic compounds and control compounds on the enzyme at different concentrations

[0347]

[0348]

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

[0350] Embodiment 24

[0351] Weed pot experiment

[0352] 1) Preparation of drug solution

[0353] Weigh 30 mg of the drug, add 500 μL of DMSO solution, then add 2 drops of Tween 80, mix well, and add sterile water to make up to 30 mL (final concentration is 1 mg / mL).

[0354] 2) Seedling cultivation

[0355] Evenly plant the seeds of morning glory, chrysanthemum, wild oats and barnyard grass in the nutrient soil, set the temperature to 25℃, 16h light + 8h dark, and water regularly. When the seeds germinate and take root and grow to the two-leaf stage, they can be used for the next experiment.

[0356] 3) Spraying

[0357] Use a handheld spray bottle to evenly spray the liquid on the weeds to be tested, set the temperature to 25°C, 16h light + 8h dark, and continue growing. Set four parallels for each group. Observe the growth of the weeds after one week.

[0358] 4) Test statistics: The number of weeds was investigated 7 days and 14 days after application, and the control effect was calculated using the formula:

[0359]

[0360] Where: 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 have better weed control activity against grass, broadleaf and sedge weeds than the control bensulfuron-methyl. The control effect of each herbicide 14 days after application is 71.6% to 100%, which is higher than the weed control activity of bensulfuron-methyl of 63.4% to 95.8%, especially against resistant weeds such as barnyard grass, morning glory and sedge. Compared with the control bensulfuron-methyl, the herbicides of the present application have faster onset, higher weed control efficiency and more thorough weed control effect, and have great application prospects.

Claims

1. An ALS inhibitor sulfonylurea herbicide, characterized in that: The compound having the structure shown in general formula I or its optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: Among them, R is selected from Y is selected from S, S=O, O=S=O, Z1, Z2, Z3 are independently selected from C, N; R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy.

2. The ALS inhibitor sulfonylurea herbicide according to claim 1, characterized in that: R2 is selected from O-R3, halogen, O=C-R4; R3 is selected from hydrogen, C1-C10 alkyl, C1-C4 halogenated hydrocarbon; R4 is selected from C1-C4 alkoxy, C1-C4 alkyl, substituted amino; R1 is selected from hydrogen, methyl, methoxy.

3. The ALS inhibitor sulfonylurea herbicide according to claim 1, characterized in that: Halogen is chlorine; R3 is selected from hydrogen, methyl, ethyl, n-butyl, ethyl chloride; R4 is selected from methoxy, ethoxy, isopropyl, methylamino, dimethylamino.

4. The ALS inhibitor sulfonylurea herbicide according to claim 1, characterized in that: The herbicides include aqueous emulsions, dispersible oil suspensions, dispersible oils, microemulsions, emulsifiable concentrates, soluble solutions, aqueous solutions, suspensions, suspended emulsions, ultra-low volume solutions, powders, wettable powders, granules, water-dispersible granules, dry suspensions, microcapsule suspensions, emulsifiable powders, effervescent granules, effervescent tablets, water-dispersible tablets and other herbicide formulations with the compound represented by general formula I as the active ingredient.

5. The ALS inhibitor sulfonylurea herbicide according to claim 1, characterized in that: Selected from the following compounds:

6. The method for preparing the sulfonylurea herbicide according to any one of claims 1 to 5, characterized in that: The following steps are involved: Firstly, bromoacetyl bromide or chloroacetic anhydride undergoes a substitution reaction with an amine compound to generate an intermediate A, then the intermediate A reacts with a thiol compound in the presence of triethylamine to generate a thioether, and finally the thioether undergoes an oxidation reaction to generate a target product.

7. The preparation method according to claim 6, characterized in that: The amine compound is selected from 2-amino-4,6-dimethoxypyrimidine and 2-amino-4-methyl-6-methoxy-1,3,5-triazine.

8. The preparation method according to claim 6, characterized in that: The thiol compound is selected from N,N-dimethyl-2-mercaptonicotinamide, methyl thiosalicylate, 2-thiophenol, 4,6-dimethyl-2-mercaptopyrimidine, 2-methoxythiophenol, o-chlorothiophenol, and ethyl o-mercaptobenzoate.

9. The preparation method according to claim 6, characterized in that: The oxidant of the oxidation reaction is meta-chloroperbenzoic acid.

10. The use of the sulfonylurea herbicide according to claims 1-9, characterized in that: Use of the herbicide in inhibiting the growth of grass or broad-leaved herbaceous plants; Furthermore, the herbicide is used to inhibit the growth of barnyard grass, foxtail grass, zinnia, morning glory, chrysanthemum, cyperus rotundus, and sedge.

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