ALS inhibitor sulfonylurea herbicides as well as preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of herbicides. Disclosed in the present invention are ALS inhibitor sulfonylurea herbicides as well as a preparation method therefor and the use thereof, comprising 22 compounds having structures shown as general formula I or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as well as a preparation method therefor and the use thereof. The herbicides after being reasonably combined have good control effects on the gramineae or broadleaf class, and the herbicides do not result in harm to soil and the environment.

Description

ALS inhibitor sulfonylurea herbicide and its preparation method and application Technical Field

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

[0002] Bensulfuron-methyl has been registered for use in my country since 1986. It is a sulfonylurea herbicide commonly used in rice fields and is an ALS inhibitor. It effectively controls most broadleaf weeds and sedges in rice fields and is very safe for both rice and subsequent crops. Bensulfuron-methyl is a highly effective, broad-spectrum, low-toxic, and low-use-rate 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 bensulfuron-methyl-resistant Cyperus difformis was discovered in a rice field in the United States in 1993, weed resistance to bensulfuron-methyl has rapidly evolved.

[0003] At present, the most reported cases of weeds of different genera in rice fields developing resistance to bensulfuron-methyl are reported, with more than 60 reports available both domestically and internationally. A total of 26 species of rice field weeds from 12 genera have developed resistance to bensulfuron-methyl.

[0004] Summary of the Invention

[0005] The present invention aims to provide an ALS inhibitor sulfonylurea herbicide, a preparation method and application thereof. The sulfonylurea herbicide has high herbicidal activity, good stability and low resistance.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0007] An ALS inhibitor sulfonylurea herbicide, the structure of which is a compound represented by general formula I or its optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0008] Wherein, 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, suspoemulsions, ultra-low volume concentrates, 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] Furthermore, 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] The preparation method of sulfonylurea herbicide comprises the following steps:

[0013] First, bromoacetyl bromide or chloroacetic anhydride reacts 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 the target product.

[0014] Furthermore, the amine compound is selected from 2-amino-4,6-dimethoxypyrimidine and 2-amino-4-methyl-6-methoxy-1,3,5-triazine.

[0015] Furthermore, the thiol compound is selected from N,N-dimethyl-2-mercaptonicotinamide, methyl thiosalicylate, 2-mercaptophenol, 4,6-dimethyl-2-mercaptopyrimidine, 2-methoxythiophenol, o-chlorothiophenol, and ethyl o-mercaptobenzoate. Furthermore, the oxidant for the oxidation reaction is m-chloroperbenzoic acid.

[0016] Application of sulfonylurea herbicides, and application of the herbicides in inhibiting the growth of grasses or broad-leaved herbaceous plants.

[0017] Furthermore, the herbicide is used to inhibit the growth of barnyard grass, foxtail grass, zinnia, morning glory, chrysanthemum, cyperus rotundus, and sedge.

[0018] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0019] "Alkyl" refers to an aliphatic hydrocarbon group, including saturated hydrocarbon groups. The alkyl portion can be either straight-chain or branched. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0020] The C1~Cn used in the present invention includes C1~C2, C1~C3...C1~Cn, where 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 group containing one to six carbon atoms.

[0021] 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 conversely indicate the tolerance of a certain cell to the drug.

[0022] The beneficial effects of the present invention are:

[0023] After reasonable combination, the drugs of the present invention have a good control effect on grasses or broad-leaved plants, and take effect faster, have high weed control efficiency, and have a more thorough weed control effect. The herbicide of the present invention will not cause harm to the soil and the environment. DETAILED DESCRIPTION

[0024] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described here are only part of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0025] Example 1

[0026] The synthesis route of GA-SM-4 is as follows:

[0027] Specific synthesis steps:

[0028] Synthesis of intermediate 1

[0029] 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 cooling slightly, concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) was slowly added dropwise, and the mixture was refluxed at 70°C for 1 h. After cooling, the reaction mixture was stripped of the solvent under reduced pressure, then dissolved in water, adjusted to a pH of approximately 7 with 10% sodium hydroxide solution, and stripped of the solvent again under reduced pressure. Column chromatography yielded 5.3 g of the product (yellow solid, 58% yield).

[0030] Synthesis of intermediate 2

[0031] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0032] Synthesis of intermediate 3

[0033] Intermediate 1 (1.3 g, 7.1 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and triethylamine (2.8 g, 21.4 mmol, 3.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 1 (2.2 g, 7.1 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.6 g of the product (white solid, 51% yield).

[0034] Synthesis of GA-SM-4

[0035] Intermediate 3 (1.6 g, 4.7 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 660 mg of the product was obtained by column chromatography (white solid, yield: 38%).

[0036] The structural formula of GA-SM-4 is as follows:

[0037] 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). 13C 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,found 368.1031.

[0038] Example 2

[0039] The synthesis route of GA-SM-5 is as follows:

[0040] Specific synthesis steps:

[0041] Synthesis of intermediate 1

[0042] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography yielded 2.4 g of the product (white solid, 34% yield).

[0043] Synthesis of intermediate 2

[0044] 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 minutes, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 4.1 g of the product (white solid, 48% yield).

[0045] Synthesis of GA-SM-5

[0046] Intermediate 2 (4.1 g, 15.6 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (100 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from 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).

[0047] The structural formula of GA-SM-5 is as follows:

[0048] 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 for C16H18N3O7S+(M+H)+:396.0860, found 396.0859.

[0049] Example 3

[0050] The synthesis route of GA-SM-7 is as follows:

[0051] Specific synthesis steps:

[0052] Synthesis of intermediate 1

[0053] Thioglycolic acid (4.9 g, 54.0 mmol, 1.0 eq.) was weighed and dissolved in a mixed solution of DCM (32.4 mL) and glacial acetic acid (32.4 mL). Triphenylmethane (15.1 mmol, 54.0 mmol, 1.0 eq.) and boron trifluoride ether solution (10.8 mL) were added, and the mixture was reacted at room temperature for 1 h. The reaction solution 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 give 5.0 g of the product (yellow liquid, yield 28%).

[0054] Synthesis of intermediate 2

[0055] 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 allowed to proceed at room temperature for 1 h. The reaction solution was extracted with saturated sodium bicarbonate, and the organic layer was adjusted to acidic pH and washed with water. The organic layers were combined and washed with saturated brine. The organic layers were 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.

[0056] Synthesis of intermediate 4

[0057] Intermediate 2 (2.3 g, 4.9 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL), and 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 mixture was reacted at room temperature for 6 h. Triethylamine was added to adjust the pH to 10, and the mixture was activated at 0°C for 30 min. Methyl 2-bromomethylbenzoate (1.5 g, 6.6 mmol, 1.5 eq.) was added and reacted at room temperature for 2 h. After the reaction, the reaction solution was washed with saturated sodium bicarbonate solution, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 500 mg of the product (white solid, 30% yield).

[0058] Synthesis of GA-SM-7

[0059] 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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 100 mg of the product (white solid, yield: 18%) by column chromatography.

[0060] The structural formula of GA-SM-7 is as follows:

[0061] 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 for C17H20N3O7S+(M+H)+:410.1016,found 410.1006.

[0062] Example 4

[0063] The synthesis route of GA-SM-9 is as follows:

[0064] Specific synthesis steps:

[0065] Synthesis of intermediate 1

[0066] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0067] Synthesis of intermediate 2

[0068] 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 minutes, Intermediate 1 (1.7 g, 6.0 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.1 g of the product (white solid, 51% yield).

[0069] Synthesis of GA-SM-9

[0070] 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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. 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.

[0071] The structural formula of GA-SM-9 is shown below:

[0072] 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 for C 16 H 19 N4O6S + (M+H) + :395.1020,found 395.1009.

[0073] Example 5

[0074] The synthesis route of GA-SM-10 is as follows:

[0075] Specific synthesis steps:

[0076] Synthesis of intermediate 1

[0077] Dithiosalicylic acid (2.0 g, 6.5 mmol, 1.0 eq.) was weighed and dissolved in dry tetrahydrofuran (30 mL), followed by the dropwise addition of DMF (0.05 eq). Oxalyl chloride (3.0 g, 19.6 mmol, 3.0 eq.) was slowly added dropwise with stirring, and the mixture was allowed to react at 30°C for 4 h. The reaction solution was evaporated under reduced pressure, dissolved in dry tetrahydrofuran (30 mL), and DIEA (2.53 g, 19.6 mmol, 3.0 eq.) was added. A solution of dimethylamine in tetrahydrofuran (2.94 g, 2 mol / L in THF, 10.0 eq.) was added dropwise via syringe. The mixture was allowed to react at room temperature for 3 h. The reaction solution was evaporated under reduced pressure and extracted with water and dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution (1 x 30 mL) and then with saturated brine (1 x 30 mL). 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%).

[0078] Synthesis of intermediate 2

[0079] Intermediate 1 (2.0 g, 5.5 mmol, 1.0 eq.) was weighed and dissolved in methanol (20 mL). Dichloromethane (15 mL) was added, followed by tris(2-carboxyethyl)phosphine hydrochloride (7.95 g, 27.7 mmol, 5.0 eq.). The reaction was allowed to react at room temperature and monitored by TLC. The reaction was complete after 1.5 h. The reaction solution was evaporated under reduced pressure and extracted with dichloromethane and water. The organic layer was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 1.9 g of the product was obtained (yellow oil, 95% yield).

[0080] Synthesis of intermediate 3

[0081] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0082] Synthesis of intermediate 4

[0083] Intermediate 2 (1.9 g, 10.7 mmol, 1.5 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Triethylamine (2.9 g, 28.6 mmol, 4.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 3 (2.0 g, 7.1 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.9 g of the product (pale yellow solid, 71% yield).

[0084] Synthesis of GA-SM-10

[0085] Intermediate 4 (1.9 g, 5.0 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 800 mg of the product was obtained by column chromatography (white solid, yield: 39%).

[0086] The structural formula of GA-SM-10 is as follows:

[0087] 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 for C 16 H 19 N4O6S + (M+H) + :395.1020,found 395.1009.

[0088] Example 6

[0089] The synthesis route of GA-SM-11 is as follows:

[0090] Specific synthesis steps:

[0091] Synthesis of intermediate 1

[0092] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography yielded 2.4 g of the product (white solid, 34% yield).

[0093] Synthesis of intermediate 2

[0094] 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 minutes, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 4.1 g of the product (white solid, 48% yield).

[0095] Synthesis of intermediate 3

[0096] Intermediate 2 (4.1 g, 15.6 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (100 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 2.5 g of the product was obtained by column chromatography (white solid, yield: 55%).

[0097] Synthesis and characterization of GA-SM-11

[0098] Intermediate 3 (2.5 g, 5.1 mmol, 1.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (1.2 g, 10.1 mmol, 2.0 eq.) were weighed and placed in a dry round-bottom flask. Under argon, ultra-dry tetrahydrofuran (10 mL) was added. Isopropylmagnesium bromide (11.38 mL, 18.2 mmol, 3.6 eq.) was slowly added via syringe at 0°C. The mixture was allowed to react at room temperature for 2 h. Isopropylmagnesium bromide (8.22 mL, 13.2 mmol, 2.6 eq.) was then slowly added via syringe. The reaction continued at room temperature for 2 h. TLC monitored the reaction completion. The mixture was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography (DCM:MeOH = 100:1) to obtain 210 mg of the product (yellow solid, 15% yield).

[0099] The structural formula of GA-SM-11 is as follows:

[0100] 1 H 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 for C 18 H 22 N3O6S + (M+H) + :408.1224,found 408.1223.

[0101] Example 7

[0102] The synthesis route of GA-SM-12 is as follows:

[0103] Specific synthesis steps:

[0104] Synthesis of intermediate 1

[0105] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0106] Synthesis of intermediate 2

[0107] 2-Thiophenol (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 allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 5.9 g of the product (white solid, 46% yield).

[0108] Synthesis of intermediate 3

[0109] 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.) were weighed and dissolved in acetone (20 mL). Anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) was added and refluxed at 65°C for 24 h. After the reaction, the solvent was evaporated under reduced pressure, 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 x 10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Purification by column chromatography afforded 2.9 g of the product (white solid, 49% yield).

[0110] Synthesis of GA-SM-12

[0111] Intermediate 3 (2.9 g, 7.6 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. 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.

[0112] The structural formula of GA-SM-12

[0113] 1 H 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 for C 16 H 19 ClN3O6S + (M+H) + :416.0678,found 416.0674.

[0114] Example 8

[0115] The synthesis route of GA-SM-13 is as follows:

[0116] Specific synthesis steps:

[0117] Synthesis of intermediate 1

[0118] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0119] Synthesis of intermediate 2

[0120] 2-Thiophenol (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 allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 5.9 g of the product (white solid, 46% yield).

[0121] Synthesis of intermediate 3

[0122] Intermediate 2 (5.0 g, 15.5 mmol, 1.0 eq.) and iodoethane (3.9 g, 24.9 mmol, 1.6 eq.) were weighed and dissolved in acetone (20 mL). Anhydrous potassium carbonate (4.3 g, 31.1 mmol, 2.0 eq.) was added and refluxed at 50°C for 24 h. After the reaction, the solvent was evaporated under reduced pressure, 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 x 10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Purification by column chromatography yielded 3.1 g of the product (white solid, 57% yield).

[0123] Synthesis of GA-SM-13

[0124] Intermediate 4 (3.1 g, 8.9 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (50 mL). m-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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. 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.

[0125] The structural formula of GA-SM-13

[0126] 1 H 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):calcd for C 16 H 20 N3O6S + (M+H) + :382.1067,found 382.2.1055.

[0127] Example 9

[0128] The synthesis route of GA-SM-14 is as follows:

[0129] Specific synthesis steps:

[0130] Synthesis of intermediate 1

[0131] Weigh chloroacetic anhydride (4.0 g, 23.4 mmol, 1.0 eq.) and add 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 28.5 mmol, 3.0 eq.). Mix thoroughly and reflux at 90°C for 1 hour. Add saturated sodium bicarbonate solution to adjust the pH to 8. Extract with DCM, dry the organic layer over anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. Column chromatography yields 1.2 g of the product (white solid, 19% yield).

[0132] Synthesis of intermediate 2

[0133] Methyl thiosalicylate (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 and reacted at room temperature for 2 h. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.0 g of the product (white solid, 52% yield).

[0134] Synthesis of GA-SM-14

[0135] Intermediate 2 (1.0 g, 2.9 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 600 mg of the product (white solid, yield: 71%) by column chromatography.

[0136] The structural formula of GA-SM-14

[0137] 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). 13C 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,found 381.0853.

[0138] Example 10

[0139] The synthesis route of GA-SM-15 is as follows:

[0140] Specific synthesis steps:

[0141] Synthesis of intermediate 1

[0142] Under argon, 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). Bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) was slowly added dropwise at 0°C and allowed to react for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography afforded 2.0 g of the product (white solid, 76% yield).

[0143] Synthesis of intermediate 2

[0144] 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 minutes, intermediate 1 (2.0 g, 8.2 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 2.0 g of the product (white solid, 74% yield).

[0145] Synthesis of GA-SM-15

[0146] Intermediate 2 (2.0 g, 6.0 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (50 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 800 mg of the product was obtained by column chromatography (white solid, yield: 37%).

[0147] The structural formula of GA-SM-15

[0148] 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,found 365.0804.

[0149] Example 11

[0150] The synthesis route of GA-SM-16 is as follows:

[0151] Specific synthesis steps:

[0152] Synthesis of intermediate 1

[0153] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography yielded 2.4 g of the product (white solid, 34% yield).

[0154] Synthesis of intermediate 2

[0155] 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 minutes, intermediate 1 (1.6 g, 5.6 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.5 g of the product (white solid, 44% yield).

[0156] Synthesis of GA-SM-16

[0157] Intermediate 2 (1.3 g, 3.6 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (40 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 512 mg of the product was obtained by column chromatography (white solid, yield: 38%).

[0158] Structural formula of GA-SM-16

[0159] 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). 13C 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.

[0160] Example 12

[0161] The synthesis route of GA-SM-17 is as follows:

[0162] Specific synthesis steps:

[0163] Synthesis of intermediate 1

[0164] 2-Mercaptonicotinic acid (4.0 g, 25.8 mmol, 1.0 eq.) and HATU (11.8 g, 30.9 mmol, 1.2 eq.) were weighed and dissolved in dry tetrahydrofuran (30 mL). DIEA (6.7 g, 51.6 mmol, 2.0 eq.) was added, and a solution of dimethylamine in tetrahydrofuran (64 mL, 2 mol / L in THF, 5.0 eq.) was added dropwise using a syringe. The mixture was reacted at room temperature for 5 h. The reaction solution was distilled under reduced pressure and extracted with water and dichloromethane. The aqueous layer was distilled under reduced pressure to obtain 2.0 g of the product (yellow liquid, 43% yield).

[0165] Synthesis of intermediate 2

[0166] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0167] Synthesis of intermediate 3

[0168] Intermediate 1 (1.1 g, 5.8 mmol, 2.0 eq.) was dissolved in dry dichloromethane (30 mL) and triethylamine (1.2 g, 11.6 mmol, 4.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 1 (800 mg, 2.9 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.0 g of the product (white solid, 46% yield).

[0169] Synthesis of GA-SM-17

[0170] Intermediate 3 (1.3 g, 3.3 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). m-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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 300 mg of the product (white solid, yield: 22%) by column chromatography.

[0171] The structural formula of GA-SM-17 is as follows:

[0172] 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.

[0173] Example 13

[0174] The synthesis route of GA-SM-19 is as follows:

[0175] Specific synthesis steps:

[0176] Synthesis of intermediate 1

[0177] 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 cooling slightly, concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) was slowly added dropwise, and refluxed at 70°C for 1 h. After cooling, the reaction solution was spin-dried to dryness, then dissolved in water, adjusted to pH 7 with 10% sodium hydroxide solution, and spin-dried again. Column chromatography yielded 5.3 g of the product (yellow solid, 58% yield).

[0178] Synthesis of intermediate 2

[0179] Weigh chloroacetic anhydride (4.0 g, 23.4 mmol, 1.0 eq.) and add 2-amino-4-methyl-6-methoxy-1,3,5-triazine (14.6 g, 28.5 mmol, 3.0 eq.). Mix thoroughly and reflux at 90°C for 1 hour. Add saturated sodium bicarbonate solution to adjust the pH to 8. Extract with DCM, dry the organic layer over anhydrous sodium sulfate, and remove the solvent by distillation under reduced pressure. Column chromatography yields 1.2 g of the product (white solid, 19% yield).

[0180] Synthesis of intermediate 3

[0181] Intermediate 1 (777 mg, 5.5 mmol, 1.0 eq.) was dissolved in dry dichloromethane (30 mL) and triethylamine (1.1 g, 11.1 mmol, 4.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 2 (600 mg, 2.8 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 745 mg of the product (white solid, 84% yield).

[0182] Synthesis of GA-SM-19

[0183] 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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 100 mg of the product was obtained by column chromatography (white solid, yield: 12%).

[0184] The structural formula of GA-SM-19 is as follows:

[0185] 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.

[0186] Example 14

[0187] The synthesis route of GA-SM-20 is as follows:

[0188] Specific synthesis steps:

[0189] Synthesis of intermediate 1

[0190] 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 cooling slightly, concentrated hydrochloric acid (15.3 g, 420.4 mmol, 3.2 eq.) was slowly added dropwise, and refluxed at 70°C for 1 h. After cooling, the reaction solution was spin-dried to dryness, then dissolved in water, adjusted to pH 7 with 10% sodium hydroxide solution, and spin-dried again. Column chromatography yielded 5.3 g of the product (yellow solid, 58% yield).

[0191] Synthesis of intermediate 2

[0192] Under argon, 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). Bromoacetyl bromide (4.9 g, 24.2 mmol, 1.5 eq.) was slowly added dropwise at 0°C and allowed to react for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography afforded 2.0 g of the product (white solid, 76% yield).

[0193] Synthesis of intermediate 3

[0194] 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 minutes, Intermediate 2 (2.0 g, 8.2 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.5 g of the product (white solid, 60% yield).

[0195] Synthesis of GA-SM-20

[0196] Intermediate 3 (1.5 g, 4.9 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). m-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 mixture 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 590 mg of the product (white solid, yield: 36%) by column chromatography.

[0197] The structural formula of GA-SM-20 is as follows:

[0198] 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.

[0199] Example 15

[0200] The synthesis route of GA-SM-21 is as follows:

[0201] Specific synthesis steps:

[0202] Synthesis of intermediate 1

[0203] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0204] Synthesis of intermediate 2

[0205] 2-Thiophenol (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 allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 5.9 g of the product (white solid, 46% yield).

[0206] Synthesis of intermediate 3

[0207] Intermediate 2 (3.0 g, 9.3 mmol, 1.0 eq.) and bromobutane (2.0 g, 14.9 mmol, 1.6 eq.) were weighed and dissolved in acetone (20 mL). Anhydrous potassium carbonate (2.6 g, 18.7 mmol, 2.0 eq.) was added and refluxed at 55°C for 24 h. After the reaction, the solvent was evaporated under reduced pressure, 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 x 10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Purification by column chromatography gave 600 mg of the product (white solid, 17% yield).

[0208] Synthesis of GA-SM-21

[0209] 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, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 103 mg of the product (white solid, yield: 24%) by column chromatography.

[0210] The structural formula of GA-SM-21 is as follows:

[0211] 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.

[0212] Example 16

[0213] The synthesis route of GA-SM-22 is as follows:

[0214] Specific synthesis steps:

[0215] Synthesis of intermediate 1

[0216] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0217] Synthesis of intermediate 2

[0218] 2-Methoxythiophenol (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 minutes, Intermediate 1 (1.0 g, 3.6 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 730 mg of the product (white solid, 60% yield).

[0219] Synthesis of GA-SM-22

[0220] Intermediate 4 (730 mg, 2.2 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture 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. The crude product was recrystallized from acetonitrile to obtain 384 mg of the product (white solid, yield: 48%).

[0221] The structural formula of GA-SM-22 is as follows:

[0222] 1H 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.

[0223] Example 17

[0224] The synthesis route of GA-SM-23 is as follows:

[0225] Specific synthesis steps:

[0226] Synthesis of intermediate 1

[0227] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0228] Synthesis of intermediate 2

[0229] 2-Thiophenol (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 allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 800 mg of the product (white solid, 66% yield).

[0230] Synthesis of GA-SM-23

[0231] Intermediate 2 (800 mg, 2.5 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 200 mg of the product (white solid, yield: 23%) by column chromatography.

[0232] The structural formula of GA-SM-23 is as follows:

[0233] 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.

[0234] Example 18

[0235] The synthesis route of GA-SM-24 is as follows:

[0236] Specific synthesis steps:

[0237] Synthesis of intermediate 1

[0238] Under argon, 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). Bromoacetyl bromide (7.805 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Column chromatography afforded 2.38 g of the product (white solid, 34% yield).

[0239] Synthesis of intermediate 2

[0240] o-Chlorothiophenol (662 mg, 4.4 mmol, 1.2 eq.) was dissolved in dry dichloromethane (50 mL) and 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 allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 400 mg of the product (white solid, 66% yield).

[0241] Synthesis of GA-SM-24

[0242] 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 mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 100 mg of the product (white solid, yield: 23%) by column chromatography.

[0243] The structural formula of GA-SM-24 is as follows:

[0244] 1 H 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). 13C 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 for C 14 H 15 ClN3O6S + (M+H) + :372.0415,found 372.0409.

[0245] Example 19

[0246] The synthesis route of GA-SM-25 is as follows:

[0247] Specific synthesis steps:

[0248] Synthesis of intermediate 1

[0249] 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 and dissolved in DMF (10 mL). The mixture was reacted at 70°C for 5 h. The reaction solution was evaporated under reduced pressure and extracted with water and dichloromethane. The organic layer was washed with aqueous solution (3 x 10 mL) and then with saturated brine (1 x 30 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. 1.5 g of the product was obtained (yellow liquid, 63% yield).

[0250] Synthesis of intermediate 2

[0251] Intermediate 1 (1.5 g, 4.1 mmol, 1.0 eq.) was weighed and dissolved in methanol (20 mL). Dichloromethane (20 mL) was added, followed by tris(2-carboxyethyl)phosphine hydrochloride (5.9 g, 20.7 mmol, 5.0 eq.). The reaction was allowed to react at room temperature and monitored by TLC. The reaction was complete after 1.5 h. The reaction solution was evaporated under reduced pressure and extracted with dichloromethane and water. The organic layer was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 1.1 g of the product was obtained (yellow oil, 70% yield).

[0252] Synthesis of intermediate 3

[0253] Intermediate 2 (1.1 g, 6.0 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Triethylamine (1.8 g, 18.1 mmol, 3.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 3 (1.8 g, 6.6 mmol, 1.1 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.1 g of the product (pale yellow solid, 52% yield).

[0254] Synthesis of GA-SM-25

[0255] Intermediate 3 (1.1 g, 2.5 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure, and recrystallized from acetonitrile to obtain a crude product. 200 mg of the product was obtained by column chromatography (white solid, yield: 17%).

[0256] The structural formula of GA-SM-25 is as follows:

[0257] 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.

[0258] Example 20

[0259] The synthesis route of GA-SM-28 is as follows:

[0260] Specific synthesis steps:

[0261] Synthesis of intermediate 1

[0262] Weigh 4.0 g, 28.5 mmol, 1.0 eq. of chloroacetic anhydride and 14.6 g, 85.6 mmol, 3.0 eq. of 2-amino-4-methyl-6-methoxy-1,3,5-triazine into a bottle and react at 90°C for 1 hour. After completion, add saturated sodium bicarbonate solution to adjust the pH to 8. Extract with dichloromethane (DCM), dry the organic layer over anhydrous sodium sulfate, and remove the solvent by vacuum distillation. Purify by column chromatography to obtain 1.2 g of the product (white solid, 69% yield).

[0263] Synthesis of intermediate 2

[0264] o-Chlorothiophenol (961 mg, 6.6 mmol, 1.2 eq.) was dissolved in dry dichloromethane (20 mL) and triethylamine (1.7 g, 16.6 mmol, 3.0 eq.) was added at 0°C. After activation for 30 minutes, Intermediate 1 (1.2 g, 5.5 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 1.1 g of the product (white solid, 59% yield).

[0265] Synthesis of GA-SM-28

[0266] Intermediate 2 (1.1 g, 3.4 mmol, 1.0 eq.) was weighed and dissolved in dry dichloromethane (30 mL). Meta-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 the reaction. The mixture was extracted with dichloromethane and water, and the organic layer was washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 300 mg of the product (white solid, yield: 25%) by column chromatography.

[0267] The structural formula of GA-SM-28 is as follows:

[0268] 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.

[0269] Example 21

[0270] The synthesis route of GA-SM-29 is as follows:

[0271] Specific synthesis steps:

[0272] Synthesis of intermediate 1

[0273] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C for 3 h. After completion of 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 dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography yielded 2.4 g of the product (white solid, 34% yield).

[0274] Synthesis of GA-SM-29

[0275] 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 minutes, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 4.1 g of the product (white solid, 48% yield).

[0276] The structural formula of GA-SM-29 is as follows:

[0277] 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.

[0278] Example 22

[0279] The synthesis route of GA-SM-30 is as follows:

[0280] Specific synthesis steps:

[0281] Synthesis of intermediate 1

[0282] Under argon, 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). Bromoacetyl bromide (7.8 g, 38.7 mmol, 1.5 eq.) was slowly added dropwise at 0°C and allowed to react for 3 h. After completion of the reaction, the pH was adjusted to acidic with 2N HCl. The mixture was extracted with water and dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. Column chromatography yielded 2.4 g of the product (white solid, 34% yield).

[0283] Synthesis of intermediate 2

[0284] 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 minutes, intermediate 1 (4.0 g, 16.3 mmol, 1.0 eq.) was added and allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to acidic with 2N HCl, and the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography afforded 4.1 g of the product (white solid, 48% yield).

[0285] Synthesis of GA-SM-30

[0286] Intermediate 2 (1.0 g, 2.7 mmol, 1.0 eq.) was weighed and added with glacial acetic acid (4 mL) and 30% hydrogen peroxide solution (1 mL). 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. The mixture was 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 300 mg of the product (white solid, yield: 29%) by column chromatography.

[0287] The structural formula of GA-SM-30 is as follows:

[0288] 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). 13C 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,found 380.0901.

[0289] Example 23

[0290] ALS enzyme activity test

[0291] (1) Sample preparation

[0292] Take 0.3 g of tobacco leaves, add 1 mL of the extract, homogenize in an ice bath, centrifuge at 4°C × 12000 rpm for 15 min, and take the supernatant for use.

[0293] (2) Sample configuration

[0294] Weigh the drug and prepare it into 10mmol / L and 1mmol / L DMSO solutions, then take 5μL of each and add it to 500μL tobacco protein extract (ie, the detection concentrations are: 100μM and 10μM respectively), mix well and test.

[0295] (3) On-machine testing

[0296] Preheat the microplate reader for 30 minutes and adjust the wavelength to 525 nm. Preheat all reagents in the kit at 25°C for 10 minutes. Set up sample and control tubes, with three replicates per group. Add reagent 1 (20 μL for sample tube, 0 for control tube), reagent 2 (100 μL for sample tube, 120 μL for control tube), and sample solution (80 μL for sample tube, 80 μL for control tube) to a 1 mL centrifuge tube in sequence. Incubate in the dark at 35°C for 1 hour. Add reagent 3 (20 μL for sample tube, 20 μL for control tube), decarboxylate in a 60°C water bath for 15 minutes, then add reagent 4 (100 μL for sample tube, 100 μL for control tube) and reagent 5 (100 μL for sample tube, 100 μL for control tube), and continue color development in a 60°C water bath for 15 minutes. 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.

[0297] (4) Calculation of inhibition rate

[0298] Formula: Enzyme inhibition rate = 1-(ΔA sample / ΔA blank control)

[0299] The results are shown in Table 1.

[0300] Table 1. Inhibition rates and IC50 values ​​of synthetic compounds and control compounds on enzymes at different concentrations

[0301] As can be seen from Table 1, 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, and GA-SM-22 on the enzyme are comparable to or better than bensulfuron-methyl as a chemical control.

[0302] Example 24

[0303] Weed pot experiment

[0304] 1) Preparation of drug solution

[0305] 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).

[0306] 2) Seedling cultivation

[0307] Evenly sow morning glory, chrysanthemum, wild oats, and barnyard grass seeds in nutrient soil at 25°C, 16 hours of light and 8 hours of darkness, and water regularly. Once the seeds germinate and root, and reach the two-leaf stage, they can be used for the next experiment.

[0308] 3) Spraying

[0309] Use a handheld spray bottle to evenly spray the liquid on the weeds to be tested. Set the temperature to 25°C, 16 hours of light + 8 hours of darkness, and continue growing. Set up four replicates per group. Observe the weed growth after one week.

[0310] 4) Test statistics: The number of weeds was investigated 7 and 14 days after application. The control efficacy was calculated using the formula:

[0311] 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.

[0312] The experimental results are shown in Table 2.

[0313] Table 2 Experimental results of Example 24

[0314] As shown in Table 2, the herbicides of this application all demonstrated superior weed control activity against grass, broadleaf, and sedge weeds compared to the control (bensulfuron-methyl). The control efficacy of each herbicide ranged from 71.6% to 100% 14 days after application, exceeding the 63.4% to 95.8% herbicidal activity of bensulfuron-methyl. The control efficacy was particularly significant against resistant weeds such as barnyardgrass, morning glory, and Cyperus diversifolius. Compared to the control (bensulfuron-methyl), the herbicides of this application demonstrated faster onset, higher weed control efficiency, and more thorough weed control, demonstrating promising 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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