A benzoheterocyclic coupled catechol derivative, its preparation method and application

Abstract

This invention relates to the pharmaceutical field, specifically to a catechol compound containing formula (I) or formula (II) and its application in the preparation of bacterial biofilm inhibitors. The catechol compounds involved in this invention have been validated in vitro, and most of the obtained compounds exhibit excellent bacterial biofilm inhibitory activity. They can be used to prepare anti-biofilm agents and have the potential to be developed into novel antibacterial drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a method for preparing catechol derivatives and their application in the preparation of bacterial biofilm inhibitors. Background Technology

[0002] The discovery of antibiotics in the 1940s was undoubtedly a victory for humanity in the fight against pathogenic microorganisms, saving countless lives. The superior bactericidal efficacy and strong selectivity of antibiotics once led people to believe that infectious diseases would become a thing of the past. However, the overuse and abuse of antibiotics have exacerbated the mutation and evolution of pathogenic microorganisms, leading to increasingly stronger drug resistance and the emergence of multidrug-resistant "superbugs." The problem of bacterial resistance is becoming increasingly prominent, with approximately 16 million patients dying directly from bacterial infections each year. Research has found that over 70% of malignant infections are related to the formation of drug-resistant biofilms. A biofilm is a complex bacterial aggregate, encapsulated in an extracellular polymeric substance (EPS) within a self-generating matrix, and affected by factors such as temperature and nutrients. After forming a biofilm, bacteria within it can evade the host's immune response, exhibiting a resistance to antimicrobial drugs 1000 times greater than that of planktonic organisms. Traditional antimicrobial drug research models have neglected the complexity and stability of bacterial resistance mechanisms. This model easily induces bacterial target mutations and rapidly develops drug resistance, thus severely hindering the development of drugs against drug-resistant bacteria. Biofilm inhibitors, as a novel type of antibacterial drug different from traditional antibiotics, have become a research hotspot in the field of anti-infectives due to their low likelihood of inducing drug resistance. Therefore, it is urgent to develop novel biofilm inhibitors against multidrug-resistant Pseudomonas aeruginosa to inhibit bacterial biofilm formation, reduce bacterial resistance, and enhance the antibacterial efficacy of antibiotics. Summary of the Invention

[0003] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention proposes a catechol compound containing the structure shown in formula (I) or formula (II), a method for its preparation, and its uses. The compound can selectively act on Pseudomonas aeruginosa and inhibit the formation of Pseudomonas aeruginosa biofilm.

[0004] In a first aspect, the invention provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0005]

[0006] Preferred, Where * represents the connection point connected to B; and This is the connection point on the other side.

[0007] A second aspect of the invention provides a pharmaceutical composition comprising at least one of the compounds of formula (I), or pharmaceutically acceptable salts, isomers, solvates or prodrugs thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0008] The compounds described in this invention, or their pharmaceutically acceptable salts, isomers, solvates, or prodrugs, or the pharmaceutical compositions thereof, can be administered in unit dose form via oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectal routes. Dosage forms may include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, lozenges, suppositories, or lyophilized powder injections. These can be conventional formulations, sustained-release formulations, controlled-release formulations, and various microparticle delivery systems.

[0009] Typically, the pharmaceutical compositions of the present invention contain 0.1% to 99.9% by weight of the compound, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof.

[0010] In some embodiments of the present invention, the administration of the pharmaceutical composition includes administering the compound, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, simultaneously, separately, or sequentially with other active pharmaceutical ingredients.

[0011] A fourth aspect of the invention provides a combination drug comprising at least one of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, and an antibiotic.

[0012] Preferably, the mass ratio of the compound of formula (I) or formula (II) or its pharmaceutically acceptable salt, isomer, solvate or prodrug to the antibiotic is 50:0.5 to 10, preferably 50:1 to 5.

[0013] Preferably, the antibiotic is ciprofloxacin.

[0014] A fourth aspect of the invention provides the use of the compound of formula (I) or formula (II) above, or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, or the pharmaceutical composition thereof, in the preparation of an antibiofilm agent.

[0015] Preferably, the biofilm is a bacterial biofilm. More preferably, the bacteria is Pseudomonas aeruginosa.

[0016] The present invention also provides the use of the compound of formula (I) or formula (II) above, or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, or the pharmaceutical composition thereof, in the preparation of an antibacterial drug.

[0017] Preferably, the bacteria are bacteria, more preferably Pseudomonas aeruginosa.

[0018] The compounds of formula (I) or formula (II) of the present invention, especially compound 2-((6-chlorobenzo[d]thiazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide, have excellent biofilm inhibitory activity.

[0019] The catechol derivatives of formula (I) or formula (II) described in this invention have the chemical structures shown in Table 1:

[0020] Table 1. Structure and Nomenclature of Compounds

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] In this application, the term "pharmaceutically acceptable salt" includes conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases.

[0028] "Pharmaceutical composition" includes products containing a therapeutically effective amount of the compounds of the present invention, as well as any products produced directly or indirectly from combinations of the compounds of the present application.

[0029] A fourth aspect of the present invention provides a method for preparing a coumarin derivative of formula (I), specifically comprising the following steps:

[0030] Route 1 includes the following steps:

[0031] (1.1) Dissolve o-phenylenediamines 1a-1d with different substituents in ethanol, slowly add CS2 dropwise, and purify the reaction solution after the reaction to obtain compounds 2a-2d;

[0032] (1.2) Dissolve 3,4-dimethoxybenzamine (6) and triethylamine in DCM, and slowly add chloroacetyl chloride (11) dropwise under ice bath; after the reaction is complete, adjust the pH to neutral with dilute hydrochloric acid, filter the solid produced, and obtain compound 7.

[0033] (1.3) Compound 7 was dissolved in DCM, and BBr3 was slowly added dropwise under an ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 8.

[0034] (1.4) Compound 8 and K2CO3 were dissolved in acetonitrile with intermediates 2a-2d and commercially available compounds 2e-2j and 3a-3o, respectively. After the reaction was completed, the reaction solution was purified to obtain compounds 9a-9j and 10a-10o.

[0035] The synthesis route at this point is:

[0036]

[0037] Route 2 includes the following steps:

[0038] (2.1) Dissolve o-aminophenols 4a-4e with different substituents in ethanol, slowly add CS2 dropwise, and purify the reaction solution after the reaction to obtain compounds 5a-5e.

[0039] (2.2) Dissolve 3,4-dimethoxybenzamine (6) and triethylamine in DCM, and slowly add bromoacetyl bromide dropwise under ice bath; after the reaction is complete, adjust the pH to neutral with dilute hydrochloric acid, filter the solid produced, and obtain compound 12;

[0040] (2.3) Compound 12 was dissolved in DCM, and BBr3 was slowly added dropwise under an ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 13.

[0041] (2.4) Compound 13 and K2CO3 were dissolved in acetonitrile with intermediates 5a-5e and commercially available compound 5f-5j, respectively. After the reaction was completed, the reaction solution was purified to obtain compound 14a-14j.

[0042] The synthesis route at this point is:

[0043]

[0044] Route 3 includes the following steps:

[0045] (3.1) 3,4-dimethoxybenzamine (6), N-Boc-glycine (15), PyBop and DIPEA were dissolved in DCM. After the reaction was completed, the reaction solution was purified to obtain compound 16.

[0046] (3.2) Dissolve compound 16 in DCM, slowly add trifluoroacetic acid, adjust the pH to weakly alkaline with NaOH aqueous solution after the reaction is complete, extract the reaction solution with DCM and then evaporate to dryness to obtain compound 17;

[0047] (3.3) Commercially available compounds 18a-18d, compound 17 and DIPEA were dissolved in ethanol. After the reaction was completed, the solids were filtered to obtain compounds 19a-19d.

[0048] (3.4) Dissolve compounds 19a-19d in DCM, slowly add BBr3 dropwise under ice bath, quench the reaction with ice water after the reaction is complete, and filter the solid to obtain compounds 20a-20d;

[0049] The synthesis route at this point is:

[0050]

[0051] Route 4 includes the following steps:

[0052] (4.1) 3,4-Dimethoxyphenylacetic acid (21), commercially available compound 2-amino-6-chlorobenzothiazole (22), PyBop and DIPEA were dissolved in DCM. After the reaction was completed, the reaction solution was purified to obtain compound 23.

[0053] (4.2) Dissolve compound 23 in DCM, slowly add BBr3 dropwise under ice bath, quench the reaction with ice water after the reaction is complete, and filter the solid to obtain compound 24;

[0054] The synthesis route at this point is:

[0055]

[0056] Route 5 includes the following steps:

[0057] (5.1) 3,4-dimethoxybenzyl bromide (25) and NaN3 (26) were dissolved in a mixed solution of THF and water. After the reaction was completed, the reaction solution was extracted by DCM and then directly evaporated to dryness to obtain compound 27.

[0058] (5.2) 6-chloro-2-mercaptobenzothiazole (3f) and triethylamine were dissolved in DCM, and 3-bromopropyne (28) was added under ice bath. After the reaction was completed, the reaction solution was extracted with DCM and then evaporated to dryness to obtain compound 29.

[0059] (5.3) Compound 29, compound 27, sodium ascorbate and copper sulfate pentahydrate were dissolved in a mixed solution of DMF and H2O. After the reaction was completed, the reaction solution was purified to obtain compound 30.

[0060] (5.4) Compound 30 was dissolved in DCM, and BBr3 was slowly added dropwise under an ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 31.

[0061] The synthesis route at this point is:

[0062]

[0063] Route Six includes the following steps:

[0064] (6.1) Dissolve amino-substituted alkanes 32a-32e with different carbon chain lengths in DCM, and slowly add chloroacetyl chloride (11) in an ice bath. After the reaction is completed, the reaction solution is extracted with DCM and then evaporated to dryness to obtain compound 33a-33e.

[0065] (6.2) Compounds 33a-33e were dissolved in acetonitrile with 6-chloro-2-mercaptobenzothiazole (3f) and 5-nitro-2-mercaptobenzothiazole (3n), respectively. After the reaction was completed, the solids were filtered to obtain compounds 34a-34h.

[0066] The synthesis route at this point is:

[0067]

[0068] Route 7 includes the following steps:

[0069] (7.1) Compound 7, 6-chloro-2-mercaptobenzothiazole (3f) and K2CO3 were dissolved in acetonitrile. After the reaction was completed, the solid produced was filtered to obtain compound 35.

[0070] The synthesis route at this point is:

[0071]

[0072] Route 8 includes the following steps:

[0073] (8.1) 2-Aminobenzothiazole (36) and triethylamine were dissolved in DCM, and chloroacetyl chloride (11) was slowly added dropwise under ice bath. After the reaction was completed, the reaction solution was purified to obtain compound 37.

[0074] (8.2) 6-chloro-2-mercaptobenzothiazole (3f), K2CO3 and compound 37 were dissolved in DMF. After the reaction was completed, the reaction solution was purified to obtain compound 38.

[0075] The synthesis route at this point is:

[0076]

[0077] Route Nine includes the following steps:

[0078] (9.1) 6-aminohexanoate methyl hydrochloride (39) and triethylamine were dissolved in DCM, and chloroacetyl chloride (11) was slowly added dropwise under ice bath. After the reaction was completed, the reaction solution was extracted with DCM and then evaporated to dryness to obtain compound 40.

[0079] (9.2) Compound 40, K2CO3 and 6-chloro-2-mercaptobenzothiazole (3f) were dissolved in DMF. After the reaction was completed, the reaction solution was purified to obtain compound 41.

[0080] (9.3) Compound 41, hydroxylamine hydrochloride and KOH were dissolved in methanol, and the reaction solution after the reaction was completed was purified to obtain compound 42;

[0081] The synthesis route at this point is:

[0082]

[0083] Route 10 includes the following steps:

[0084] (10.1) Compound 7, K2CO3 and chloro-substituted thiophenol 43a-43c were dissolved in acetonitrile. After the reaction was completed, the reaction solution was purified to obtain compound 44a-44c.

[0085] (10.2) Compounds 44a-44c were dissolved in DCM, and BBr3 was slowly added dropwise under an ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compounds 45a-45c.

[0086] The synthesis route at this point is:

[0087]

[0088] Route 11 includes the following steps:

[0089] (11.1) Compound 7, K2CO3 and 2-mercaptothiazole (46) were dissolved in acetonitrile. After the reaction was completed, the reaction solution was purified to obtain compound 47.

[0090] (11.2) Compound 47 was dissolved in DCM, and BBr3 was slowly added dropwise under an ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 48.

[0091] The synthesis route at this point is:

[0092]

[0093] The compounds according to embodiments of the present invention possess at least the following beneficial effects:

[0094] (1) This invention provides a catechol compound containing the structures shown in formula (I) and (II), wherein compound 10f exhibits excellent bacterial biofilm inhibition activity, IC 50 The value is low.

[0095] (2) The preparation methods of the compounds shown in formula (I) and formula (II) of this invention have the advantages of short route, high yield, convenient post-processing and good economy. Attached Figure Description

[0096] Figure 1The effect of compound 10f combined with ciprofloxacin on the growth of Pseudomonas aeruginosa PAO1. Detailed Implementation

[0097] The present invention will be further described below with reference to specific embodiments.

[0098] Example 1: Preparation of 6-chloro-1H-benzo[d]imidazol-2-thiol (2a).

[0099] Commercially available compound 1a, 4-chloro-o-phenylenediamine (500.00 mg, 3.51 mmol), and NaOH (168.40 mg, 4.21 mmol) were dissolved in 10 mL of ethanol. CS2 (801.80 mg, 10.53 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 30 min, then refluxed at 78 °C for 3 h. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, concentrated, and purified by column chromatography (PE:EA = 3:1). Product 2a was collected as a pale yellow solid, 438.00 mg, yield: 67.60%. 1 H NMR (400MHz, DMSO-d6) δ12.66 (s, 2H), 7.13 (d, J = 3.3Hz, 3H). 13 C NMR (101MHz, DMSO) δ169.75,133.69,131.70,127.15,122.69,111.00,109.64.

[0100] Example 2: Preparation of 2-mercapto-1H-benzo[d]imidazol-6-nitrile (2b).

[0101] Using commercially available compound 4-cyano-o-phenylenediamine (1b) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 2b was collected as a white solid of 311.80 mg, with a yield of 48.51%. 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 2H), 7.55 (d, J = 7.5Hz, 2H), 7.26 (d, J = 8.8Hz, 1H). 13 C NMR (101MHz, DMSO) δ171.15,136.13,132.81,127.47,119.78,113.33,110.68,104.70.

[0102] Example 3: Preparation of 6-(trifluoromethyl)-1H-benzo[d]imidazol-2-thiol (2c).

[0103] Using commercially available compound 4-trifluoromethyl o-phenylenediamine (1c) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 2c was collected as a white solid of 436.30 mg, with a yield of 70.41%. 1 H NMR (400MHz, DMSO-d6) δ12.90(s,2H),7.45(d,J=8.3Hz,1H),7.37(s,1H),7.30(d,J=8.3Hz,1H). 13 C NMR(101MHz,DMSO)δ170.88,135.50,132.69,125.02(q, 1 J C-F =271.7Hz), 123.28(q, 2 J C-F =31.9Hz), 119.96(q, 3 J C-F =3.8Hz), 110.33, 106.57(q, 3 J C-F =4.1Hz).

[0104] Example 4: Preparation of 6-(tert-butyl)-1H-benzo[d]imidazol-2-thiol (2d).

[0105] Using commercially available compound 4-tert-butyl-o-phenylenediamine (1d) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 2d was collected as a white solid of 524.40 mg, with a yield of 83.36%. 1 H NMR (400MHz, DMSO-d6) δ12.40 (s, 2H), 7.18 (dd, J = 8.4, 1.8Hz, 1H), 7.10–7.05 (m, 2H), 1.27 (s, 9H). 13 C NMR (101MHz, DMSO) δ168.44,145.70,132.72,130.55,120.19,109.43,106.33,34.87,31.92(3C).

[0106] Example 5: Preparation of 5-methylbenzo[d]oxazol-2-thiol (5a).

[0107] Using commercially available compound 2-amino-4-methylphenol (4a) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 5a was collected as a white solid of 524.70 mg, with a yield of 76.18%. 1H NMR (400MHz, DMSO-d6) δ13.76(s,1H),7.36(d,J=7.9Hz,1H),7.05(d,J=7.2Hz,2H),2.36(s,3H). 13 C NMR (101MHz, DMSO) δ180.66,146.81,135.30,131.69,124.79,111.00,109.97,21.29.

[0108] Example 6: Preparation of 5-methoxybenzo[d]oxazole-2-thiol (5b).

[0109] Using commercially available compound 2-amino-4-methoxyphenol (4b) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 3b was collected as a brown solid of 264.90 mg, with a yield of 67.68%. 1 H NMR (400MHz, DMSO-d6) δ13.78(s,1H),7.40(d,J=8.8Hz,1H),6.81(d,J=8.9Hz,1H),6.75(s,1H),3.77(s,3H). 13 C NMR (101MHz, DMSO) δ181.07,157.65,142.89,132.43,110.89,110.49,96.06,56.34.

[0110] Example 7: Preparation of 5-nitrobenzo[d]oxazole-2-thiol (5c).

[0111] Using commercially available compound 2-amino-4-nitrophenol (4c) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 3c was collected as a yellow solid of 358.80 mg, with a yield of 93.79%. 1 H NMR (400MHz, DMSO-d6) δ14.22(s,1H),8.17(d,J=8.9Hz,1H),7.92(s,1H),7.72(d,J=8.9Hz,1H). 13 C NMR (101MHz, DMSO) δ181.93,152.48,145.15,132.72,120.54,110.81,106.19.

[0112] Example 8: Preparation of 6-nitrobenzo[d]oxazole-2-thiol (5d).

[0113] Using commercially available compound 2-amino-5-nitrophenol (4d) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 3d was collected as a yellow solid of 179.80 mg, with a yield of 47.00%.1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.21 (d, J = 8.7Hz, 1H), 7.39 (d, J = 8.6Hz, 1H). 13 C NMR (101MHz, DMSO) δ182.43,148.07,143.87,137.72,122.23,110.63,106.46.

[0114] Example 9: Preparation of 6-fluorobenzo[d]oxazol-2-thiol (5e).

[0115] Using commercially available compound 2-amino-5-fluorophenol (4e) and CS2 as raw materials, the same synthesis method as compound 2a was used. Product 3e was collected as a pink solid, 519.00 mg, with a yield of 78.06%. 1 H NMR (400MHz, DMSO-d6) δ13.96(s,1H),7.55(dd,J=8.4,2.3Hz,1H),7.23(dd,J=8.7,4.8Hz,1H),7.15(td,J=9.4,9.0,2.3Hz,1H). 13 CNMR(101MHz,DMSO)δ181.15,159.40(d, 1 J C-F =240.6Hz), 148.67(d, 3 J C-F =14.0Hz), 128.34, 112.47 (d, 2 J C-F =24.5Hz), 111.27(d, 3 J C-F =9.8Hz), 99.47(d, 2 J C-F =29.3Hz).

[0116] Example 10: Preparation of 2-chloro-N-(3,4-dimethoxybenzyl)acetamide (7).

[0117] 3,4-Dimethoxybenzamine (740.20 mg, 4.43 mmol) and triethylamine (0.62 mL, 4.87 mmol) were dissolved in 5 mL of DCM and the reaction was carried out under argon protection. Then, chloroacetyl chloride (0.36 mL, 4.43 mmol) was slowly added dropwise under ice bath conditions, and the reaction was stirred at 0 °C for 30 min, followed by stirring at room temperature for another 30 min. After the reaction was complete, the pH was adjusted to neutral with dilute hydrochloric acid, and the resulting solid was filtered to give product 7 as a white solid of 877.50 mg, yield: 81.17%. 1H NMR (400MHz, Chloroform-d) δ6.82 (d, J = 8.0Hz, 4H), 4.46–4.38 (m, 2H), 4.12–4.06 (m, 2H), 3.90–3.83 (m, 6H). 13 C NMR (101MHz, CDCl3) δ165.74,149.25,148.73,129.83,120.22,111.28,111.21,55.97,55.94,43.76,42.64.

[0118] Example 11: Preparation of 2-chloro-N-(3,4-dihydroxybenzyl)acetamide (8).

[0119] Compound 7 (3000.00 mg, 12.31 mmol) was dissolved in DCM, and 1 mol / L BBr3 (73.86 ml, 73.86 mmol) was slowly added dropwise under ice bath conditions. After reacting for 30 min, the reaction was quenched with ice water. The reaction solution was extracted with EA, washed with saturated NaCl water, dried over anhydrous Na2SO4, and purified by column chromatography (DCM:MeOH = 25:1). Product 8 was collected as a white solid of 2301.50 mg, yield: 86.78%. 1 H NMR(400MHz, DMSO-d6)δ8.82(d,J=30.3Hz,2H),8.56(t,J=5.4Hz,1H),6.68–6.66(m ,1H),6.65(s,1H),6.52(dd,J=8.0,2.0Hz,1H),4.12(d,J=5.8Hz,2H),4.08(s,2H). 13 C NMR (101MHz, DMSO) δ166.12,145.59,144.80,130.01,118.91,115.78,115.57,43.14,42.71.

[0120] Example 12: Preparation of 2-(6-chloro-1H-benzo[d]imidazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (9a).

[0121] Compound 8 (150.00 mg, 0.70 mmol) and compound 2a, 6-chloro-2-mercaptobenzimidazole (154.80 mg, 0.77 mmol), were dissolved in 3 mL of acetonitrile. K₂CO₃ (193.50 mg, 1.40 mmol) was added, and the mixture was reacted at 50 °C for 4 h. After the reaction was complete, the reaction solution was extracted with EA, washed with saturated NaCl water, dried over anhydrous Na₂SO₄, and purified by column chromatography (DCM:MeOH = 25:1). Product 9a was collected as a pale yellow solid, 187.10 mg, yield: 73.47%. 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.80(s,2H),8.64(s,1H),7.50(s,1H),7.44(d,J=7.6Hz,1H),7.14( d,J=8.2Hz,1H),6.67(s,1H),6.62(d,J=7.9Hz,1H),6.51(d,J=7.6Hz,1H),4.16–4.10(m,2H),4.08(s,2H). 13 C NMR (101MHz, DMSO) δ167.31,145.55,144.68,130.14,122.00,118.69,115.73,115.46,42.76,35.52.

[0122] Example 13: Preparation of 2-(6-cyano-1H-benzo[d]imidazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (9b).

[0123] Using compounds 8 and 2b as raw materials, the same synthesis method as compound 9a was used. Product 9b was collected as a white solid of 199.80 mg, with a yield of 80.54%. 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),8.80(s,2H),8.65(t,J=5.6Hz,1H),7.96(s,1H),7.59(d,J=8.3Hz,1 H),7.53(d,J=8.3Hz,1H),6.67(s,1H),6.62(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H),4.13(d,J=3.0Hz,4H). 13 C NMR (101MHz, DMSO) δ167.12,155.75,145.56,144.70,130.14,125.76,120.49,118.72,115.73,115.48,103.77,42.78,35.48.

[0124] Example 14: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)thio)acetamide (9c).

[0125] Using compounds 8 and 2c as raw materials, the same synthesis method as compound 9a was used. Product 9c was collected as a white solid, 136.50 mg, with a yield of 50.00%. 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),8.78(s,2H),8.65(t,J=5.3Hz,1H),7.78(s,1H),7.61(d,J=8.3Hz,1 H),7.45(d,J=8.4Hz,1H),6.67(s,1H),6.62(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H),4.12(d,J=6.9Hz,4H). 13 C NMR (101MHz, DMSO) δ167.18,145.55,144.69,130.14,118.69,115.72,115.46,42.78,35.52.

[0126] Example 15: Preparation of 2-((6-(tert-butyl)-1H-benzo[d]imidazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (9d).

[0127] Using compounds 8 and 2d as raw materials, the same synthesis method as compound 9a was used. Product 9d was collected as a white solid of 236.40 mg, with a yield of 87.61%. 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.83(s,1H),8.75(s,1H),8.66(t,J=5.3Hz,1H),7.51–7.38(m,1H),7.30(d,J=13.9Hz,1H),7.20(dd,J =8.5,1.6Hz,1H),6.67(d,J=2.0Hz,1H),6.62(d,J=8.0Hz,1H),6.51(dd,J=8.0,1.8Hz,1H),4.12(d,J=5.7Hz,2H),4.03(s,2H),1.33(s,9H). 13 C NMR (101MHz, MeOD) δ206.63,170.02,151.04,146.46,146.33,145.54,131.52,121.10,120.25,116.35,116.11,44.23,36.18,35.67,32.53.

[0128] Example 16: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)acetamide (9e).

[0129] Using compound 8 and commercially available compound 6-nitro-2-mercaptobenzimidazole (2e) as raw materials, the same synthesis method as compound 9a was used. Product 9e was collected as a yellow solid of 121.40 mg, with a yield of 46.32%. 1 H NMR (400MHz, DMSO-d6) δ13.30(s,1H),8.78(d,J=16.9Hz,2H),8.66(t,J=5.6Hz,1H),8.31(s,1H),8.06(dd,J=8.4, 1.7Hz,1H),7.60(d,J=8.8Hz,1H),6.67(s,1H),6.62(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H),4.14(d,J=8.7Hz,4H). 13 C NMR (101MHz, DMSO) δ167.02,145.56,144.69,142.61,130.15,118.69,117.98,115.72,115.47,42.79,35.53.

[0130] Example 17: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-fluoro-1H-benzo[d]imidazol-2-yl)thio)acetamide (9f).

[0131] Using compound 8 and commercially available compound 6-fluoro-2-mercaptobenzimidazole (2f) as raw materials, the same synthesis method as compound 9a was used. Product 9f was collected as a gray oily liquid, 91.30 mg, yield: 37.56%. 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.79(s,2H),8.64(s,1H),7.41(s,1H),7.25(s,1H),6. 97(t,J=8.8Hz,1H),6.69–6.57(m,2H),6.50(d,J=7.5Hz,1H),4.16–4.09(m,2H),4.06(s,2H). 13 C NMR (101MHz, DMSO) δ167.39,145.54,144.67,130.14,118.68,115.72,115.45,42.75,35.54.

[0132] Example 18: Preparation of 2-(1H-benzo[d]imidazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (9g).

[0133] Using compound 8 and commercially available compound 2-mercaptobenzimidazole (2g) as raw materials, the synthesis method was the same as that for compound 9a. 9g of product was collected as a white solid of 219.20mg, with a yield of 95.07%. 1 H NMR(400MHz, Methanol-d4)δ9.67(s,1H),9.39(s,1H),8.83–8.70(m,2H),8.42(dd,J=5.8,3.0Hz, 2H),8.08(s,1H),7.97(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),5.55(d,J=5.3Hz,2H),5.26(s,2H). 13 C NMR (101MHz, MeOD) δ205.51,168.78,161.65,150.33,145.15,144.35,130.36,121.99,119.09,115.18,114.93,43.05,34.92.

[0134] Example 19: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-ethoxy-1H-benzo[d]imidazol-2-yl)thio)acetamide (9h).

[0135] Using compound 8 and commercially available compound 6-ethoxy-2-mercaptobenzimidazole (2h) as raw materials, the same synthesis method as compound 9a was used. Product 9h was collected as a pale yellow solid of 214.60 mg, with a yield of 82.10%. 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.80(s,2H),8.66(s,1H),7.31(d,J=39.6Hz,1H),6.95(d,J=54.6Hz,1H),6.77–6.71(m,1H), 6.70–6.65(m,1H),6.62(dd,J=7.9,3.6Hz,1H),6.54–6.48(m,1H),4.13(d,J=5.4Hz,2H),4.02(d,J=6.6Hz,4H),1.38–1.28(m,3H). 13 C NMR (101MHz, DMSO) δ167.62,145.55,144.67,130.13,118.69,115.74,115.45,63.87,42.75,35.68,15.24.

[0136] Example 20: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-methoxy-1H-benzo[d]imidazol-2-yl)thio)acetamide (9i).

[0137] Using compound 8 and commercially available compound 6 methoxy-2-mercaptobenzimidazole (2i) as raw materials, the same synthesis method as compound 9a was used. Product 9i was collected as a white solid of 190.90 mg, with a yield of 53.12%. 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.82(s,2H),8.66(s,1H),7.31(d,J=34.1Hz,1H),6.97(d,J=51.4Hz,1H),6.75(dd, J=8.7,2.4Hz,1H),6.67(s,1H),6.62(d,J=8.0Hz,1H),6.54–6.48(m,1H),4.13(d,J=5.7Hz,2H),4.02(s,2H),3.76(s,3H). 13 C NMR (101MHz, DMSO) δ167.63,145.56,144.69,130.15,118.71,115.75,115.47,55.91,42.76,35.67.

[0138] Example 21: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-methyl-1H-benzo[d]imidazol-2-yl)thio)acetamide (9j).

[0139] Using compound 8 and commercially available compound 6-methyl-2-mercaptobenzimidazole (2j) as raw materials, the same synthesis method as compound 9a was used. Product 9j was collected as a white solid of 129.00 mg, with a yield of 37.57%. 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.82(s,2H),8.66(t,J=5.5Hz,1H),7.42–7.12(m,2H),6.94(d,J=8.1Hz,1 H),6.68–6.65(m,1H),6.62(d,J=8.0Hz,1H),6.53–6.48(m,1H),4.12(d,J=5.7Hz,2H),4.04(s,2H),2.38(s,3H). 13 C NMR (101MHz, DMSO) δ167.59,145.56,144.68,130.15,118.69,115.75,115.45,42.75,35.59,21.68.

[0140] Example 22: Preparation of 2-(benzo[d]thiazolyl-2-ylthio)-N-(3,4-dihydroxybenzyl)acetamide (10a).

[0141] Using compound 8 and commercially available compound 2-mercaptobenzothiazole (3a) as raw materials, the same synthesis method as compound 9a was used. Product 10a was collected as a white solid of 114.40 mg, with a yield of 47.31%. 1 H NMR (400MHz, DMSO-d6) δ8.81(s,2H),8.67(s,1H),8.01(d,J=7.9Hz,1H),7.83(d,J=8.0Hz,1H),7.47(t,J=7.5Hz,1H) ,7.37(t,J=7.5Hz,1H),6.68(s,1H),6.63(d,J=7.9Hz,1H),6.52(d,J=7.9Hz,1H),4.18(s,2H),4.14(d,J=4.7Hz,2H). 13 C NMR (101MHz, DMSO) δ166.72,166.48,153.06,145.58,144.74,135.22,130. 13,126.83,124.95,122.27,121.56,118.78,115.75,115.54,42.86,37.10.

[0142] Example 23: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-methoxybenzo[d]thiazo-2-yl)thio)acetamide (10b).

[0143] Using compound 8 and commercially available compound 6-methoxy-2-mercaptobenzothiazole (3b) as starting materials, the same synthesis method as compound 9a was used. Product 10b was collected as a white solid of 157.10 mg, with a yield of 59.62%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=22.8Hz,2H),8.64(t,J=5.6Hz,1H),7.72(d,J=8.9Hz,1H),7.60(d,J=2.5Hz,1H),7.05( dd,J=8.9,2.5Hz,1H),6.68(d,J=1.5Hz,1H),6.63(d,J=8.0Hz,1H),6.54–6.49(m,1H),4.13(d,J=5.2Hz,4H),3.81(s,3H). 13C NMR (101MHz, DMSO) δ166.59,163.20,157.17,147.50,145.57,144.72,136.71, 130.13,122.09,118.77,115.74,115.56,115.54,105.35,56.16,42.83,37.15.

[0144] Example 24: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-methoxybenzo[d]thiazo-2-yl)thio)acetamide (10c).

[0145] Using compound 8 and commercially available compound 5-methoxy-2-mercaptobenzothiazole (3c) as raw materials, the same synthesis method as compound 9a was used. Product 10c was collected as a white solid of 196.20 mg, with a yield of 74.45%. 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=23.5Hz,2H),8.66(t,J=5.5Hz,1H),7.86(d,J=8.8Hz,1H),7.37(d,J=2.1Hz,1H),7.0 0(dd,J=8.8,2.3Hz,1H),6.69(s,1H),6.64(d,J=8.0Hz,1H),6.53(d,J=8.0Hz,1H),4.15(d,J=5.6Hz,4H),3.83(s,3H). 13 C NMR(101MHz,DMSO)δ167.67,166.50,159.14,154.38,145.58,144.73,130.14, 126.77,122.52,118.79,115.73,115.55,114.19,104.95,55.97,42.86,37.08.

[0146] Example 25: Preparation of N-(3,4-dihydroxybenzyl)-2-((4-methylbenzo[d]thiazo-2-yl)thio)acetamide (10d).

[0147] Using compound 8 and commercially available compound 4-methyl-2-mercaptobenzothiazole (3d) as starting materials, the same synthesis method as compound 9a was used. Product 10d was collected as a white solid of 156.00 mg, with a yield of 62.60%. 1H NMR (400MHz, DMSO-d6) δ8.80(s,2H),8.66(t,J=4.6Hz,1H),7.81(d,J=6.8Hz,1H),7.26(d,J=7.1H z,2H),6.68(s,1H),6.62(d,J=7.9Hz,1H),6.51(d,J=8.0Hz,1H),4.20–4.11(m,4H),2.58(s,3H). 13 C NMR(101MHz,DMSO)δ166.59,165.36,152.28,145.58,144.75,135.00,131.16, 130.09,127.25,124.89,119.56,118.83,115.72,115.61,42.93,37.18,18.33.

[0148] Example 26: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-methylbenzo[d]thiazo-2-yl)thio)acetamide (10e).

[0149] Using compound 8 and commercially available compound 6-methyl-2-mercaptobenzothiazole (3e) as raw materials, the same synthesis method as compound 9a was used. Product 10e was collected as a brown solid, 74.50 mg, with a yield of 29.52%. 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.79(s,1H),7.71(d,J=8.2Hz,1H),7.28(d,J=8.1Hz,1H),6 .68(s,1H),6.64(d,J=7.9Hz,1H),6.51(d,J=7.8Hz,1H),4.16(s,2H),4.14(s,2H),2.41(s,3H). 13 C NMR(101MHz,DMSO)δ166.52,165.28,151.21,145.68,144.84,135.36,134.60, 130.03,128.14,121.86,121.14,118.71,115.79,115.59,42.85,37.10,21.41.

[0150] Example 27: Preparation of 2-(6-chlorobenzo[d]thiazolyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (10f).

[0151] Using compound 8 and commercially available compound 6-chloro-2-mercaptobenzothiazole (3f) as raw materials, the same synthesis method as compound 9a was used. Product 10f was collected as a white solid of 200.90 mg, with a yield of 75.36%.1 H NMR (400MHz, DMSO-d6) δ8.80(s,2H),8.66(t,J=4.8Hz,1H),8.17(d,J=2.0Hz,1H),7.80(d,J=8.7Hz,1H),7.49(dd, J=8.7,2.0Hz,1H),6.70–6.66(m,1H),6.63(d,J=8.0Hz,1H),6.54–6.48(m,1H),4.18(s,2H),4.14(d,J=5.1Hz,2H). 13 C NMR (101MHz, DMSO) δ168.11,166.38,151.86,145.58,144.74,136.80,130. 11,129.33,127.22,122.59,121.98,118.78,115.74,115.54,42.86,37.15.

[0152] Example 28: Preparation of 2-(4-chlorobenzo[d]thiazolyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (10 g).

[0153] Using compound 8 and commercially available compound 4-chloro-2-mercaptobenzothiazole (3g) as raw materials, the same synthesis method as compound 9a was used. 10g of the product was collected as a white solid of 208.30mg, with a yield of 78.13%. 1 H NMR (400MHz, DMSO-d6) δ8.88–8.74(m,2H),8.70(t,J=5.5Hz,1H),7.99(d,J=7.8Hz,1H),7.56(d,J=7.5Hz,1H),7.35(t,J= 7.9Hz,1H),6.68(d,J=1.6Hz,1H),6.63(d,J=8.0Hz,1H),6.52(dd,J=8.0,1.6Hz,1H),4.20(s,2H),4.14(d,J=5.6Hz,2H). 13 C NMR (101MHz, DMSO) δ168.91,166.31,149.72,145.58,144.76,136.81,130. 02,126.93,125.80,125.14,121.32,118.85,115.75,115.59,42.95,37.38.

[0154] Example 29: Preparation of 2-(5-chlorobenzo[d]thiazo-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (10h).

[0155] Using compound 8 and commercially available compound 5-chloro-2-mercaptobenzothiazole (3h) as raw materials, the synthesis method was the same as that of compound 9a. The product was collected as a white solid of 190.00 mg after 10h, with a yield of 71.27%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=25.5Hz,2H),8.67(t,J=5.6Hz,1H),8.04(d,J=8.6Hz,1H),7.88(d,J=1.7Hz,1H),7.42 (dd,J=8.6,1.8Hz,1H),6.70–6.66(m,1H),6.63(d,J=8.0Hz,1H),6.55–6.49(m,1H),4.18(s,2H),4.14(d,J=5.7Hz,2H). 13 C NMR (101MHz, DMSO) δ169.69,166.32,153.95,145.58,144.75,134.02,131. 65,130.10,124.92,123.69,120.99,118.78,115.73,115.55,42.87,37.19.

[0156] Example 30: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-fluorobenzo[d]thiazo-2-yl)thio)acetamide (10i).

[0157] Using compound 8 and commercially available compound 6-fluoro-2-mercaptobenzothiazole (3i) as raw materials, the synthesis method was the same as that for compound 9a. Product 10i was collected as a white solid of 203.60 mg, with a yield of 79.82%. 1 H NMR(400MHz, DMSO-d6)δ8.80(d,J=20.2Hz,2H),8.69–8.58(m,1H),7.94(dd,J=8.6,2.6Hz,1H),7.84(dd,J =8.9,4.8Hz,1H),7.33(td,J=9.0,2.7Hz,1H),6.72–6.58(m,2H),6.52(d,J=7.9Hz,1H),4.21–4.08(m,4H). 13 C NMR(101MHz,DMSO)δ166.60,166.54,159.57(d, 1 J C-F =242.5Hz),149.88,145.53,144.69,136.45(d, 3 J C-F =11.7Hz), 130.12, 122.61(d, 3 JC-F =9.4Hz), 118.77, 115.00(d, 2 J C-F =24.6Hz),115.12,114.87,108.81(d, 2 J C-F =27.6Hz), 42.86, 37.10.

[0158] Example 31: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-fluorobenzo[d]thiazo-2-yl)thio)acetamide (10j).

[0159] Using compound 8 and commercially available compound 5-fluoro-2-mercaptobenzothiazole (3j) as raw materials, the same synthesis method as compound 9a was used. Product 10j was collected as a white solid of 179.50 mg, with a yield of 70.10%. 1 H NMR(400MHz, DMSO-d6)δ8.80(s,2H),8.67(s,1H),8.05(dd,J=8.6,5.3Hz,1H),7.71–7.57( m,1H),7.28(t,J=8.9Hz,1H),6.74–6.57(m,2H),6.52(d,J=7.9Hz,1H),4.21–4.08(m,4H). 13 C NMR(101MHz,DMSO)δ169.91,166.37,161.72(d, 1 J C-F =240.9Hz), 153.91(d, 3 J C-F =12.3Hz),145.57,144.73,130.95(d, 4 J C-F =1.5Hz), 130.11, 123.46(d, 3 J C-F =9.9Hz),118.78,115.72,115.53,113.05(d, 2 J C-F =24.7Hz), 107.81(d, 2 J C-F =24.1Hz), 42.87, 37.14.

[0160] Example 32: Preparation of N-(3,4-dihydroxybenzyl)-2-((4-fluorobenzo[d]thiazo-2-yl)thio)acetamide (10k).

[0161] Using compound 8 and commercially available compound 4-fluoro-2-mercaptobenzothiazole (3k) as raw materials, the synthesis method was the same as that for compound 9a. Product 10k was collected as a white solid of 212.50 mg, with a yield of 83.30%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=26.2Hz,2H),8.70(t,J=5.5Hz,1H),7.85(d,J=7.8Hz,1H),7.43–7.29(m ,2H),6.67(d,J=1.7Hz,1H),6.64(d,J=8.0Hz,1H),6.53(dd,J=8.0,1.7Hz,1H),4.23(s,2H),4.15(s,2H). 13 C NMR(101MHz,DMSO)δ168.19,166.36,153.90(d, 1 J C-F =253.2Hz),145.54,144.71,141.40(d, 2 J C-F =13.7Hz), 138.01(d, 4 J C-F =3.8Hz), 130.03, 125.96(d, 3 J C-F =7.1Hz), 118.40(d, 3 J C-F =4.3Hz),118.38,115.74,115.50,112.65(d, 2 J C-F =17.7Hz), 42.89, 37.31.

[0162] Example 33: Preparation of 2-(5-bromobenzo[d]thiazolyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (10l).

[0163] Using compound 8 and commercially available compound 5-bromo-2-mercaptobenzothiazole (3l) as raw materials, the same synthesis method as compound 9a was used. Product 10l was collected as a white solid of 144.70 mg, yield: 48.60%. 1 H NMR(400MHz,DMSO-d6)δ8.80(s,2H),8.68(t,J=5.4Hz,1H),8.06–7.95(m,2H),7.53(dd,J=8.5,1.7Hz ,1H),6.70–6.67(m,1H),6.64(d,J=8.0Hz,1H),6.55–6.49(m,1H),4.18(s,2H),4.14(d,J=5.5Hz,2H).13 C NMR (101MHz, DMSO) δ169.48,166.30,154.25,145.57,144.74,134.47,130. 09,127.56,124.02,123.91,119.68,118.77,115.73,115.54,42.87,37.19.

[0164] Example 34: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-(trifluoromethyl)benzo[d]thiazo-2-yl)thio)acetamide (10m).

[0165] Using compound 8 and commercially available compound 5-trifluoromethyl-2-mercaptobenzothiazole (3m) as raw materials, the synthesis method was the same as that for compound 9a. Product 10m was collected as a white solid of 120.70 mg, with a yield of 65.53%. 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.76(s,1H),8.69(t,J=5.7Hz,1H),8.27(d,J=8.4Hz,1H),8.13(s,1H),7.70(d,J=9 .5Hz,1H),6.69(d,J=1.8Hz,1H),6.63(d,J=8.0Hz,1H),6.53(dd,J=8.0,1.9Hz,1H),4.22(s,2H),4.15(d,J=5.7Hz,2H). 13 C NMR (101MHz, DMSO) δ170.28,166.27,152.71,145.57,144.74,139.50,130.09,127.75(d, 3 J C-F =32.2Hz),126.07,123.68,120.98(q, 4 J C-F =16.73,Hz),118.75,118.08(q, 5 J C-F =4.1Hz).,115.71,115.55,42.88,37.21.

[0166] Example 35: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-nitrobenzo[d]thiazo-2-yl)thio)acetamide (10n).

[0167] Using compound 8 and commercially available compound 5-nitro-2-mercaptobenzothiazole (3n) as raw materials, the same synthesis method as compound 9a was used. Product 10n was collected as a yellow solid of 86.70 mg, with a yield of 32.82%.1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.75(s,1H),8.70(t,J=5.7Hz,1H),8.54(s,1H),8.29(d,J=8.7Hz, 1H),8.21(d,J=8.6Hz,1H),6.73–6.58(m,2H),6.53(d,J=7.7Hz,1H),4.23(s,2H),4.15(d,J=5.2Hz,2H). 13 C NMR (101MHz, DMSO) δ171.85,166.25,152.75,146.88,145.57,144.74,142. 44,130.10,123.43,119.18,118.74,116.05,115.71,115.55,42.89,37.25.

[0168] Example 36: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-nitrobenzo[d]thiazo-2-yl)thio)acetamide (10o).

[0169] Using compound 8 and commercially available compound 6-nitro-2-mercaptobenzothiazole (3o) as raw materials, the same synthesis method as compound 9a was used. Product 10o was collected as a yellow solid of 171.80 mg, with a yield of 65.03%. 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=2.5Hz,1H),8.81(s,2H),8.72(d,J=6.1Hz,1H),8.29(dd,J=9.0,2.5Hz,1H),7. 96(d,J=8.9Hz,1H),6.68(s,1H),6.64(d,J=8.0Hz,1H),6.52(d,J=7.6Hz,1H),4.25(s,2H),4.15(d,J=5.1Hz,2H). 13 C NMR (101MHz, DMSO) δ174.85,166.15,156.91,145.58,144.76,144.04,136. 00,130.09,122.40,121.59,119.28,118.78,115.75,115.57,42.90,37.32.

[0170] Example 37: Preparation of 2-bromo-N-(3,4-dimethoxybenzyl)acetamide (12).

[0171] Using compound 6, namely 3,4-dimethoxybenzamine (1000.00 mg, 5.98 mmol), triethylamine (0.91 ml, 7.18 mmol), and bromoacetyl bromide (1.05 ml, 11.96 mmol), as starting materials, the same method as compound 7 was used for synthesis. The yield of compound 12 was 1593.90 g, with a yield of 92.58%. 1 H NMR (400MHz, Chloroform-d) δ6.82 (s, 2H), 6.80 (s, 1H), 6.76 (s, 1H), 4.39 (d, J = 5.6Hz, 2H), 3.89 (s, 2H), 3.86 (s, 6H). 13 C NMR (101MHz, CDCl3) δ165.35,149.23,148.69,129.86,120.13,111.27,111.13,55.96,55.93,44.06,29.15.

[0172] Example 38: Preparation of 2-bromo-N-(3,4-dihydroxybenzyl)acetamide (13).

[0173] Using compound 12 (2000.00 mg, 6.94 mmol) and 1 mol / L BBr3 (41.68 ml, 41.68 mmol) as starting materials, the same method as compound 8 was used for synthesis. Compound 13 was collected as a white solid of 1636.80 mg, with a yield of 90.75%. 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.77(s,1H),8.60(s,1H),6.65(s,2H),6.51(d,J=7.5Hz,1H),4.10(s,2H),3.87(s,2H). 13 C NMR (101MHz, DMSO) δ166.19,145.61,144.81,129.95,118.90,115.78,115.57,42.82,30.01.

[0174] Example 39: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-methylbenzo[d]oxazol-2-yl)thio)acetamide (14a).

[0175] Using compounds 13 and 5a as raw materials, the same synthesis method as compound 9a was used. Product 14a was collected as a white solid of 186.90 mg, with a yield of 94.06%. 1H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.79(s,1H),8.68(s,1H),7.50(d,J=8.0Hz,1H),7.43(s,1H),7.1 2(d,J=7.9Hz,1H),6.69(s,1H),6.65(d,J=7.9Hz,1H),6.53(d,J=7.6Hz,1H),4.15(s,4H),2.41(s,3H). 13 C NMR(101MHz,DMSO)δ166.32,164.24,150.01,145.58,144.72,141.94,134.46, 130.11,125.51,118.75,118.64,115.72,115.52,110.00,42.84,36.07,21.42.

[0176] Example 40: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-methoxybenzo[d]oxazol-2-yl)thio)acetamide (14b).

[0177] Using compounds 13 and 5b as raw materials, the same synthesis method as compound 9a was used. Product 14b was collected as a white solid of 120.30 mg, with a yield of 57.85%. 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=11.3Hz,2H),8.66(s,1H),7.51(d,J=8.5Hz,1H),7.19(s,1 H),6.88(d,J=7.6Hz,1H),6.75–6.59(m,2H),6.53(d,J=7.4Hz,1H),4.14(s,4H),3.79(s,3H). 13 C NMR(101MHz,DMSO)δ166.28,164.87,157.38,146.31,145.58,144.71,142.69, 130.14,118.74,115.70,115.51,112.23,110.72,102.53,56.25,42.84,36.02.

[0178] Example 41: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-nitrobenzo[d]oxazol-2-yl)thio)acetamide (14c).

[0179] Using compounds 13 and 5c as raw materials, the same synthesis method as compound 9a was used. Product 14c was collected as a yellow solid of 140.70 mg, with a yield of 64.96%. 1H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.77(s,1H),8.72(t,J=5.1Hz,1H),8.46(s,1H),8.25(d,J=8.9Hz,1H),7.8 8(d,J=8.9Hz,1H),6.68(s,1H),6.64(d,J=8.0Hz,1H),6.53(d,J=7.9Hz,1H),4.23(s,2H),4.15(d,J=5.5Hz,2H). 13 C NMR (101MHz, DMSO) δ168.53,165.96,155.39,145.59,145.37,144.77,142. 20,130.08,120.89,118.78,115.72,115.56,114.33,111.33,42.91,36.34.

[0180] Example 42: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-nitrobenzo[d]oxazol-2-yl)thio)acetamide (14d).

[0181] Using compounds 13 and 5d as raw materials, the same synthesis method as compound 9a was used. Product 14d was collected as a yellow solid, 70.60 mg, with a yield of 32.60%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=12.7Hz,2H),8.73(t,J=6.3Hz,1H),8.58(s,1H),8.27(d,J=8.7Hz,1H),7.82 (d,J=8.7Hz,1H),6.68(s,1H),6.64(d,J=8.0Hz,1H),6.53(d,J=7.7Hz,1H),4.24(s,2H),4.15(d,J=5.1Hz,2H). 13 C NMR (101MHz, DMSO) δ170.60,165.90,150.99,147.14,145.56,144.74,144. 25,130.06,121.41,118.77,118.59,115.71,115.54,107.20,42.91,36.40.

[0182] Example 43: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-fluorobenzo[d]oxazol-2-yl)thio)acetamide (14e).

[0183] Using compounds 13 and 5e as raw materials, the same synthesis method as compound 9a was used. Product 14e was collected as a white solid of 107.10 mg, with a yield of 53.28%. 1 H NMR(400MHz,DMSO-d6)δ8.81(s,2H),8.73–8.63(m,1H),7.75–7.55(m,2H),7.32–7.13( m,1H),6.68(s,1H),6.64(dd,J=7.8,5.3Hz,1H),6.56–6.48(m,1H),4.21–4.08(m,4H). 13 C NMR(101MHz,DMSO)δ166.24,164.91(d, 4 J C-F =2.3Hz), 159.65(d, 1 J C-F =241.0Hz), 151.63(d, 3 J C-F =15.1Hz),145.56,144.72,138.29,130.10,119.12(d, 3 J C-F =10.2Hz),118.76,115.72,115.51,112.60(d, 2 J C-F =24.2Hz), 99.18(d, 2 J C-F =28.9Hz), 42.86, 36.14.

[0184] Example 44: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-fluorobenzo[d]oxazol-2-yl)thio)acetamide (14f).

[0185] Using compound 13 and commercially available compound 5-fluorobenzoxazole-2-thiol (5f) as raw materials, the same synthesis method as compound 9a was used. Product 14f was collected as a white solid of 154.60 mg, with a yield of 76.92%. 1 H NMR (400MHz, DMSO-d6) δ8.81(s,2H),8.69(t,J=4.6Hz,1H),7.66(dd,J=8.9,4.3Hz,1H),7.51(dd,J=8.7,2.5Hz,1H),7 .18(td,J=9.4,2.5Hz,1H),6.69(s,1H),6.65(d,J=8.0Hz,1H),6.56–6.49(m,1H),4.18(s,2H),4.15(d,J=5.5Hz,2H). 13C NMR(101MHz,DMSO)δ166.63,166.15,159.89(d, 1 J C-F =238.2Hz), 148.27(d, 4 J C-F =0.70Hz),145.58,144.74,142.65(d, 3 J C-F =13.8Hz),130.10,118.76,115.72,115.53,111.86(d, 2 J C-F =26.2Hz), 111.32(d, 3 J C-F =10.4Hz), 105.40(d, 2 J C-F =26.1Hz), 42.86, 36.11.

[0186] Example 45: Preparation of 2-(6-chlorobenzo[d]oxazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetate (14 g).

[0187] Using compound 13 and compound 6-chloro-2-mercaptobenzoxazole (5g) as raw materials, the same synthesis method as compound 9a was used. 14g of product was collected as 162.00mg of white solid, with a yield of 76.96%. 1 H NMR (400MHz, DMSO-d6) δ8.80(s,2H),8.69(t,J=5.1Hz,1H),7.84(d,J=1.4Hz,1H),7.63(d,J=8.5Hz,1H),7.4 4–7.35(m,1H),6.68(s,1H),6.64(d,J=8.0Hz,1H),6.53(d,J=7.9Hz,1H),4.17(s,2H),4.14(d,J=5.4Hz,2H). 13 C NMR(101MHz,MeOD)δ167.72,165.13,152.02,144.97,144.28,140.36,129. 56,129.51,124.78,118.80,118.65,114.78,114.65,110.33,43.04,34.89.

[0188] Example 46: Preparation of 2-(5-chlorobenzo[d]oxazol-2-yl)thio)-N-(3,4-dihydroxybenzyl)acetamide (14h).

[0189] Using compound 13 and commercially available compound 5-chloro-2-mercaptobenzoxazole (5h) as raw materials, the same synthesis method as compound 9a was used. The product was collected as a white solid of 152.90 mg after 14h, with a yield of 72.64%. 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.92(s,1H),8.85(s,1H),7.00(dd,J=8.6,2.5Hz,1H),6.88(d,J=8.6Hz ,1H),6.84(s,1H),6.80(d,J=2.5Hz,1H),6.73–6.68(m,1H),6.67(d,J=8.0Hz,1H),4.78(s,2H),4.08(s,2H). 13 C NMR (101MHz, DMSO) δ172.37,157.33,148.17,145.44,145.24,137.16,127. 56,125.10,122.65,121.28,119.85,117.87,116.21,115.76,45.60,33.00.

[0190] Example 47: Preparation of 2-(benzo[d]oxazol-2-ylthio)-N-(3,4-dihydroxybenzyl)acetamide (14i).

[0191] Using compound 13 and commercially available compound 2-mercaptobenzoxazole (5i) as raw materials, the same synthesis method as compound 9a was used. Product 14i was collected as a yellow solid of 131.5 mg, with a yield of 57.03%. 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=16.1Hz,2H),8.69(t,J=5.3Hz,1H),7.63(d,J=7.5H z,2H),7.40–7.26(m,2H),6.72–6.61(m,2H),6.53(d,J=8.0Hz,1H),4.23–4.07(m,4H). 13 C NMR (101MHz, DMSO) δ166.34,164.35,151.74,145.55,144.70,141.71,130. 10,125.10,124.74,118.73,118.67,115.73,115.49,110.64,42.84,36.03.

[0192] Example 48: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-methylbenzo[d]oxazol-2-yl)thio)acetamide (14j).

[0193] Using compound 13 and commercially available compound 6-methyl-2-mercaptobenzoxazole (5j) as raw materials, the same synthesis method as compound 9a was used. Product 14j was collected as a white solid of 141.80 mg, with a yield of 71.36%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=17.6Hz,2H),8.67(t,J=5.7Hz,1H),7.49(d,J=8.1Hz,1H),7.44(s,1H),7.16(d,J=8. 0Hz, 1H), 6.69 (d, J = 1.7Hz, 1H), 6.64 (d, J = 8.0Hz, 1H), 6.53 (dd, J = 8.0, 1.7Hz, 1H), 4.14 (d, J = 3.4Hz, 4H), 2.42 (s, 3H). 13 C NMR(101MHz,DMSO)δ166.35,163.46,152.03,145.58,144.73,139.58,134.66, 130.13,126.03,118.77,118.08,115.73,115.53,110.74,42.84,36.07,21.58.

[0194] Example 49: Preparation of tert-butyl (2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)carbamate (16).

[0195] Compound 6, 3,4-dimethoxybenzamine (500.00 mg, 2.99 mmol), and compound 15, N-Boc-glycine (628.50 mg, 3.59 mmol), were dissolved in 5 mL of DCM. PyBop (1868.20 mg, 3.59 mmol) and DIPEA (1.60 mL, 8.97 mmol) were added, and the mixture was reacted at room temperature for 12 h. After the reaction was complete, the reaction solution was extracted sequentially with DCM, washed with water, dried over anhydrous Na2SO4, and purified by column chromatography (PE:EA = 1:1). Compound 16 was collected as a white viscous solid, 436.40 mg, yield: 89.69%. 1 H NMR (400MHz, Chloroform-d) δ6.79 (s, 3H), 5.41 (s, 1H), 4.35 (d, J = 5.7Hz, 2H), 3.84 (s, 6H), 3.80 (d, J = 5.1Hz, 2H), 1.40 (s, 9H). 13C NMR (101MHz, CDCl3) δ169.55,156.18,149.08,148.41,130.51,119.96,111.17,111.08,80.23,55.91,55.86,44.38,43.23,28.25(3C).

[0196] Example 50: Preparation of 2-amino-N-(3,4-dimethoxybenzyl)acetamide (17).

[0197] Compound 16 (436.40 mg, 1.35 mmol) was dissolved in 18 mL of DCM, and 2 mL of trifluoroacetic acid was slowly added dropwise. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to weakly alkaline with NaOH aqueous solution. The reaction solution was extracted with a large amount of DCM, dried with anhydrous Na2SO4, and the organic phase was evaporated to dryness. Compound 17 was collected as a white solid of 274.60 mg, yield: 90.70%. 1 HNMR (400MHz, Chloroform-d) δ7.55 (s, 1H), 6.84 (s, 3H), 4.41 (d, J = 5.8Hz, 2H), 3.88 (s, 6H), 3.40 (s, 2H). 13 C NMR (101MHz, CDCl3) δ172.51,149.11,148.42,131.03,120.10,111.30,111.19,55.95,55.92,44.77,42.88.

[0198] Example 51: Preparation of 6-chloro-N-(3,4-dimethoxybenzyl)benzo[d]thiazole-2-carboxamide (19a).

[0199] Commercially available compound 18a, namely 2,6-dichlorobenzothiazole (173.30 mg, 0.85 mmol), and compound 17 (285.70 mg, 1.27 mmol) were dissolved in 5 mL of ethanol. DIPEA (0.21 mL, 1.27 mmol) was added, and the mixture was refluxed at 80 °C for 12 h. After the reaction was complete, a white solid precipitated. Filtering yielded compound 19a as a white solid of 178.30 mg, yield: 53.53%. 1H NMR (400MHz, DMSO-d6) δ8.53–8.40(m,2H),7.81(s,1H),7.36(d,J=8.5Hz,1H),7.25(d,J=8.5Hz,1H),6.85(d ,J=4.3Hz,2H),6.80(d,J=8.1Hz,1H),4.25(d,J=5.5Hz,2H),4.07(d,J=4.4Hz,2H),3.71(s,3H),3.69(s,3H). 13 C NMR (101MHz, DMSO) δ168.96,167.34,151.60,149.06,148.20,132.87,132.16,126 .09,125.27,121.11,119.79,119.45,112.15,111.75,56.04,55.85,47.11,42.32.

[0200] Example 52: Preparation of N-(3,4-dimethoxybenzyl)-2-((5-nitrobenzo[d]thiazolyl)amino)acetamide (19b).

[0201] Using compound 17 and commercially available compound 2-chloro-5-nitrobenzothiazole (18b) as raw materials, the same synthesis method as compound 19a was used. Product 19b was collected as a yellow solid of 167.20 mg, with a yield of 88.40%. 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.55(t,J=5.8Hz,1H),8.09(d,J=2.1Hz,1H),7.97(d,J=8.6Hz,1H),7.91(dd,J=8.6 ,2.2Hz,1H),6.88(d,J=8.0Hz,2H),6.84(d,J=8.2Hz,1H),4.27(d,J=5.8Hz,2H),4.13(s,2H),3.72(s,3H),3.70(s,3H). 13 C NMR (101MHz, DMSO) δ169.03,168.65,153.02,149.05,148.24,146.52,139.44,132 .12,122.16,119.80,116.16,112.26,112.08,111.80,55.98,55.86,47.14,42.33.

[0202] Example 53: Preparation of N-(3,4-dimethoxybenzyl)-2-((6-nitrobenzo[d]thiazolyl)amino)acetamide (19c).

[0203] Using compound 17 and commercially available compound 2-chloro-6-nitrobenzothiazole (18c) as raw materials, the same synthesis method as compound 19a was used. Product 19c was collected as a yellow solid of 221.00 mg, with a yield of 78.45%. 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.73(d,J=2.3Hz,1H),8.56(t,J=5.7Hz,1H),8.13(dd,J=8.9,2.4Hz,1H),7.48(d ,J=8.9Hz,1H),6.92–6.86(m,2H),6.82(d,J=8.2Hz,1H),4.27(d,J=5.8Hz,2H),4.17(s,2H),3.73(s,3H),3.71(s,3H). 13 C NMR (101MHz, DMSO) δ171.56,168.44,158.29,149.08,148.25,141.36,132.06,131 .96,122.46,119.82,118.27,117.76,112.17,111.80,56.04,55.86,47.18,42.39.

[0204] Example 54: Preparation of N-(3,4-dimethoxybenzyl)-2-((5-nitrobenzo[d]oxazol-2-yl)amino)acetamide (19d).

[0205] Using compound 17 and commercially available compound 2-chloro-5-nitrobenzoxazole (18d) as raw materials, the same synthesis method as compound 19a was used. Product 19d was collected as a pale yellow solid, 84.40 mg, with a yield of 87.38%. 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.56(t,J=5.8Hz,1H),8.04(d,J=2.3Hz,1H),7.98(dd,J=8.7,2.3Hz,1H),7.62( d,J=8.7Hz,1H),6.91–6.85(m,2H),6.83–6.78(m,1H),4.25(d,J=5.9Hz,2H),4.02(s,2H),3.72(s,3H),3.71(s,3H). 13 C NMR (101MHz, DMSO) δ168.56,164.94,153.00,149.07,148.24,144.90,144.48,132 .12,119.86,117.47,112.14,111.84,110.83,109.36,56.02,55.88,45.64,42.36.

[0206] Example 55: Preparation of 2-(6-chlorobenzo[d]thiazolyl)amino)-N-(3,4-dihydroxybenzyl)acetamide (20a).

[0207] Using compound 19a and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 20a was collected as a white solid, 91.80 mg, with a yield of 97.05%. 1 H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.57 (t, J = 5.6Hz, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.46 (d, J = 8. 6Hz,1H),7.38(dd,J=8.6,1.9Hz,1H),6.71–6.63(m,2H),6.58–6.50(m,1H),4.27–4.05(m,4H). 13 C NMR (101MHz, DMSO) δ168.13,167.31,145.53,145.53,144.70,130.19,129. 56,127.16,127.02,122.24,118.85,117.71,115.74,115.61,47.53,42.48.

[0208] Example 56: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-nitrobenzo[d]thiazolyl)amino)acetamide (20b).

[0209] Using compound 19b and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 20b was collected as a yellow solid, 76.40 mg, with a yield of 81.63%. 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.48(t,J=5.8Hz,1H),8.10(d,J=2.2Hz,1H),7.98(d,J=8.6Hz,1H),7.9 1(dd,J=8.6,2.2Hz,1H),6.69–6.62(m,2H),6.54(dd,J=8.0,1.9Hz,1H),4.14(d,J=5.8Hz,2H),4.11(s,2H). 13 C NMR (101MHz, DMSO) δ169.06,168.26,152.37,146.56,145.53,144.64,139. 08,130.40,122.26,118.70,116.31,115.72,115.49,112.17,47.12,42.33.

[0210] Example 57: Preparation of N-(3,4-dihydroxybenzyl)-2-((6-nitrobenzo[d]thiazolyl)amino)acetamide (20c).

[0211] Using compound 19c and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 20c was collected as a yellow solid, 25.70 mg, with a yield of 91.53%. 1 H NMR (400MHz, DMSO-d6) δ9.03(t,J=5.4Hz,1H),8.73(d,J=2.2Hz,1H),8.49(t,J=5.7Hz,1H),8.12(dd,J= 8.9, 2.3Hz, 1H), 7.50 (d, J = 8.9Hz, 1H), 6.71–6.63 (m, 2H), 6.55 (d, J = 8.0Hz, 1H), 4.16 (d, J = 5.4Hz, 4H). 13 C NMR (101MHz, DMSO) δ171.48,168.19,158.12,145.54,144.65,141.37,131. 89,130.39,122.46,118.73,118.29,117.76,115.72,115.49,47.16,42.34.

[0212] Example 58: Preparation of N-(3,4-dihydroxybenzyl)-2-((5-nitrobenzo[d]oxazol-2-yl)amino)acetamide (20d).

[0213] Using compound 19d and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 20d was collected as a yellow solid, 40.00 mg, with a yield of 85.87%. 1 H NMR(400MHz, DMSO-d6)δ8.75(t,J=5.9Hz,1H),8.47(t,J=5.4Hz,1H),8.10–8.04(m,1H),8.03–7.94(m,1H),7 .61(d,J=8.7Hz,1H),6.75–6.62(m,2H),6.54(d,J=7.9Hz,1H),4.14(d,J=5.5Hz,2H),3.99(d,J=6.0Hz,2H). 13 C NMR (101MHz, DMSO) δ168.33,164.93,152.99,145.53,144.90,144.64,144. 50,130.44,118.77,117.44,115.68,115.55,110.88,109.34,45.60,42.35.

[0214] Example 59: Preparation of 2-(6-chlorobenzo[d]thiazolyl)amino)-N-(3,4-dimethoxybenzyl)acetamide (23).

[0215] Commercially available compound 22, 2-amino-6-chlorobenzothiazole (500.00 mg, 2.71 mmol), and compound 21, 3,4-dimethoxyphenylacetic acid (637.50 mg, 3.25 mmol), were dissolved in 5 mL of DCM. PyBop (1692.30 mg, 3.25 mmol) and DIPEA (1.42 mL, 8.13 mmol) were added, and the mixture was reacted at room temperature for 12 h. After the reaction was complete, the reaction solution was extracted sequentially with DCM, washed with water, dried over anhydrous Na2SO4, and purified by column chromatography (PE:EA = 1:1). Compound 23 was collected as a white solid, 563.10 mg, yield: 57.26%. 1 H NMR(400MHz,Chloroform-d)δ9.76(s,1H),7.79(d,J=1.9Hz,1H),7.62(d,J=8.6Hz,1H),7.38(dd,J =8.6,2.1Hz,1H),6.85(d,J=8.1Hz,1H),6.82–6.76(m,2H),3.89(s,3H),3.85(s,3H),3.80(s,2H). 13 C NMR (101MHz, CDCl3) δ169.80,158.46,149.59,148.95,146.69,133.37,129.63, 127.04,124.79,121.75,121.56,121.13,112.37,111.79,55.97,55.92,43.10.

[0216] Example 60: Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-(3,4-dihydroxyphenyl)acetamide (24).

[0217] Using compound 23 and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 24 was collected as a white solid of 212.20 mg, with a yield of 91.86%. 1H NMR (400MHz, DMSO-d6) δ12.68–12.52(m,1H),8.89(q,J=2.9Hz,1H),8.79(q,J=2.9Hz,1H),8.17–8.07(m,1H),7. 83–7.68(m,1H),7.45(dt,J=5.0,2.6Hz,1H),6.74(s,1H),6.70–6.65(m,1H),6.58(d,J=6.8Hz,1H),3.61(s,2H). 13 C NMR (101MHz, DMSO) δ171.35,159.28,147.84,145.58,144.79,133.57,128.01,126.90,125.65,122.15,121.87,120.52,117.01,115.97,41.75.

[0218] Example 61: Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-(3,4-dihydroxyphenyl)acetamide (27).

[0219] Compound 25, namely 3,4-dimethoxybenzyl bromide (100.00 mg, 0.43 mmol), was dissolved in 3 ml of THF. Then, 1 ml of aqueous solution of compound 26, namely NaN3 (84.40 mg, 1.30 mmol), was added. The mixture was stirred at 80 °C for 12 h. The reaction solution was extracted with DCM, washed with water and dried. The organic phase was then evaporated to dryness to obtain crude intermediate 27, which was a yellow oily liquid. This crude product was directly used in the next reaction.

[0220] Example 62: Preparation of 6-chloro-2-(prop-2-yn-1-ylthio)benzo[d]thiazole (29).

[0221] Compound 3F, namely 6-chloro-2-mercaptobenzothiazole (150.00 mg, 0.74 mmol), and triethylamine (98.20 mg, 0.97 mmol) were dissolved in 5 ml of DCM. 3-bromopropyne (115.00 mg, 0.97 mmol) was added under ice bath conditions, and the reaction was stirred for 1 h. The reaction solution was extracted with DCM, washed with water, dried, and the organic phase was evaporated to dryness. Intermediate 29 was collected as a yellow solid of 159.40 mg, yield: 89.85%. 1 H NMR (400MHz, Chloroform-d) δ7.81(d,J=8.7Hz,1H),7.76(d,J=1.9Hz,1H),7.41(dd,J=8.7,1.9Hz,1H),4.14(d,J=2.6Hz,2H),2.33(t,J=2.6Hz,1H). 13C NMR (101MHz, CDCl3) δ165.26,151.57,136.62,130.43,126.91,122.43,120.71,78.09,72.48,21.66.

[0222] Example 63: Preparation of 6-chloro-2-(((1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)benzo[d]thiazole (30).

[0223] Intermediate 27 (150.00 mg, 0.78 mmol), intermediate 29 (93.50 mg, 0.39 mmol), sodium ascorbate (195.20 mg, 0.98 mmol), and copper sulfate pentahydrate (243.40 mg, 0.98 mmol) were added to a reaction flask. 4 mL of a 1:1 mixture of DMF and H₂O was added, and the mixture was reacted at 50 °C for 12 h. The reaction solution was extracted with EA, washed with saturated NaCl water, dried over anhydrous Na₂SO₄, and purified by column chromatography (PE:EA = 1:1). Compound 30 was collected as a white solid, 110.80 mg, yield: 65.62%. 1 H NMR(400MHz,Chloroform-d)δ7.75–7.69(m,2H),7.50(s,1H),7.38(dd,J=8.7,2.0Hz ,1H),6.81(s,2H),6.74(s,1H),5.42(s,2H),4.66(s,2H),3.88(s,3H),3.79(s,3H). 13 C NMR (101MHz, DMSO) δ167.50,151.82,149.15,149.14,142.89,136.73,129.44,128.54, 127.21,124.30,122.72,121.96,120.96,112.34,112.20,55.94,55.85,53.19,28.01.

[0224] Example 64: Preparation of 4-((4-((((6-chlorobenzo[d]thiazol-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzene-1,2-diol (31).

[0225] Using compound 30 and BBr3 as raw materials, the same synthesis method as compound 8 was used. Compound 31 was collected as a white solid, 55.60 mg, with a yield of 59.71%. 1H NMR(400MHz,DMSO-d6)δ9.02(s,2H),8.20–8.14(m,1H),8.08(s,1H),7.86(d,J=8.7Hz,1H ),7.54–7.47(m,1H),6.73–6.65(m,2H),6.59(d,J=8.0Hz,1H),5.36(s,2H),4.68(s,2H). 13 C NMR(101MHz,DMSO)δ167.61,151.84,145.86,145.81,142.73,136.74,129.42,1 27.23,127.06,124.18,122.74,121.99,119.68,116.00,115.97,53.21,28.02.

[0226] Example 65: Preparation of 2-chloro-N-propylacetamide (33a).

[0227] Compound 32a, i.e., n-propylamine (400.00 mg, 6.77 mmol), was dissolved in DCM. The reaction was carried out under argon protection. Compound 11, i.e., chloroacetyl chloride (1.09 ml, 13.53 mmol), was slowly added dropwise under ice bath. After reacting for 1 h, the reaction solution was extracted with DCM, washed with water, dried over anhydrous Na2SO4, and the organic phase was evaporated to dryness to obtain crude intermediate 33a, which was an orange-yellow liquid. This was directly added to the next reaction step.

[0228] Example 66: Preparation of 2-chloro-N-butylacetamide (33b).

[0229] Using commercially available compounds n-butylamine (32b) and chloroacetyl chloride (11) as raw materials, ketone compound 33a was synthesized. The crude intermediate 33b was collected as an orange-yellow liquid and directly added to the next reaction step.

[0230] Example 67: Preparation of 2-chloro-N-pentylacetamide (33c).

[0231] Using commercially available compounds n-pentylamine (32c) and chloroacetyl chloride (11) as raw materials, ketone compound 33a was synthesized. The crude intermediate 33c was collected as an orange-yellow liquid and directly added to the next reaction step.

[0232] Example 68: Preparation of 2-chloro-N-hexylacetamide (33d).

[0233] Using commercially available compounds n-hexylamine (32d) and chloroacetyl chloride (11) as raw materials, ketone compound 33a was synthesized. The crude intermediate 33d was collected as an orange-yellow liquid and directly added to the next reaction step.

[0234] Example 69: Preparation of 2-chloro-N-heptylacetamide (33e).

[0235] Using commercially available compounds n-heptylamine (32e) and chloroacetyl chloride (11) as raw materials, ketone compound 33a was synthesized. The crude intermediate 33e was collected as an orange-yellow liquid and directly added to the next reaction step.

[0236] Example 70: Preparation of 2-(6-chlorobenzo[d]thiazo-2-yl)thio)-N-propylacetamide (34a).

[0237] Using compounds 33a and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 34a was collected as a white solid of 131.20 mg, with a yield of 87.23%. 1 H NMR(400MHz,Chloroform-d)δ7.76(dd,J=5.2,3.3Hz,2H),7.42(dd,J=8.7,1.8Hz,1H),7.2 6(s,1H),3.97(s,2H),3.24(q,J=6.7Hz,2H),1.50(h,J=7.2Hz,2H),0.86(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.73,167.01,151.01,136.60,130.72,127.13,121.96,120.92,41.58,36.18,22.53,11.28.

[0238] Example 71: Preparation of N-butyl-2-((6-chlorobenzo[d]thiazo-2-yl)thio)acetamide (34b).

[0239] Using compounds 33b and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 34b was collected as a white solid of 139.10 mg, with a yield of 88.36%. 1 H NMR(400MHz,Chloroform-d)δ7.76(d,J=8.1Hz,2H),7.42(d,J=8.7Hz,1H),7.22(s,1H),3.97(s,2H) ,3.27(q,J=6.7,6.3Hz,2H),1.45(p,J=7.7,7.1Hz,2H),1.27(h,J=7.2Hz,2H),0.84(t,J=7.3Hz,3H). 13C NMR (101MHz, CDCl3) δ167.68,166.98,151.01,136.61,130.72,127.12,121.95,120.92,39.56,36.17,31.25,19.93,13.62.

[0240] Example 72: Preparation of 2-(6-chlorobenzo[d]thiazo-2-yl)thio)-N-hexylacetamide (34c).

[0241] Using compounds 33d and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 34c was collected as a white solid, 81.00 mg, with a yield of 47.24%. 1 H NMR(400MHz,Chloroform-d)δ7.77(dd,J=5.3,3.2Hz,2H),7.42(dd,J=8.7,2.0Hz,1H),7.21(s,1H), 3.97(s,2H),3.26(q,J=6.8Hz,2H),1.45(p,J=6.9Hz,2H),1.19(d,J=9.7Hz,6H),0.87–0.74(m,3H). 13 C NMR (101MHz, CDCl3) δ167.65,166.98,151.01,136.60,130.74,127.10,121.96,120.91,39.86,36.11,31.38,29.18,26.47,22.48,13.93.

[0242] Example 73: Preparation of 2-(6-chlorobenzo[d]thiazo-2-yl)thio)-N-heptylacetamide (34d).

[0243] Using compounds 33e and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 34d was collected as a white solid, 76.30 mg, with a yield of 42.75%. 1 H NMR(400MHz,Chloroform-d)δ7.76(dd,J=5.3,3.3Hz,2H),7.42(dd,J=8.7,2.0Hz,1H),7.22(s,1H),3.97(s,2H) ,3.26(q,J=6.8Hz,2H),1.51–1.39(m,2H),1.19(td,J=6.9,2.8Hz,6H),1.14–1.07(m,2H),0.84(t,J=7.1Hz,3H). 13CNMR (101MHz, CDCl3) δ167.66,166.99,151.00,136.60,130.74,127.10,121.96,120.90,39.85,36.10,31.68,29.21,28.89,26.76,22.53,14.03.

[0244] Example 74: Preparation of 2-((5-nitrobenzo[d]thiazo-2-yl)thio)-N-propylacetamide (34e).

[0245] Using compounds 33a and 3n as raw materials, the same synthesis method as compound 9a was used. Compound 34e was collected as a white solid of 120.20 mg, with a yield of 81.96%. 1 H NMR(400MHz,Chloroform-d)δ8.67(d,J=1.9Hz,1H),8.22(dd,J=8.8,2.0Hz,1H),7.90(d,J=8.8Hz, 1H), 6.96 (s, 1H), 4.02 (s, 2H), 3.25 (q, J = 6.7Hz, 2H), 1.50 (h, J = 7.3Hz, 2H), 0.86 (t, J = 7.4Hz, 3H). 13 C NMR (101MHz, CDCl3) δ170.80,167.19,152.34,146.96,142.08,121.61,119.31,116.45,41.68,36.31,22.61,11.26.

[0246] Example 75: Preparation of N-butyl-2-((5-nitrobenzo[d]thiazo-2-yl)thio)acetamide (34f).

[0247] Using compounds 33b and 3n as raw materials, the same synthesis method as compound 9a was used. Compound 34f was collected as a yellow solid, 128.80 mg, with a yield of 84.04%. 1 H NMR(400MHz,Chloroform-d)δ8.66(d,J=2.1Hz,1H),8.21(dd,J=8.8,2.2Hz,1H),7.90(d,J=8.8Hz,1H),6.96(s,1 H), 4.01 (s, 2H), 3.27 (q, J = 6.9Hz, 2H), 1.45 (p, J = 7.2Hz, 2H), 1.27 (dq, J = 14.5, 7.3Hz, 2H), 0.83 (t, J = 7.3Hz, 3H). 13C NMR (101MHz, CDCl3) δ170.80,167.13,152.34,146.94,142.08,121.60,119.31,116.45,39.69,36.31,31.33,19.97,13.62.

[0248] Example 76: Preparation of 2-(5-nitrobenzo[d]thiazo-2-yl)thio)-N-pentylacetamide (34 g).

[0249] Using compounds 33c and 3n as raw materials, the same synthesis method as compound 9a was used. Compound 34g was collected as a white solid (82.20 mg), yield: 51.42%. 1 H NMR(400MHz,Chloroform-d)δ8.67(d,J=2.1Hz,1H),8.22(dd,J=8.8,2.2Hz,1H),7.90(d,J=8.8Hz,1H),6.96(s,1 H), 4.01 (s, 2H), 3.27 (q, J = 6.8Hz, 2H), 1.47 (p, J = 7.1Hz, 2H), 1.20 (dd, J = 8.3, 4.5Hz, 4H), 0.77 (t, J = 6.9Hz, 3H). 13 CNMR(101MHz, CDCl3)δ170.83,167.14,152.33,146.95,142.07,121.60,119.32,116.45,39.95,36.26,28.98(2C),22.26,13.86.

[0250] Example 77: Preparation of N-hexyl-2-((5-nitrobenzo[d]thiazo-2-yl)thio)acetamide (34h).

[0251] Using compounds 33d and 3n as raw materials, the same synthesis method as compound 9a was used. Compound 34h was collected as a white solid of 110.60 mg, with a yield of 66.43%. 1 H NMR(400MHz,Chloroform-d)δ8.66(d,J=2.1Hz,1H),8.22(dd,J=8.8,2.1Hz,1H),7.90(d,J=8.8Hz,1H),6.96 (s,1H),4.01(s,2H),3.27(q,J=6.8Hz,2H),1.46(p,J=7.0Hz,2H),1.27–1.11(m,6H),0.77(t,J=6.9Hz,3H). 13C NMR (101MHz, CDCl3) δ170.83,167.14,152.33,146.95,142.07,121.60,119.31,116.45,39.98,36.26,31.37,29.24,26.50,22.49,13.90.

[0252] Example 78: Preparation of 2-(6-chlorobenzo[d]thiazolyl)thio)-N-(3,4-dimethoxybenzyl)acetamide (35).

[0253] Using compounds 7 and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 35 was collected as a white solid of 212.50 mg, with a yield of 83.82%. 1 H NMR(400MHz,Chloroform-d)δ7.75–7.70(m,1H),7.54(d,J=8.6Hz,2H),7.40–7.31(m,1H),6.69(d, J=5.8Hz,2H),6.65(d,J=8.6Hz,1H),4.38(d,J=5.5Hz,2H),4.00(s,2H),3.82(s,3H),3.71(s,3H). 13 C NMR (101MHz, CDCl3) δ167.56,166.70,150.82,149.01,148.38,136.49,130.72,130 .20,127.00,121.95,120.82,119.82,111.00,110.86,55.87,55.71,43.85,36.11.

[0254] Example 79: Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (37).

[0255] Using commercially available compound 36, 2-aminobenzothiazole (250.00 mg, 1.66 mmol), triethylamine (0.23 ml, 1.83 mmol), and compound 11, chloroacetyl chloride (0.27 ml, 3.33 mmol), as starting materials, the synthesis method was the same as that for compound 7. Compound 37 was collected as a white solid of 323.50 mg, with a yield of 85.97%. 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),8.00(d,J=7.8Hz,1H),7.77(d,J=8.0Hz,1H),7.45(t,J=7.5Hz,1H),7.33(t,J=7.5Hz,1H),4.47(s,2H). 13C NMR (101MHz, DMSO) δ166.42, 131.93, 126.71 (2C), 124.26 (2C), 122.28 (2C), 121.16, 43.02.

[0256] Example 80: Preparation of N-(benzo[d]thiazol-2-yl)-2-((6-chlorobenzo[d]thiazol-2-yl)thio)acetamide (38).

[0257] Using compounds 37 and 3f as raw materials, the same synthesis method as compound 9a was used. Compound 38 was collected as a pale yellow solid, 127.30 mg, with a yield of 64.96%. 1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.24–8.12(m,1H),7.97(d,J=7.9Hz,1H) ,7.86–7.71(m,2H),7.45(t,J=7.7Hz,2H),7.31(t,J=7.5Hz,1H),4.56(s,2H). 13 C NMR (101MHz, DMSO) δ167.40,167.13,158.15,151.68,148.98,136.88,131.9 3,129.48,127.29,126.67,124.18,122.62,122.23,122.10,121.15,37.07.

[0258] Example 81: Preparation of methyl 6-(2-chloroacetamido)hexanoate (40).

[0259] Using compound 39, namely methyl 6-aminohexanoate hydrochloride (250.00 mg, 1.38 mmol), triethylamine (0.52 ml, 4.13 mmol), and compound 11, namely chloroacetyl chloride (0.33 ml, 4.13 mmol), as raw materials, the synthesis method was the same as that of compound 33a. The crude intermediate 40 was collected as a yellow oily liquid and was directly used in the next reaction.

[0260] Example 82: Preparation of methyl hexanoate (41) of 6-(2-((6-chlorobenzo[d]thiazol-2-yl)thio)acetamido)hexanoate.

[0261] Intermediate 40 (185.30 mg, 0.89 mmol) and compound 3f, 6-chloro-2-mercaptobenzothiazole (150.00 mg, 0.74 mmol), were dissolved in 3 mL of DMF. K₂CO₃ (153.40 mg, 1.11 mmol) was added, and the mixture was reacted at 50 °C for 4 h. After the reaction was complete, the reaction solution was extracted with DCM, washed with water, dried over anhydrous Na₂SO₄, and recrystallized with DCM and PE. Compound 41 was collected as a pale yellow solid, 126.40 mg, yield: 44.15%. 1 H NMR(400MHz,Chloroform-d)δ7.77(dd,J=5.2,3.2Hz,2H),7.42(dd,J=8.7,1.9Hz,1H),7.23(s,1H),3.97(s,2H),3.65 (s,3H),3.27(q,J=6.6Hz,2H),2.17(t,J=7.4Hz,2H),1.60–1.51(m,2H),1.51–1.43(m,2H),1.24(p,J=7.7,7.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ173.88,167.70,166.95,150.99,136.58,130.78,127.16,121.96,120.94,51.52,39.58,36.12,33.74,28.94,26.26,24.41.

[0262] Example 83: Preparation of 6-(2-((6-chlorobenzo[d]thiazo-2-yl)thio)acetamide)-N-hydroxyhexamamide (42).

[0263] Hydroxylamine hydrochloride (166.70 mg, 2.58 mmol) and KOH (289.50 mg, 5.16 mmol) were reacted in 5 mL of methanol with stirring for 30 min. After filtration, the filtrate was collected, and compound 41 (100.00 mg, 0.26 mmol) was added. The reaction was continued with stirring for another 30 min. After the reaction was complete, the pH was adjusted to 7 with dilute hydrochloric acid, and ice water was added. A white solid precipitated out. After filtration, compound 42 was obtained as a white solid, 30.00 mg, with a yield of 29.75%. 1H NMR(400MHz, DMSO-d6)δ8.30(t,J=5.5Hz,1H),8.17(d,J=2.1Hz,1H),7.84–7.74(m,1H),7.49(dd,J=8.7,2.2Hz,1H), 4.12(s,2H),3.08(q,J=6.5Hz,2H),2.14(t,J=7.4Hz,2H),1.42(dq,J=22.5,7.4Hz,4H),1.24(tt,J=9.7,6.0Hz,2H). 13 C NMR (101MHz, DMSO) δ175.06,168.11,166.38,151.85,136.76,129.35,127.22,122.52,121.98,44.33,37.20,34.30,29.11,26.38,24.74.

[0264] Example 84: Preparation of 2-((2-chlorophenyl)thio)-N-(3,4-dimethoxybenzyl)acetamide (44a).

[0265] Using compound 7 and commercially available compound 43a o-chlorothiophenol as raw materials, the same synthesis method as compound 9a was used. Compound 44a was collected as a white solid of 242.50 mg, with a yield of 91.33%. 1 H NMR(400MHz,Chloroform-d)δ7.36(d,J=7.7Hz,1H),7.21(d,J=4.0Hz,2H),7.16(dd,J=7.8,4.4Hz,1H),7.05(s,1H),6.75(d,J =8.1Hz,1H),6.69(dd,J=8.1,1.8Hz,1H),6.66(d,J=1.7Hz,1H),4.37(d,J=5.8Hz,2H),3.86(s,3H),3.75(s,3H),3.72(s,2H). 13 C NMR (101MHz, CDCl3) δ167.20,149.13,148.51,133.93,132.98,130.18,129.83 ,127.80,127.65,127.33,119.97,111.17,110.88,55.94,55.77,43.68,36.39.

[0266] Example 85: Preparation of 2-((3-chlorophenyl)thio)-N-(3,4-dimethoxybenzyl)acetamide (44b).

[0267] Using compounds 7 and 43b (m-chlorobenzylthiophenol) as raw materials, the same synthesis method as compound 9a was used. Compound 44b was collected as a white solid of 231.50 mg, with a yield of 87.19%. 1 H NMR(400MHz,Chloroform-d)δ7.25(s,1H),7.19(d,J=6.8Hz,2H),7.12(dt,J=6.8,1.9Hz,1H),6.98(s,1H ),6.77(d,J=8.7Hz,1H),6.71–6.67(m,2H),4.38(d,J=5.8Hz,2H),3.86(s,3H),3.78(s,3H),3.68(s,2H). 13 C NMR (101MHz, CDCl3) δ167.14,149.15,148.55,136.70,135.07,130.30,130.15 ,127.69,126.78,125.83,119.97,111.23,110.96,55.93,55.81,43.74,36.99.

[0268] Example 86: Preparation of 2-((4-chlorophenyl)thio)-N-(3,4-dimethoxybenzyl)acetamide (44c).

[0269] Using compounds 7 and 43c as raw materials, p-chlorobenzylthiophenol was synthesized using the same method as compound 9a. Compound 44c was collected as a white solid of 207.50 mg, with a yield of 64.08%. 1 H NMR(400MHz,Chloroform-d)δ7.24(d,J=8.5Hz,2H),7.18(d,J=8.6Hz,2H),6.96(s,1H),6.76(d ,J=8.1Hz,1H),6.69–6.63(m,2H),4.36(d,J=5.8Hz,2H),3.87(s,3H),3.78(s,3H),3.65(s,2H). 13 C NMR (101MHz, CDCl3) δ167.29,149.13,148.57,133.79,133.06,132.79,130.1 7,129.54,129.40(2C),119.94,111.17,111.01,55.94,55.80,43.69,37.43.

[0270] Example 87: Preparation of 2-((2-chlorophenyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (45a).

[0271] Using compound 44a and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 45a was collected as a pale yellow oily liquid, 138.00 mg, with a yield of 42.62%. 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.77(s,1H),8.55(t,J=5.6Hz,1H),7.43(ddd,J=19.7,7.9,1.1Hz,2H),7.34–7.27 (m,1H),7.19(td,J=7.7,1.3Hz,1H),6.67–6.61(m,2H),6.48(dd,J=8.0,1.8Hz,1H),4.11(d,J=5.8Hz,2H),3.76(s,2H). 13 C NMR (101MHz, DMSO) δ167.45,145.57,144.73,136.24,130.97,130.18,129.78,128.16,127.66,126.91,118.82,115.73,115.59,42.77,35.55.

[0272] Example 88: Preparation of 2-((3-chlorophenyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (45b).

[0273] Using compounds 44b and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 45b was collected as a pale yellow oily liquid, 74.60 mg, with a yield of 23.60%. 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.77(s,1H),8.50(t,J=5.6Hz,1H),7.46–7.43(m,1H),7.30(q,J=4.9,4.2Hz,2 H),7.24(dt,J=6.6,2.3Hz,1H),6.67–6.62(m,2H),6.46(dd,J=8.0,1.9Hz,1H),4.10(d,J=5.7Hz,2H),3.74(s,2H). 13 CNMR(101MHz,DMSO)δ167.77,145.56,144.71,139.43,134.06,130.89,130.15,127.16,126.57,126.01,118.72,115.76,115.57,42.73,36.36.

[0274] Example 89: Preparation of 2-((4-chlorophenyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (45c). Using compound 44c and BBr3 as starting materials, the synthesis method was the same as for compound 8. Product 45c was collected as a white solid, 161.70 mg, yield: 49.94%. 1 H NMR (400MHz, DMSO-d6) δ8.46(t,J=5.6Hz,1H),7.40–7.32(m,4H),6.64(d,J=7.8Hz,2H),6.47–6.41(m,1H),4.09(d,J=5.8Hz,2H),3.68(s,2H). 13 C NMR (101MHz, DMSO) δ167.84,145.55,144.70,135.74,130.98,130.20,130.16(2C),129.27(2C),118.78,115.71,115.55,42.69,36.86.

[0275] Example 90: Preparation of N-(3,4-dimethoxybenzyl)-2-(thiazolyl-5-ylthio)acetamide (47).

[0276] Using compounds 7 and 46 (i.e., 2-mercaptothiazole) as raw materials, the synthesis method was the same as that for compound 9a. Compound 47 was collected as a white solid of 187.20 mg, with a yield of 70.37%. 1 H NMR(400MHz,Chloroform-d)δ7.77(s,1H),7.57(d,J=3.4Hz,1H),7.24(d,J=3.4Hz,1H),6. 79–6.76(m,2H),6.74(s,1H),4.40(d,J=5.7Hz,2H),3.88(s,2H),3.86(s,3H),3.80(s,3H). 13 C NMR (101MHz, CDCl3) δ168.24,163.97,149.05,148.30,142.23,130.54,119.85,119.71,111.10,110.73,55.94,55.79,43.57,37.00.

[0277] Example 91: Preparation of 2-((4-chlorophenyl)thio)-N-(3,4-dihydroxybenzyl)acetamide (48).

[0278] Using compound 47 and BBr3 as raw materials, the same synthesis method as compound 8 was used. Product 48 was collected as a brown oily liquid, 126.80 mg, with a yield of 92.61%. 1H NMR (400MHz, DMSO-d6) δ8.81(d,J=23.6Hz,2H),8.57(t,J=5.4Hz,1H),7.71(d,J=3.3Hz,1H),7.6 4(d,J=3.3Hz,1H),6.65(d,J=8.1Hz,2H),6.53–6.46(m,1H),4.12(d,J=5.7Hz,2H),4.00(s,2H). 13 C NMR (101MHz, DMSO) δ166.76,163.81,145.55,144.71,143.10,130.12,120.90,118.80,115.73,115.54,42.81,37.76.

[0279] Example 92: Determination of the biofilm inhibition rate of the derivative against Pseudomonas aeruginosa PAO1 by crystal violet staining method.

[0280] Experimental method: Dilute overnight cultured Pseudomonas aeruginosa PAO1 to OD using LB medium. 600 =0.01; Prepare the compound to the working concentration using a bacterial culture medium, and add 150 μL to a 96-well plate. Simultaneously set up a positive control group (Azithromycin), a blank control group (culture medium + bacteria), and a negative control group (culture medium only). Each group has 4–6 replicates. Incubate the 96-well plate at 37°C for 16 h. Carefully aspirate the bacterial culture and wash three times with 150 μL of PBS solution. Stain with 150 μL of 0.1% crystal violet solution for 30 min. Carefully aspirate the crystal violet and wash three times with 150 μL of PBS solution. After drying, dissolve the crystal violet in 150 μL of 30% glacial acetic acid solution and shake well on a micro-shaker for 5 min before measuring the OD. 550 ; Calculate biofilm inhibition rate

[0281] =[(Control OD值 -Blank OD值 )-(Drug group) OD值 -Blank OD值 )] / (Control OD值 -Blank OD值 ()×100%. IC50 of coumarin derivatives determined by crystal violet staining. 50 The results are shown in Table 2:

[0282] Table 2. Biofilm inhibition rate of catechol derivatives against Pseudomonas aeruginosa PAO1

[0283]

[0284] a. For all compounds, their IC50 50 All results were obtained when the biofilm inhibition rate of the positive control drug azithromycin was >50%.

[0285] Experimental results: The compounds shown in Table 1 all exhibited good biomembrane inhibitory activity, and the IC50 values ​​of all compounds were [missing data]. 50 All were below 10 μM. Among them, 15 compounds (9f, 10b, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10o, 14g, 20c, 34g, 45b) had IC50 values. 50 At the nM level, compound 10f exhibited optimal biofilm inhibitory activity, IC50... 50 =0.257±0.164μM, and its anti-biofilm activity was superior to that of the positive control drug azithromycin.

[0286] Example 89: Detection of combined use of compound 10f and ciprofloxacin.

[0287] Experimental method: Prepare a stock solution (10 mM) of compound 10f using cell-grade DMSO, and dilute the overnight cultured bacteria to OD200. 600 After adding 100 μL of the stock solution to a 96-well plate, the compound and antibiotic were added. The stock solution of the test compound was diluted to 0.0625, 0.125, 0.25, 0.5, and 1.0 μM using ABTGC medium. The antibiotic ciprofloxacin was diluted to MIC (0.25 μg / ml), 1 / 2 MIC, 1 / 4 MIC, 1 / 8 MIC, and 1 / 16 MIC for later use. Blank group (culture medium only) and Control group (bacteria only) were also set up. After incubation at 37°C for 24 hours, the 96-well plate was removed from the incubator, and the OD of the bacteria in each well was measured using a microplate reader. 600 The bactericidal ability of the compound was tested.

[0288] Experimental results: such as Figure 1 As shown, the combined use of compound 10f and the antibiotic ciprofloxacin significantly enhanced the sensitivity of ciprofloxacin to Pseudomonas aeruginosa PAO1 (deeper blue indicates greater bacterial growth), resulting in good bactericidal effects even at sub-MIC concentrations. When compound 10f was administered in combination with 1 / 2 MIC ciprofloxacin, the bacterial survival rate was comparable to that of ciprofloxacin administered alone at the MIC concentration, almost 0%. When 10f was administered in combination with 1 / 8 MIC ciprofloxacin, the bacterial survival rate was approximately 50%. This synergistic effect may be due to the ability of compound 10f to inhibit biofilm formation.

[0289] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: Equation (I) Formula (II).

2. The compound of formula (1) or formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein It has the following chemical structure: 。 3. A pharmaceutical composition, characterized in that, It includes the compound of formula (I) or formula (II) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

4. A combination drug comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and an antibiotic.

5. The combination drug according to claim 4, wherein the mass ratio of the compound of formula (I) or formula (II) or its pharmaceutically acceptable salt to the antibiotic is 50:0.5~10.

6. Use of the compound of formula (I) or formula (II) of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a Pseudomonas aeruginosa biofilm inhibitor.

7. The use of the compound of formula (I) or formula (II) of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of an antimicrobial agent for Pseudomonas aeruginosa.

8. A method for preparing the compound of formula (I) or formula (II) as described in claim 1, comprising any one of the following routes. Route 1 includes the following steps: (1.1) Dissolve o-phenylenediamines 1a-1d with different substituents in ethanol, slowly add CS2 dropwise, and purify the reaction solution after the reaction to obtain compounds 2a-2d; (1.2) Dissolve 3,4-dimethoxybenzylamine (6) and triethylamine in DCM, and slowly add chloroacetyl chloride (11) dropwise under ice bath; after the reaction is complete, adjust the pH to neutral with dilute hydrochloric acid, filter the solid produced, and obtain compound 7; (1.3) Compound 7 was dissolved in DCM, and BBr3 was slowly added dropwise under ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 8. (1.4) Compound 8 and K2CO3 were dissolved in acetonitrile with intermediates 2a-2d, commercially available compounds 2e-2j, and 3a-3o, respectively. After the reaction was completed, the reaction solution was purified to obtain compounds 9a-9j and 10a-10o. The synthesis route at this point is: Route 2 includes the following steps: (2.1) Dissolve o-aminophenols 4a-4e with different substituents in ethanol, slowly add CS2 dropwise, and purify the reaction solution after the reaction to obtain compounds 5a-5e; (2.2) Dissolve 3,4-dimethoxybenzylamine (6) and triethylamine in DCM, and slowly add bromoacetyl bromide dropwise under ice bath; after the reaction is complete, adjust the pH to neutral with dilute hydrochloric acid, filter the solid produced, and obtain compound 12; (2.3) Compound 12 was dissolved in DCM, and BBr3 was slowly added dropwise under ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 13. (2.4) Compound 13 and K2CO3 were dissolved in acetonitrile with intermediates 5a-5e and commercially available compound 5f-5j, respectively. After the reaction was completed, the reaction solution was purified to obtain compound 14a-14j. The synthesis route at this point is: Route 3 includes the following steps: (3.1) 3,4-Dimethoxybenzylamine (6), N-Boc-glycine (15), PyBop and DIPEA were dissolved in DCM. After the reaction was completed, the reaction solution was purified to obtain compound 16. (3.2) Dissolve compound 16 in DCM, slowly add trifluoroacetic acid, adjust the pH to weakly alkaline with NaOH aqueous solution after the reaction is complete, extract the reaction solution with DCM and then evaporate to dryness to obtain compound 17; (3.3) Compounds 18a-18d and 17 were dissolved in ethanol with DIPEA. After the reaction was completed, the solids were filtered to obtain compounds 19a-19d. (3.4) Dissolve compounds 19a-19d in DCM, slowly add BBr3 dropwise under ice bath, quench the reaction with ice water after the reaction is complete, and filter the solid to obtain compounds 20a-20d; The synthesis route at this point is: Route 4 includes the following steps: (4.1) 3,4-Dimethoxyphenylacetic acid (21), commercially available compound 2-amino-6-chlorobenzothiazole (22), PyBop and DIPEA were dissolved in DCM. After the reaction was completed, the reaction solution was purified to obtain compound 23. (4.2) Dissolve compound 23 in DCM, slowly add BBr3 dropwise under ice bath, quench the reaction with ice water after the reaction is complete, and filter the solid to obtain compound 24; The synthesis route at this point is: Route 5 includes the following steps: (5.1) 3,4-dimethoxybenzyl bromide (25) and NaN3 (26) were dissolved in a mixed solution of THF and water. After the reaction was completed, the reaction solution was extracted by DCM and then directly evaporated to dryness to obtain compound 27. (5.2) 6-chloro-2-mercaptobenzothiazole (3f) and triethylamine were dissolved in DCM, and 3-bromopropyne (28) was added under ice bath. After the reaction was completed, the reaction solution was extracted with DCM and then evaporated to dryness to obtain compound 29. (5.3) Compound 29, compound 27, sodium ascorbate and copper sulfate pentahydrate were dissolved in a mixed solution of DMF and H2O. After the reaction was completed, the reaction solution was purified to obtain compound 30. (5.4) Compound 30 was dissolved in DCM, and BBr3 was slowly added dropwise under ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 31. The synthesis route at this point is: Route Six includes the following steps: (6.1) Dissolve amino-substituted alkanes 32a-32e with different carbon chain lengths in DCM, and slowly add chloroacetyl chloride (11) in an ice bath. After the reaction is completed, the reaction solution is extracted with DCM and then evaporated to dryness to obtain compounds 33a-33e. (6.2) Compounds 33a-33e were dissolved in acetonitrile with 6-chloro-2-mercaptobenzothiazole (3f) and 5-nitro-2-mercaptobenzothiazole (3n), respectively. After the reaction was completed, the solids were filtered to obtain compounds 34a-34h. The synthesis route at this point is: Route 7 includes the following steps: (7.1) Compound 7, 6-chloro-2-mercaptobenzothiazole (3f), and K2CO3 were dissolved in acetonitrile. After the reaction was completed, the solid produced was filtered to obtain compound 35. The synthesis route at this point is: Route 8 includes the following steps: (8.1) Commercially available compound 2-aminobenzothiazole (36) and triethylamine were dissolved in DCM, and chloroacetyl chloride (11) was slowly added dropwise under ice bath. After the reaction was completed, the reaction solution was purified to obtain compound 37. (8.2) 6-chloro-2-mercaptobenzothiazole (3f), K2CO3 and compound 37 were dissolved in DMF. After the reaction was completed, the reaction solution was purified to obtain compound 38. The synthesis route at this point is: Route Nine includes the following steps: (9.1) Commercially available compound methyl 6-aminohexanoate hydrochloride (39) and triethylamine were dissolved in DCM, and chloroacetyl chloride (11) was slowly added dropwise under ice bath. After the reaction was completed, the reaction solution was extracted with DCM and then evaporated to dryness to obtain compound 40. (9.2) Compound 40, K2CO3 and 6-chloro-2-mercaptobenzothiazole (3f) were dissolved in DMF. After the reaction was completed, the reaction solution was purified to obtain compound 41. (9.3) Compound 41, hydroxylamine hydrochloride and KOH were dissolved in methanol, and the reaction solution after the reaction was completed was purified to obtain compound 42; The synthesis route at this point is: Route 10 includes the following steps: (10.1) Compound 7, K2CO3, and chlorosubstituted thiophenols 43a-43c were dissolved in acetonitrile. After the reaction was completed, the reaction solution was purified to obtain compounds 44a-44c. (10.2) Dissolve compounds 44a-44c in DCM, slowly add BBr3 dropwise under ice bath, quench the reaction with ice water after the reaction is completed, and purify the reaction solution to obtain compounds 45a-45c; The synthesis route at this point is: Route 11 includes the following steps: (11.1) Compound 7, K2CO3, and 2-mercaptothiazole (46) were dissolved in acetonitrile. After the reaction was completed, the reaction solution was purified to obtain compound 47. (11.2) Compound 47 was dissolved in DCM, and BBr3 was slowly added dropwise under ice bath. After the reaction was completed, ice water was added to quench the reaction. The reaction solution was purified to obtain compound 48. The synthesis route at this point is: 。

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