Covalent small molecule compound and application and pharmaceutical composition thereof

Abstract

The invention provides a covalent small molecule compound and application and a pharmaceutical composition thereof, and relates to the technical field of pharmaceutical chemistry. The covalent small molecule compound provided by the invention can be combined with specific amino acid in the schistosome to form a covalent bond so as to inhibit the biological function of the schistosome. The covalent small molecule compound provided by the invention has a good killing effect on schistosomiasis and adult schistosomiasis, can be used for preparing drugs for treating schistosomiasis, and overcomes the technical problem of poor curative effect or ineffective treatment caused by drug resistance generated by long-term use of existing anti-schistosomiasis drugs; important scientific basis and research value are provided for research and development of novel anti-schistosomiasis drugs. The result of the embodiment shows that the insect reduction rate of the covalent small molecule compound provided by the invention can reach 82.35% (superior to praziquantel) in the juvenile insect stage, the insect reduction rate of the covalent small molecule compound in the adult stage can reach 63.63%, and the covalent small molecule compound shows relatively high activity of killing schistosome in vivo.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more particularly to a covalent small molecule compound, its applications, and pharmaceutical compositions thereof. Background Technology

[0002] Schistosomiasis is a parasitic disease caused by infecting humans with trematodes of the genus Schistosoma, commonly occurring in tropical and subtropical regions. There are five main types of schistosomiasis: Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, Schistosoma intercalatum, and Schistosoma mekongiensis. Schistosomiasis japonicum is a type of intestinal schistosomiasis.

[0003] Due to the lack of vaccines, the current global treatment of schistosomiasis primarily relies on praziquantel, the only first-line drug available. Praziquantel boasts advantages such as high efficacy, short treatment duration, and few adverse reactions, and is effective against all schistosomes, but its efficacy against juvenile schistosomes is poor. Furthermore, since its introduction, praziquantel has been used extensively and for a long period, leading to an increased risk of drug resistance. To address this issue, there is an urgent need to research new anti-schistosomiasis drugs. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a covalent small molecule compound, its application, and a pharmaceutical composition thereof. The covalent small molecule compound provided by the present invention has a good killing effect on both juvenile and adult schistosomes, and can overcome the drug resistance that has developed from long-term use of existing anti-schistosomiasis drugs.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a covalent small molecule compound or a pharmaceutically acceptable salt thereof, said covalent small molecule compound having the structure shown in any one of Formulas I to IV:

[0007]

[0008] In the structures shown in Formulas I to IV, R1 is a group containing a carbonyl group, a carbon-carbon unsaturated bond, an ester group, an epoxy group, a cyano group, an alkyl group, a haloalkyl group, an aryl group, or a heteroaryl group; R2 and R3 are independently -H, halogen, alkyl, alkoxy, cyano, haloalkyl, thioalkyl, or alkylacyl; and R4 is sulfur, oxygen, -CH2-CH2-, or -CH=CH-.

[0009] This invention provides a covalent small molecule compound or a pharmaceutically acceptable salt thereof, wherein the covalent small molecule compound has the structure shown in any of Formulas I to IV. The electrophilic covalent warhead (R1 group) in the covalent small molecule compound provided by this invention can bind to cysteine ​​residues in the SjTGR enzyme within schistosomes (such as Schistosoma japonicum) to form a covalent bond, inhibiting its biological function. The covalent small molecule compound provided by this invention exhibits good killing activity against both juvenile and adult schistosomes, and can be used to prepare drugs for treating schistosomiasis. This overcomes the technical problem of poor efficacy or ineffective treatment caused by drug resistance resulting from long-term use of existing anti-schistosomiasis drugs, providing important scientific basis and research value for the development of novel anti-schistosomiasis drugs.

[0010] The results of the examples show that the covalent small molecule compound provided by the present invention can achieve a worm reduction rate of 82.35% (superior to praziquantel) when treating the juvenile stage of Schistosoma japonicum, and a worm reduction rate of 63.63% when treating the adult stage, demonstrating high in vivo activity against Schistosoma japonicum. Detailed Implementation

[0011] This invention provides a covalent small molecule compound or a pharmaceutically acceptable salt thereof, said covalent small molecule compound having the structure shown in any one of Formulas I to IV:

[0012]

[0013] In the structures shown in Formulas I to IV, R1 is a group containing a carbonyl group, a carbon-carbon unsaturated bond, an ester group, an epoxy group, a cyano group, an alkyl group, a haloalkyl group, an aryl group, or a heteroaryl group; R2 and R3 are independently -H, halogen, alkyl, alkoxy, cyano, haloalkyl, thioalkyl, or alkylacyl; and R4 is sulfur, oxygen, -CH2-CH2-, or -CH=CH-.

[0014] In this invention, R1 is a group containing a carbonyl group, a carbon-carbon unsaturated bond, an ester group, an epoxy group, a cyano group, an alkyl group, a haloalkyl group, an aryl group, or a heteroaryl group; the carbonyl group is preferably any of the following structures (where * indicates a linking site):

[0015]

[0016] In this invention, the group containing carbon-carbon unsaturated bonds is preferably... The ester-containing group is preferably... The epoxy-containing group is preferably... The cyano-containing group is preferably... The alkyl-containing group is preferably... The alkyl-containing group is preferably... The aryl-containing group is preferably... The heteroaryl group is preferably...

[0017] In this invention, R1 is a group that can form a covalent bond with an amino acid residue.

[0018] In this invention, R2 and R3 are independently -H, halogen, alkyl, alkoxy, cyano (-CN), haloalkyl, thioalkyl, or alkanoyl; among R2 and R3, the halogen is preferably -F or -Cl, the alkyl is preferably -CH3, the alkoxy is preferably -OCH3, the haloalkyl is preferably -CF3, the thioalkyl is preferably -SCH3 or -SC2H5, and the alkanoyl is preferably -COCH3 or -COC2H5. In this invention, R2 and R3 are electron-donating or electron-withdrawing substituents.

[0019] In this invention, R4 is sulfur, oxygen, -CH2-CH2- or -CH=CH-.

[0020] In this invention, the covalent small molecule compound preferably has any one of the structures of compound 1 to compound 50 (specific examples are shown in the embodiments).

[0021] Existing drugs, such as praziquantel, are effective against adult Schistosoma worms, but their efficacy against juvenile Schistosoma worms is poor. This difference may be related to the physiological and metabolic characteristics of adult and larval Schistosoma worms. Praziquantel's main mechanism of action is through voltage-gated calcium channels on the surface of the Schistosoma worm. Adult Schistosoma worms have mature surface structures, making them more easily adsorbed and penetrated by drugs, and their calcium channels are abundant, making them sensitive to drugs. However, the expression or structure of calcium channels in juvenile Schistosoma worms may not be fully developed, leading to reduced drug binding efficiency. The covalent small molecule compound provided by this invention can form covalent bonds with amino acid residues within the Schistosoma worm, inhibiting its biological function. It has a good killing effect on both juvenile and adult Schistosoma worms and can overcome the technical problem of poor efficacy or ineffective treatment caused by drug resistance resulting from long-term use of existing anti-schistosomiasis drugs.

[0022] In this invention, the covalent small molecule compound can be prepared by the following method:

[0023] Compounds A and B were mixed with an organic solvent to carry out a substitution reaction, yielding covalent small molecule compounds as shown in Formulas I to IV.

[0024] Unless otherwise specified, all raw materials involved in this invention are commercially available products or prepared using methods well known to those skilled in the art.

[0025] In this invention, when the covalent small molecule compound has the structure shown in Formula I, compound A has the structure shown in Formula V; when the covalent small molecule compound has the structure shown in Formula II, compound A has the structure shown in Formula VI; when the covalent small molecule compound has the structure shown in Formula III, compound A has the structure shown in Formula VII; when the covalent small molecule compound has the structure shown in Formula IV, compound A has the structure shown in Formula VIII. In this invention, compound B has the structure shown in Formula IX, where X is a halogen or a hydroxyl group, and the halogen is -Cl or -Br. In this invention, R1, R2, R3, and R4 in the structures shown in Formulas V to IX are consistent with R1, R2, R3, and R4 in the structures shown in Formulas I to IV.

[0026]

[0027] This invention does not have any particular requirements regarding the source of compound A; it can be obtained from commercially available products or prepared in-house. Taking compound A having the structure shown in formula V, where R4 in formula V is sulfur, as an example, compound A can be prepared by the following method:

[0028] A condensation reaction was carried out by mixing substituted aniline, substituted phenylboronic acid, copper acetate, potassium carbonate, benzoic acid and a first solvent to obtain a diphenylamine intermediate compound;

[0029] The diphenylamine intermediate compound was mixed with sulfur, iodine, and a second solvent to undergo a cyclization reaction, yielding compound A.

[0030] In this invention, the substituted aniline, the substituted phenylboronic acid, and the diphenylamine intermediate compound sequentially have the following structures:

[0031]

[0032] In this invention, the molar ratio of the substituted aniline to the substituted phenylboronic acid can be 1:3; the molar amount of copper acetate is preferably 20% of the total molar amount of the substituted aniline and substituted phenylboronic acid; the molar ratio of the substituted aniline to potassium carbonate is preferably 1:1; and the molar ratio of the substituted aniline to benzoic acid is preferably 1:0.5. In this invention, the copper acetate acts as a catalyst, the potassium carbonate as a base, and the benzoic acid as an additive or ligand. In this invention, the first solvent is preferably ethyl acetate. This invention does not have particular requirements on the amount of the first solvent, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured. In this invention, the temperature of the condensation reaction is preferably 80°C, and the time is preferably 4 hours.

[0033] In this invention, the molar ratio of sulfur, iodine, and substituted aniline is preferably 2:2:1; the iodine acts as an oxidant and electrophilic activator, promoting the efficient construction of sulfur-containing heterocyclic compounds by activating sulfur atoms or key intermediates. In this invention, the second solvent is preferably 1,2-dichlorobenzene. There are no particular requirements on the amount of the second solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured. In this invention, the cyclization reaction is preferably carried out at a temperature of 175°C and a time of 6–12 hours, preferably under nitrogen atmosphere.

[0034] In this invention, the reaction formulas involved in preparing compound A (having the structure shown in formula V, where R4 in formula V is sulfur) are as follows:

[0035]

[0036] In this invention, taking the covalent small molecule compound having the structure shown in Formula I as an example, the reaction formula involved in the substitution reaction is as follows:

[0037]

[0038] In this invention, the molar ratio of compound A to compound B is preferably 1:1 to 3, and can be 1:1.1, 1:1.2, 1:1.5, 1:2, or 1:3. The organic solvent can be N,N-dimethylformamide, dichloromethane, formic acid, toluene, acetic anhydride, or dimethyl sulfoxide. This invention does not have specific requirements for the amount of organic solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured. In this invention, when compound A reacts with compound B to generate an acid, an acid-binding agent can also be added to the mixture of compound A, compound B, and the organic solvent. The acid-binding agent is preferably potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, 1,3-dicyclohexylcarbodiimide, or triethylamine. The molar ratio of compound A to the acid-binding agent is preferably 1:1 to 5, and can be 1:1.1, 1:1.2, 1:1.5, 1:2, 1:3, 1:4, or 1:5.

[0039] In this invention, the temperature of the substitution reaction is preferably 0–120°C, which can be 0, 20, 30, 35, 50, 80, 100, or 120°C, and the time is preferably 1–48 h, which can be 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, or 48 h; the substitution reaction is preferably carried out under stirring. After the substitution reaction is completed, the present invention preferably separates the resulting reaction solution by TLC or cools the resulting reaction solution to room temperature and then places it in a refrigerator to cool until solid precipitation occurs, and then performs solid-liquid separation and solid washing sequentially to obtain covalent small molecule compounds represented by Formulas I to IV.

[0040] The method for preparing the covalent small molecule compound provided by the present invention is simple to operate and yields a high amount of the target compound.

[0041] This invention provides the use of the covalent small molecule compounds or their pharmaceutically acceptable salts described above in the preparation of medicaments for treating schistosomiasis. In this invention, the medicament is preferably used to kill juvenile and adult schistosomes; the schistosomes preferably include *Schistosoma japonicum*.

[0042] The present invention provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is a covalent small molecule compound or a pharmaceutically acceptable salt thereof as described in the above technical solutions.

[0043] In this invention, the mass percentage of the covalent small molecule compound or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.05-99%, and can be 0.1-70%; the dosage form of the pharmaceutical composition is preferably tablet, granule, powder, solution, emulsion, suspension, syrup, injection or capsule.

[0044] To further illustrate the present invention, the covalent small molecule compounds, their applications, and pharmaceutical compositions provided by the present invention are described in detail below with reference to examples, but these should not be construed as limiting the scope of protection of the present invention.

[0045] Example 1

[0046] Preparation of Compound 1

[0047]

[0048] Phenothiazine (0.1 mmol), 3-bromopropyne (0.12 mmol), and potassium tert-butoxide (0.15 mmol) were reacted in 2 mL of N,N-dimethylformamide solution at room temperature with stirring for 4 h. Compound 1 was isolated by TLC, yielding 21.3 mg in 90% yield. The structure of compound 1 was analyzed, and the structural confirmation data are as follows:

[0049] IR(KBr,cm -1 )3293,3064,2979,2935,1687,1594,1463,1362,1255,1216,1179,1132,1107,1050,916,854,748,647; 1 H NMR (400MHz, CDCl3, ppm) δ7.26(t,J=9.2Hz,4H),7.18(d,J=7.6Hz,2H),7.00(t,J=7.2Hz,2H),4.57(d,J=2.1Hz,2H),2.51(d,J=2.2Hz,1H).13 C NMR (100MHz, CDCl3) δ 144.2, 127.5, 127.1, 123.4, 123.0, 114.8, 79.2, 74.4, 38.6. MS (EI, 70eV) m / z 237, 198, 167, 154, 140. Identification data indicate that compound 1 was successfully prepared.

[0050] Example 2

[0051] Preparation of compound 2

[0052]

[0053] Phenothiazine (0.1 mmol) and triethylamine (0.2 mmol) were added to 2 mL of ultra-dry dichloromethane solution under a nitrogen atmosphere. Acryloyl chloride (0.15 mmol) was then slowly added dropwise under ice bath conditions with stirring for 0.5 h. Finally, the temperature was raised to room temperature and the reaction was carried out for 12 h. Compound 2 was isolated by TLC, yielding 7.6 mg in 30% solution. The structure of compound 2 was analyzed, and the structural confirmation data are as follows:

[0054] IR(KBr,cm -1 )3072,3030,2926,2859,1676,1614,1463,1407,1325,1258,1185,1129,1034,978,896,784,756,731,652; 1 H NMR (400MHz, CDCl3, ppm) δ7.56(d,J=7.9Hz,2H),7.43(dd,J=7.7,1.2Hz,2H),7.32(td,J=7.7,1.5Hz,2H),7.22( td,J=7.6,1.3Hz,2H),6.55(dd,J=16.7,2.0Hz,1H),6.42(dd,J=16.7,10.1Hz,1H),5.72(dd,J=10.1,2.0Hz,1H). 13 C NMR (100MHz, CDCl3) δ 164.0, 138.4, 132.7, 129.5, 128.5, 127.9, 127.2, 126.9, 126.8, 38.6. MS (EI, 70eV) m / z 253, 198, 166, 154, 140. Identification data indicate that compound 2 was successfully prepared.

[0055] Example 3

[0056] Preparation of compound 3

[0057]

[0058] Phenothiazine (0.1 mmol) and formic acid (1 mL) were mixed and refluxed at 100 °C for 6 h. Compound 3 was isolated by TLC, yielding 8.1 mg in 35.68%. The structure of compound 3 was analyzed, and the structural confirmation data are as follows:

[0059] IR(KBr,cm -1 )3064,2923,2845,1687,1471,1446,1328,1261,1151,750,661; 1 HNMR (400MHz, CDCl3, ppm) δ8.60 (s, 1H), 7.69 (d, J = 7.9Hz, 1H), 7.28 (dt, J = 14.3, 6.4Hz, 4H), 7.18 (dd, J = 19.2, 6.9Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 161.1, 137.4, 135.2, 130.9, 129.5, 127.8, 127.7, 127.5, 127.2, 127.1, 125.7, 121.9. MS (EI, 70eV) m / z 227, 198, 167, 154, 140. Identification data indicate that compound 3 was successfully prepared.

[0060] Example 4

[0061] Preparation of compound 4

[0062]

[0063] Phenothiazine (0.1 mmol), KOH (0.12 mmol), and NaI (0.012 mmol) were added to 2 mL of N,N-dimethylformamide solution under a nitrogen atmosphere. The reaction was carried out at room temperature for 5 min. Finally, an N,N-dimethylformamide solution containing ethyl bromoacetate (0.112 mmol) was added to the reaction mixture, and the reaction was carried out at 50 °C for 48 h. Compound 4 was obtained by TLC, yielding 14.6 mg in 51.2%. The structure of compound 4 was analyzed, and the structural confirmation data are as follows:

[0064] IR(KBr,cm -1 )3061,2979,1737,1572,1463,1364,1306,1199,1121,1022,927,865,745; 1H NMR (400MHz, CDCl3, ppm) δ7.11 (dt, J=7.2, 3.2Hz, 4H), 6.93 (d, J=7.1Hz, 2H), 6 .63(d,J=8.2Hz,2H),4.53(s,2H),4.33(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ169.9,144.2,127.3,127.0,123.4,123.0,114.6,61.6,51.1,14.2.MS(EI,70eV)m / z 285,212,198,180,154.HRMS(ESI)m / z[M+H]+calcd forC16H15NO2S286.0896,found286.0913.

[0065] The identification data indicate that compound 4 was successfully prepared.

[0066] Example 5

[0067] Preparation of compound 5

[0068]

[0069] Phenothiazine (0.1 mmol) was dissolved in 1 mL of dichloromethane solution, followed by the sequential addition of triethylamine (0.12 mmol) and 4-dimethylaminopyridine (0.01 mmol). Then, bromoacetyl bromide (0.3 mmol) dissolved in dichloromethane solution was slowly added dropwise to the reaction mixture at 0 °C for 8 h at room temperature. 23.2 mg of compound 5 was obtained by TLC separation, with a yield of 73%. The structure of compound 5 was analyzed, and the structural confirmation data are as follows:

[0070] IR(KBr,cm -1 )3064,2960,2923,2850,1687,1572,1465,1331,1264,1236,1165,1101,1028,983,865,818,767,647,599; 1 H NMR (400MHz, CDCl3 ppm) δ7.61(d,J=7.9Hz,2H),7.45(dd,J=7.7,1.3Hz,2H),7.34(td,J=7.7,1.5Hz,2H),7.25(td,J=7.6,1.2Hz,2H), 4.01(s,2H). 13¹³C NMR (100MHz, CDCl₃) δ 165.8, 138.1, 127.7, 127.4, 127.3, 126.6, 27.1. MS (EI, 70eV) m / z 320, 239, 212, 198, 166. Identification data indicate that compound 5 was successfully prepared.

[0071] Example 6

[0072] Preparation of compound 6

[0073]

[0074] Phenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the mixture was heated to 80 °C for 12 h. Compound 6 was isolated by TLC, yielding 25.38 mg in 92.3%. The structure of compound 6 was analyzed, and the structural confirmation data are as follows:

[0075] IR(KBr,cm -1 )3061,2954,1687,1465,1339,1252,1171,1126,1034,759,703,655,619,523; 1 H NMR (400MHz, CDCl3 ppm) δ7.59(d,J=7.9Hz,2H),7.45(dd,J=7.7,1.4Hz,2H),7.34(td,J=7.7,1.5Hz,2H),7.25(td,J=7.6,1.3Hz,2H),4.20(s,2H). 13 C NMR (100MHz, CDCl3) 165.5, 137.9, 133.2, 128.2, 127.5, 127.4, 126.6, 41.9. MS (EI, 70eV) m / z 273, 212, 199, 166, 154.

[0076] The identification data indicate that compound 6 was successfully prepared.

[0077] Example 7

[0078] Preparation of compound 7

[0079]

[0080] Phenothiazine (0.1 mmol) and cyanoacetic acid (0.1 mmol) were added to 5 mL of acetic anhydride, and the reaction was carried out at 100 °C for 1 h. The reaction solution was cooled to room temperature and then placed in a refrigerator to cool until a solid precipitated. The solid was filtered and washed with ethanol to give 21.33 mg of compound 7, with a yield of 80.17%. The structure of compound 7 was analyzed, and the structural confirmation data are as follows:

[0081] IR(KBr,cm -1 )3066,2923,2259,1681,1586,1465,1362,1311,1264,1174,1034,874,762,588; 1 H NMR (400MHz, CDCl3, ppm) δ7.54-7.50(m,2H),7.47(d,J=7.8Hz,1H),7.43-7.36(m,2H),7.36-7.30(m,2H),7.26(d,J=7.6Hz,1H),2.24(s,2H). 13 C NMR (100MHz, CDCl3) δ 169.5, 161.2, 138.9, 137.4, 128.0, 127.6, 127.2, 127.0, 126.9, 113.6, 26.1, 23.1. MS (EI, 70eV) m / z 266, 198, 167, 154, 140. Identification data indicate that compound 7 was successfully prepared.

[0082] Example 8

[0083] (1) Preparation of compound 8-1

[0084]

[0085] Compound 7 (0.1 mmol) and benzaldehyde (0.12 mmol) were added to 2 mL of acetonitrile, followed by the addition of acetic acid (0.2 mmol) and piperidine (0.2 mmol), and the mixture was refluxed at 88 °C for 5 h. 15.47 mg of compound 8-1 was obtained by TLC, with a yield of 43.7%. The structure of compound 8-1 was analyzed, and the structural confirmation data are as follows:

[0086] IR(KBr,cm -1 )3061,2923,2850,2217,1667,1594,1572,1460,1325,1261,1185,1025,947,756,728,689,563; 1H NMR (400MHz, CDCl3 ppm) δ7.87 (s, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.50-7.45 (m, 2H), 7.38-7.26 (m, 5H), 7.21-7.09 (m, 4H). 13 C10 NMR (100MHz, CDCl3) 162.0, 153.9, 138.2, 132.8, 132.6, 132.1, 130.4, 129.2, 128.2, 127.5, 127.3, 126.3, 114.2, 107.3. MS (EI, 70eV) m / z 354, 199, 174, 166, 154. Identification data indicate that compound 8-1 was successfully prepared.

[0087] (2) Preparation of compound 8-2

[0088]

[0089] Compound 7 (0.1 mmol) and 3-methylbenzaldehyde (0.12 mmol) were added to 2 mL of acetonitrile, followed by the addition of acetic acid (0.2 mmol) and piperidine (0.2 mmol), and the mixture was refluxed at 88 °C for 5 h. 15.09 mg of compound 8-2 was obtained by TLC, with a yield of 41%. The structure of compound 8-2 was analyzed, and the structural confirmation data are as follows:

[0090] IR(KBr,cm -1 )3066,3019,2923,2217,1681,1586,1465,1364,1311,1258,1205,1126,1034,944,762,689,591; 1 H NMR (400MHz, CDCl3 ppm)δ8.03(s,1H),7.65(s,2H),7.53(d,J=6.1Hz,3H),7.46(dd,J=7.7,1.5Hz,1H),7.35(d,J=1.4Hz,4H),7.25(d,J=1.4Hz,2H),2.40(s,3H). 13 C NMR (100MHz, CDCl3)169.4,154.1,139.0,138.3,133.5,132.8,132.1,131.0,129.1,1 28.1,128.0,127.6,127.4,127.3,127.2,127.0,126.9,126.3,23.1.MS(EI,70eV)m / z 368,199,166,154,140.

[0091] The identification data indicate that compound 8-2 was successfully prepared.

[0092] (3) Preparation of compound 8-3

[0093]

[0094] Compound 7 (0.1 mmol) and 4-methylbenzaldehyde (0.12 mmol) were added to 2 mL of acetonitrile, followed by the addition of acetic acid (0.2 mmol) and piperidine (0.2 mmol), and the mixture was refluxed at 88 °C for 5 h. 17.25 mg of compound 8-3 was obtained by TLC, with a yield of 46.88%. The structure of compound 8-3 was analyzed, and the structural confirmation data are as follows:

[0095] IR(KBr,cm -1 )3064,2222,1679,1586,1463,1325,1261,1191,1093,1014,944,762; 1 H NMR (400MHz, CDCl3 ppm)δ8.01(s,1H),7.79(s,1H),7.64(d,J=7.1Hz,2H),7.53(d,J=7.6Hz,2H), 7.45(d,J=5.1Hz,2H),7.37-7.33(m,4H),7.25(d,J=14.6Hz,2H),2.24(s,3H). 13 C NMR (100MHz, CDCl3) 161.7, 152.4, 138.8, 138.1, 132.8, 131.6, 129.5, 128.2, 128.0, 127.5, 127.3, 127.0, 126.8, 126.3, 114.0, 23.1. MS (EI, 70eV) m / z 368, 199, 166, 154, 140. Identification data indicate that compound 8-3 was successfully prepared.

[0096] Example 9

[0097] Preparation of compound 9

[0098]

[0099] Phenothiazine (0.1 mmol) and NaOH (0.12 mmol) were added to 2 mL of N,N-dimethylformamide solution, followed by epichlorohydrin (0.12 mmol), and the reaction was carried out at room temperature for 1 h. Compound 9 was isolated by TLC, yielding 8.45 mg in 33.12%. The structure of compound 9 was analyzed, and the structural confirmation data are as follows:

[0100] IR(KBr,cm-1 )3061,2921,2855,2319,1574,1467,1359,1246,1221,1106,1037,903,858,747,625,516; 1 H NMR (400MHz, CDCl3 ppm) δ7.21-7.14(m,4H),7.02-6.94(m,4H),4.22(dd,J=15.5,3.0Hz,1H),3.92(dd,J=15.5,4. 6Hz,1H),3.33(ddd,J=7.2,4.3,3.0Hz,1H),2.98(t,J=4.5Hz,1H),2.81(dd,J=4.8,2.7Hz,1H). 13 C NMR (100MHz, CDCl3) 162.0, 144.9, 127.4, 127.3, 124.2, 122.9, 115.3, 50.9, 50.3, 46.8. MS (EI, 70eV) m / z 335, 226, 199, 166, 154.

[0101] The identification data indicate that compound 9 was successfully prepared.

[0102] Example 10

[0103] Preparation of compound 10

[0104]

[0105] Phenothiazine (0.1 mmol) and NaH (0.1 mmol) were reacted in 2 mL of ultradry N,N-dimethylformamide solution at room temperature for 20 min, followed by the addition of chloroacetonitrile (0.1 mmol) and heating at 80 °C for 3 h, and finally reacting at room temperature for 12 h. Compound 10 was isolated by TLC, yielding 4.76 mg in 20.02%. The structure of compound 10 was analyzed, and the structural confirmation data are as follows:

[0106] IR(KBr,cm -1 )2956,2923,2855,1749,1469,1380,1264,1190,1083,971,858,749,654; 1 H NMR (400MHz, CDCl3 ppm) δ7.53-7.25(m,8H),2.24(s,2H). 13C NMR(100MHz, CDCl3)127.85,127.83,127.6,124.3,124.05,124.04,123.7,114.3.MS(EI,70eV)m / z 238,199,166,154,140.HRMS(ESI)m / z[M+H]+calcd for C14H10N2S239.0638, found 239.0647.

[0107] The identification data indicate that compound 10 was successfully prepared.

[0108] Example 11

[0109] Preparation of compound 11

[0110]

[0111] Phenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, 2-bromopropionyl bromide (0.15 mmol) was added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 11 was isolated by TLC, yielding 24.77 mg in 74.6%. The structure of compound 11 was analyzed, and the structural confirmation data are as follows:

[0112] IR(KBr,cm -1 )3069,2974,2921,2864,1687,1586,1465,1362,1258,1160,1070,989,764,650; 1 H NMR (400MHz, CDCl3 ppm) δ7.81-7.24 (m, 8H), 4.80 (s, 1H), 1.84 (d, J = 5.9Hz, 3H). 13 C10 NMR (100MHz, CDCl3) 162.0, 153.9, 138.2, 132.8, 132.6, 132.1, 130.4, 129.2, 128.2, 127.5, 127.3, 126.3, 114.2, 107.3. MS (EI, 70eV) m / z 335, 226, 199, 166, 154. Identification data indicate that compound 11 was successfully prepared.

[0113] Example 12

[0114] (1) Preparation of compound 12-1

[0115]

[0116] Compound 6 (0.1 mmol), phenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 10.01 mg of compound 12-1 was obtained by TLC separation, with a yield of 30%. The structure of compound 12-1 was analyzed, and the structural confirmation data are as follows:

[0117] IR(KBr,cm -1 )3065,2964,2919,2853,1702,1588,1495,1467,1450,1386,1308,1262,1223,1176,1089,1027,974,885,753,691; 1 H NMR (400MHz, CDCl3 ppm)δ7.60(d,J=6.6Hz,2H),7.51-7.49(m,2H),7.38-7.35(m,2H),7.30(d,J=6.2Hz, 2H),7.26-7.22(m,2H),6.99-6.94(m,1H),6.82(dt,J=7.8,1.1Hz,2H),4.79(s,2H). 13 C NMR (100MHz, CDCl3)166.9,157.7,137.7,129.5,128.2,127.4,127.3,126.7,126.6,126.6,121.6,114.7,66.6.MS(EI,70eV)m / z 333,212,199,180,166.HRMS(ESI)m / z[M+H]+calcd forC20H15NO2S 334.0896, found 334.0903.

[0118] The identification data indicate that compound 12-1 was successfully prepared.

[0119] (2) Preparation of compound 12-2

[0120]

[0121] Compound 6 (0.1 mmol), 2-fluorophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. Compound 12-2 was isolated by TLC, yielding 5.64 mg in a 16.07% yield. The structure of compound 12-2 was analyzed, and the structural confirmation data are as follows:

[0122] IR(KBr,cm -1)3069,2963,2921,2853,1698,1589,1508,1463,1384,1323,1261,1182,1124,1081,1034,986,804,756,703,667,756; 1 H NMR (400MHz, CDCl3 ppm)δ7.60(d,J=7.8Hz,2H),7.50(d,J=7.7Hz,3H),7.37(s,2H),7.29(s,3H),7.06-7.01(m,1H),6.90(d,J=8.5Hz,1H),4.87(s,2H). 13 C10 NMR (100MHz, CDCl3) 166.5, 137.6, 128.3, 128.2, 127.6, 127.4, 127.4, 127.3, 126.6, 124.3, 122.3, 122.2, 116.5, 116.3, 115.9, 67.7. MS (EI, 70eV) m / z 351, 212, 199, 180, 166. HRMS (ESI) m / z [M+H]+ calcd for C20H14NO2FS 352.0802, found 352.0824. Identification data indicate that compound 12-2 was successfully prepared.

[0123] (3) Preparation of compound 12-3

[0124]

[0125] Compound 6 (0.1 mmol), 2-bromophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 11.20 mg of compound 12-3 was obtained by TLC, with a yield of 27.18%. The structure of compound 12-3 was analyzed, and the structural confirmation data are as follows:

[0126] IR(KBr,cm -1 )3063,2971,2925,1687,1463,1356,1280,1258,1154,1070,1034,986,868,762,658,551; 1H NMR (400MHz, CDCl3 ppm)δ7.62(d,J=7.2Hz,2H),7.52-7.49(m,3H),7.38-7.35(m,2H),7.30-7.28(m,2 H),7.22-7.17(m,1H),6.88-6.82(m,1H),6.78(dd,J=8.3,1.3Hz,1H),4.87(s,2H). 13 C NMR (100MHz, CDCl3)166.2,154.3,137.7,133.5,128.4,128.26,128.25,127.5,127.3,126.6,122.7,113.5,112.1,67.4.MS(EI,70eV)m / z 413,212,199,180,160.HRMS(ESI)m / z[M+H]+calcd for C20H14NO2SBr 412.0001,found412.0024.

[0127] The identification data indicate that compound 12-3 was successfully prepared.

[0128] (4) Preparation of compound 12-4

[0129]

[0130] Compound 6 (0.1 mmol), 3-fluorophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. Compound 12-4 (5.32 mg, yield 14.99%) was obtained by TLC. The structure of compound 12-4 was analyzed, and the structural confirmation data are as follows:

[0131] IR(KBr,cm -1 )3069,2968,2926,2853,1701,1614,1592,1488,1465,1314,1255,1137,1081,936,848,756; 1 HNMR (400MHz, CDCl3 ppm)δ7.58(s,2H),7.51(d,J=6.3Hz,1H),7.38(td,J=7.7,1.5Hz,3H),7.30(d,J=6. 4Hz,3H),7.21-7.16(m,1H),6.68-6.64(m,1H),6.56(d,J=15.0Hz,1H),4.78(s,2H). 13C NMR (100MHz, CDCl3)166.4,162.2,159.0,137.67,130.3,130.2,128.3,127.5,1 27.3,126.5,110.20,110.17,108.6,108.4,102.8,102.5,66.6.MS(EI,70eV)m / z 351,212,199,180,166.HRMS(ESI)m / z[M+H]+calcd forC20H14NO2FS 352.0802,found 352.08094.

[0132] The identification data indicate that compound 12-4 was successfully prepared.

[0133] (5) Preparation of compound 12-5

[0134]

[0135] Compound 6 (0.1 mmol), 4-fluorophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 6.72 mg of compound 12-5 was obtained by TLC, with a yield of 19.15%. The structure of compound 12-5 was analyzed, and the structural confirmation data are as follows:

[0136] IR(KBr,cm -1 )3069,2968,2926,2853,1701,1614,1592,1488,1465,1314,1255,1137,1081,936,848,756; 1 HNMR (400MHz, CDCl3 ppm)δ7.59(d,J=7.7Hz,2H),7.51-7.49(m,2H),7.39-7.35(m,2H),7.31-7.28(m,2H),6.94-6.90(m,2H),6.78-6.74(m,2H),4.76(s,2H). 13C NMR (100MHz, CDCl3)166.80,158.90,156.53,153.84,137.66,128.23,127.43,127.34,126.63,126.60,126.5 9,115.98,115.90,115.82,115.74,67.22.MS(EI,70eV)m / z351,212,199,180,166.HRMS(ESI)m / z[M+H]+calcd for C20H14NO2FS 352.0802,found352.0820.

[0137] The identification data indicate that compound 12-5 was successfully prepared.

[0138] (6) Preparation of compound 12-6

[0139]

[0140] Compound 6 (0.1 mmol), 4-methylphenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 8.26 mg of compound 12-6 was obtained by TLC, with a yield of 23.80%. The structure of compound 12-6 was analyzed, and the structural confirmation data are as follows:

[0141] IR(KBr,cm -1 )3068,2925,2855,1683,1590,1510,1467,1322,1264,1225,1176,1079,982,821,759,701,590; 1 HNMR (400MHz, CDCl3 ppm)δ7.61(d,J=7.8Hz,2H),7.51-7.49(m,2H),7.37-7.35(m,2H),7.30-7.27( m,2H),7.06(d,J=8.3Hz,2H),6.75(d,J=8.6Hz,2H),4.78(s,2H),2.29(s,3H). 13C NMR (100MHz, CDCl3)167.1,155.7,137.8,130.8,129.93,129.91,128.2,128.0 ,127.4,127.3,127.1,126.9,126.7,115.3,114.6,66.7,20.6.MS(EI,70eV)m / z 413,212,199,180,166.HRMS(ESI)m / z[M+H]+calcd for C21H17NO2S 348.1053, found 348.1072.

[0142] The identification data indicate that compound 12-6 was successfully prepared.

[0143] (7) Preparation of compound 12-7

[0144]

[0145] Compound 6 (0.1 mmol), 2-chloro,3-bromophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 10.31 mg of compound 12-7 was obtained by TLC, with a yield of 23.20%. The structure of compound 12-7 was analyzed, and the structural confirmation data are as follows:

[0146] IR(KBr,cm -1 )3066,2923,2848,1698,1578,1460,1379,1261,1182,1079,1031,978,888,764,703,619; 1 H NMR (400MHz, CDCl3 ppm)δ7.62(d,J=7.8Hz,2H),7.51(dd,J=7.7,1.3Hz,2H),7.39(td,J=7.7,1.5Hz,2 H),7.33-7.29(m,2H),7.16-7.08(m,2H),6.67(dd,J=7.8,1.8Hz,1H),4.90(s,2H). 13C NMR (100MHz, CDCl3)165.9,155.9,137.6,136.0,128.30,128.26,127.5,127.4,126.6,126.6, 123.2,113.1,111.2,67.7.MS(EI,70eV)m / z446,220,212,199,190.HRMS(ESI)m / z[M+H]+calcd for C20H13NO2SClBr445.9612,found445.9642.

[0147] The identification data indicate that compound 12-7 was successfully prepared.

[0148] (8) Preparation of compound 12-8

[0149]

[0150] Compound 6 (0.1 mmol), 3-chloro,2-bromophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 12.32 mg of compound 12-8 was obtained by TLC, with a yield of 27.75%. The structure of compound 12-8 was analyzed, and the structural confirmation data are as follows:

[0151] IR(KBr,cm -1 )3061,2956,2927,2853,1700,1576,1452,1376,1256,1178,1075,1033,984,887,767,703; 1 HNMR (400MHz, CDCl3 ppm)δ7.63(d,J=7.8Hz,2H),7.54(d,J=7.7Hz,2H),7.42(d,J=8.9Hz,2H),7 .35-7.26(m,3H),7.04(t,J=8.2Hz,1H),6.78(d,J=9.2Hz,1H),4.92(s,2H). 13 C10 NMR (100MHz, CDCl3) 165.9, 154.7, 137.5, 128.3, 127.8, 127.5, 127.4, 126.3, 124.0, 112.2, 67.5. MS (EI, 70eV) m / z 446, 220, 212, 199, 190. HRMS (ESI) m / z [M+H]+ calcd for C20H13NO2SClBr 445.9612, found 445.9637. Identification data indicate that compound 12-8 was successfully prepared.

[0152] (9) Preparation of compound 12-9

[0153]

[0154] Compound 6 (0.1 mmol), 4-methoxythiophenol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 14.32 mg of compound 12-9 was obtained by TLC, with a yield of 37.68%. The structure of compound 12-9 was analyzed, and the structural confirmation data are as follows:

[0155] IR(KBr,cm -1 )2836,1676,1592,1496,1460,1328,1283,1247,1179,1123,1031,832,759,658,523; 1 H NMR (400MHz, CDCl3 ppm) δ7.59(d,J=6.5Hz,2H),7.51-7.45(m,4H),7.39-7.34(m,2H),7.30-7.24(m,2H),6.86(d,J=8.8Hz,2H),3.86(s,2H),3.81(s,3H). 13 CNMR (100MHz, CDCl3) 168.2, 159.6, 138.5, 134.6, 134.3, 133.4, 128.1, 127.2, 127.1, 125.0, 116.1, 114.7, 55.4, 39.2. MS (EI, 70eV) m / z 378, 212, 199, 180, 171. HRMS (ESI) m / z [M+H]+ calcd for C21H17NO2S2 380.0776, found 380.0794. Identification data indicate that compound 12-9 was successfully prepared.

[0156] (10) Preparation of compound 12-10

[0157]

[0158] Compound 6 (0.1 mmol), benzyl mercaptan (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 12.12 mg of compound 12-10 was obtained by TLC, with a yield of 33.39%. The structure of compound 12-10 was analyzed, and the structural confirmation data are as follows:

[0159] IR(KBr,cm-1 )3336,3061,3030,2923,1673,1592,1460,1412,1320,1264,1241,1160,1123,1073,1031,910,759,703,652,574,523,476; 1 H NMR (400MHz, CDCl3 ppm) δ7.68-7.24 (m, 13H), 3.94 (s, 2H), 3.33 (d, J = 2.6Hz, 2H). 13 C NMR (100MHz, CDCl3)168.8,138.5,137.6,133.8-133.1(m),129.4,128.6,128.1,127.2,127.1,114.7,36.2,31.8.MS(EI,70eV)m / z 363,241,212,199,167.HRMS(ESI)m / z[M+H]+calcd for C21H17NOS2364.0824, found 364.0845.

[0160] The identification data indicate that compound 12-10 was successfully prepared.

[0161] (11) Preparation of compound 12-11

[0162]

[0163] Compound 6 (0.1 mmol), cyclohexanethiol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 11.78 mg of compound 12-11 was obtained by TLC, with a yield of 33.18%. The structure of compound 12-11 was analyzed, and the structural confirmation data are as follows:

[0164] IR(KBr,cm-1)3064,2929,2856,1676,1460,1325,1264,1238,1129,1036,764,658,579; 1H NMR (400MHz, CDCl3 ppm)δ7.63(d,J=7.9Hz,2H),7.49(dd,J=7.7,1.5Hz,2H),7.37(td,J=7.7,1.5Hz,2H),7.31-7.25(m,2H),3.48(s,2H),2.90 (ddq,J=10.8,7.7,3.7Hz,1H),1.97(d,J=9.5Hz,2H),1.75(d,J=5.2Hz,2H),1.62(d,J=11.4Hz,1H),1.34-1.23(m,5H).13C NMR(100MHz,CDCl3).MS(EI,70eV)m / z 355,241,230,212,199.HRMS(ESI)m / z[M+H]+calcd for C20H21NOS2356.1137,found 356.1105. Identification data indicate that compound 12-11 was successfully prepared.

[0165] (12) Preparation of compound 12-12

[0166]

[0167] Compound 6 (0.1 mmol), selenoyl alcohol (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. Compound 12-12 was obtained by TLC separation, with a yield of 40.38%. The structure of compound 12-12 was confirmed as follows:

[0168] IR(KBr,cm-1)3058,2932,1673,1586,1465,1322,1264,1160,1101,1025,764,736,692,644,602,470; 1 HNMR (400MHz, CDCl3 ppm) δ7.56-7.47 (m, 5H), 7.30 (d, J = 30.6Hz, 8H), 3.88 (s, 2H). 13CNMR (100MHz, CDCl3) 169.2, 138.5, 133.4, 133.4, 129.6, 129.2, 128.2-128.0 (m), 127.7, 127.15, 127.09, 28.9. MS (EI, 70eV) m / z 395, 212, 199, 180, 171. HRMS (ESI) m / z [M+H]+ calcd for C20H15NOSSe 398.0112, found 398.0131. Identification data indicate that compound 12-12 was successfully prepared.

[0169] (13) Preparation of compounds 12-13

[0170]

[0171] Compound 6 (0.1 mmol), aniline (0.1 mmol), KI (0.1 mmol), and triethylamine (0.1 mmol) were added to 2 mL of acetone and reacted at 50 °C for 12 h. 11.32 mg of compounds 12-13 were obtained by TLC, with a yield of 34.04%. The structures of compounds 12-13 were analyzed, and the structural confirmation data are as follows:

[0172] IR(KBr,cm -1 )3064,2929,1684,1606,1507,1463,1370,1308,1258,1182,1126,1033,982,756,692; 1 HNMR (400MHz, CDCl3 ppm)δ7.60(d,J=7.7Hz,2H),7.52(s,2H),7.41(s,2H),7.33(d,J=7.6Hz,2 H),7.17(d,J=7.7Hz,2H),6.75(t,J=7.1Hz,2H),6.53(s,2H),4.02(s,2H). 13 C NMR (100MHz, CDCl3) 169.2, 147.1, 137.7, 129.3, 129.3, 128.3, 128.0, 127.5, 127.3, 127.0, 126.9, 118.6, 118.0, 115.2, 113.1, 46.6. MS (EI, 70eV) m / z 332, 199, 166, 154, 140. HRMS (ESI) m / z [M+H]+ calcd for C20H16N2OS 333.1056, found 333.1075. Identification data indicate that compounds 12-13 were successfully prepared.

[0173] (14) Preparation of compounds 12-14

[0174]

[0175] 0.1 mmol of 2-chlorophenothiazine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 27.9 mg of 2-chloro-1-(2-chloro-10H-phenothiazin-10-yl)acetone was obtained by TLC, with a yield of 90%. 0.1 mmol of 2-chloro-1-(2-chloro-10H-phenothiazin-10-yl)acetone, 0.1 mmol of 2-hydroxyacetophenone, 0.1 mmol of KI, and 0.1 mmol of triethylamine were added to 2 mL of acetone and reacted at 50 °C for 12 h. 10.56 mg of compound 12-14 was obtained by TLC, with a yield of 25.82%. The structure of compound 12-14 was analyzed, and the structural confirmation data are as follows:

[0176] IR(KBr,cm -1 )2963,2926,2848,1740,1665,1609,1468,1376,1328,1267,1171,1126,1087,1023,810; 1 H NMR (400MHz, CDCl3 ppm)δ7.89(d,J=6.7Hz,2H),7.65(s,1H),7.53(t,J=7.9Hz,2H),7.43-7.37(m,2H), 7.30(dd,J=20.3,8.1Hz,2H),6.83(d,J=6.6Hz,2H),4.97-4.77(m,2H),2.55(s,3H). 13 C NMR (100MHz, CDCl3)196.8,166.3,161.4,138.7,137.1,133.14,131.11,130.6,12 8.7,128.5,127.9,127.7,127.6,127.1,126.3,114.3,66.3,26.4.MS(EI,70eV)m / z 409,221,199,166,154.HRMS(ESI)m / z[M+H]+calcdfor C22H16NO2SCl 411.0929,found411.0953.

[0177] The identification data indicate that compounds 12-14 were successfully prepared.

[0178] (15) Preparation of compounds 12-15

[0179]

[0180] 0.1 mmol of 2-methoxyphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the mixture was heated to 80 °C for 12 h. 26.26 mg of 2-chloro-1-(2-methoxy-10H-phenthiazin-10-yl)ethyl ketone was obtained by TLC, with a yield of 86.1%. 0.1 mmol of 2-chloro-1-(2-methoxy-10H-phenthiazin-10-yl)ethyl ketone, 0.1 mmol of 4-hydroxyacetophenone, 0.1 mmol of KI, and 0.1 mmol of triethylamine were then added to 2 mL of acetone and reacted at 50 °C for 12 h. 9.17 mg of compound 12-15 was obtained by TLC, with a yield of 22.62%. The structure of compound 12-15 was analyzed, and the structural confirmation data are as follows:

[0181] IR(KBr,cm -1 )3064,2963,2929,2848,1698,1673,1594,1471,1364,1266,1219,1177,1028,835,753,596; 1 H NMR (400MHz, CDCl3 ppm)δ7.90-7.87(m,2H),7.57-7.53(m,1H),7.51(dd,J=7.7,1.6Hz,1H),7.39-7.36(m,1H),7.35(dd,J=7.7,1.6Hz, 1H),7.32-7.28(m,1H),7.17(d,J=2.5Hz,1H),6.88-6.84(m,3H),4.89(t,J=13.2Hz,2H),3.82(s,3H),2.54(s,3H). 13 C NMR (100MHz, CDCl3)196.8,166.2,161.5,159.4,138.9,137.55,131.0,130.6,128.7 ,128.3,127.6,127.3,126.5,114.3,113.9,112.5,66.3,55.8,26.4.MS(EI,70eV)m / z 378,221,195,166,156.HRMS(ESI)m / z[M+H]+calcd for C23H19NO4S406.1108,found406.1130.

[0182] The identification data indicate that compound 12-15 was successfully prepared.

[0183] Example 13

[0184] Preparation of compound 13

[0185]

[0186] A mixture of compound 6 (0.1 mmol), succinimide (0.1 mmol), and anhydrous potassium carbonate (0.125 mmol) in 20 mL of dimethyl sulfoxide solution was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the coarse precipitate was filtered off. Compound 13 was isolated by TLC, yielding 20.37 mg in 60.63%. The structure of compound 13 was analyzed, and the structural confirmation data are as follows:

[0187] IR(KBr,cm -1 )3059,2946,1780,1710,1590,1462,1419,1378,1304,1260,1176,1056,910,825,767,666,598; 1 H NMR (400MHz, CDCl3 ppm) δ17.62-7.20(m,8H),4.38(s,2H),2.74(s,4H). 13 C18H14N2O3S NMR (100MHz, CDCl3) 176.7, 164.7, 137.5, 128.2, 127.4, 127.2, 126.9, 40.7, 28.3. MS (EI, 70eV) m / z 336, 240, 212, 198, 180. HRMS (ESI) m / z [M+H]+ calcd for C18H14N2O3S 339.0798, found 339.0811. Identification data indicate that compound 13 was successfully prepared.

[0188] Example 14

[0189] Preparation of compound 14

[0190]

[0191] A mixture of compound 6 (0.1 mmol), maleimide (0.1 mmol), and anhydrous potassium carbonate (0.125 mmol) in 20 mL of dimethyl sulfoxide solution was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the coarse precipitate was filtered off. Compound 14 was isolated by TLC, yielding 22.15 mg in 65.98%. The structure of compound 14 was analyzed, and the structural confirmation data are as follows:

[0192] IR(KBr,cm -1)2960,2925,2853,1784,1716,1584,1465,1421,1378,1304,1260,1180,1097,1025,759; 1 H NMR(400MHz, CDCl3 ppm)δ7.56-7.18(m,8H),2.61(s,2H).13CNMR 13 C10 NMR (100MHz, CDCl3) 176.7, 164.7, 137.5, 128.2, 127.4, 127.2, 126.9, 40.7, 28.3. MS (EI, 70eV) m / z 334, 240, 212, 198, 180. Identification data indicate that compound 14 was successfully prepared.

[0193] Example 15

[0194] Preparation of compound 15

[0195]

[0196] Phenothiazine (0.1 mmol) and sodium hydride (0.1 mmol) were added to 2 mL of N,N-dimethylformamide solution and reacted at room temperature for 4 h. After the reaction was complete, an N,N-dimethylformamide solution containing 1,3-dibromopropane (0.1 mmol) was added, and the reaction was carried out at 0 °C for 3 h. Compound 15 was isolated by TLC, yielding 16.75 mg in 52.5%. The structure of compound 15 was analyzed, and the structural confirmation data are as follows:

[0197] IR(KBr,cm -1 )3064,2963,2926,2859,1600,1569,1457,1334,1286,1250,1236,1039,748; 1 H NMR (400MHz, CDCl3 ppm) δ7.26-7.19(m,4H),7.02-6.94(m,4H),4.12(t,J=6.5Hz,2H),3.56(t,J=6.3Hz,2H),2.35(p,J=6.4Hz,2H). 13C15H14NSBr (100MHz, CDCl3) 145.1, 127.7, 127.4, 125.8, 122.8, 115.7, 45.2, 31.1, 29.8. MS (EI, 70eV) m / z 321, 239, 212, 198, 180. HRMS (ESI) m / z [M+H]+ calcd for C15H14NSBr 320.0103, found 320.0095. Identification data indicate that compound 15 was successfully prepared.

[0198] Example 16

[0199] Preparation of compound 16

[0200]

[0201] Phenothiazine (0.1 mmol), 2,5-dichloropyrimidine (0.1 mmol), and potassium carbonate (1.0 eq) were added to 2 mL of dimethyl sulfoxide solution under a nitrogen atmosphere, and the reaction was carried out at 80 °C for 12 h. Compound 16 was obtained by TLC, yielding 12.53 mg in 40.3%. The structure of compound 16 was analyzed, and the structural confirmation data are as follows:

[0202] IR(KBr,cm -1 )3059,2923,2853,1634,1575,1533,1479,1463,1409,1314,1261,1132,759; 1 H NMR (400MHz, CDCl3 ppm) δ8.34(s,2H),7.75(d,J=8.1Hz,2H),7.48(d,J=7.8Hz,2H),7.39(t,J=7.1Hz,2H),7.26(t,J=7.1Hz,2H). 13 C16 NMR (100MHz, CDCl3) 158.35, 155.99, 139.72, 133.34, 128.38, 128.07, 126.59, 126.35, 122.54. MS (EI, 70eV) m / z 311, 278, 253, 224, 198. HRMS (ESI) m / z [M+H]+ calcd for C16H10N3SCl 312.0357, found 312.0363. Identification data indicate that compound 16 was successfully prepared.

[0203] Example 17

[0204] Preparation of compound 17

[0205]

[0206] Phenothiazine (0.1 mmol), 4-bromobenzonitrile (0.12 mmol), potassium carbonate (0.5 mmol), Pd(OAc)₂ (0.02 mmol), P(t-Bu)₃ (0.03 mmol), and toluene (20 mL) were stirred at 120 °C under a nitrogen atmosphere for 24 h. Compound 17 was obtained by TLC in a yield of 15.79 mg (52.62%). The structure of compound 17 was analyzed, and the structural confirmation data are as follows:

[0207] IR(KBr,cm -1 )3065,2925,2218,1613,1584,1506,1460,1314,1260,1176,1124,827,753; 1 H NMR (400MHz, CDCl3 ppm) δ7.49(dd,J=16.6,8.3Hz,4H),7.33(q,J=8.0Hz,4H),7.23(t,J=7.2Hz,2H),7.10(d,J=8.8Hz,2H). 13 C NMR (100MHz, CDCl3)148.99,141.02,133.62,133.13,128.93,127.43,126.26,125.93,119.50,116.81,104.16.MS(EI,70eV)m / z 300,239,212,198,166.HRMS(ESI)m / z[M+H]+calcd for C16H12NO2S 301.0767, found 301.0758.

[0208] The identification data indicate that compound 17 was successfully prepared.

[0209] Example 18

[0210] Preparation of compound 18

[0211]

[0212] At 0 °C, phenothiazine (0.1 mmol) and propargyl acid (0.1 mmol) were added to a dichloromethane solution, followed by the addition of 1,3-dicyclohexylcarbodiimide (0.1 mmol). The reaction mixture was then heated to room temperature and allowed to react for 1.5 h. Compound 18 was isolated by TLC, yielding 10.19 mg in 40.6%. The structure of compound 18 was analyzed, and the structural confirmation data are as follows:

[0213] IR(KBr,cm -1)3251,3066,2937,2853,2105,1653,1468,1325,1292,1264,1207,1191,1143,902,762; 1 H NMR (400MHz, CDCl3 ppm) δ7.68 (d, J = 7.6 Hz, 2H), 7.47 (s, 2H), 7.32 (d, J = 22.2 Hz, 4H), 3.06 (s, 1H). 13 C15H15NOS (100MHz, CDCl3) 152.4, 152.2, 151.8, 127.8, 127.2, 127.0-126.8 (m), 82.3, 81.3, 76.1, 75.7, 58.7, 26.2, 25.3. MS (EI, 70eV) m / z 251, 223, 198166, 154. HRMS (ESI) m / z [M+H]+ calcd for C15H15NOS 258.0947, found 258.0925. Identification data indicate that compound 18 was successfully prepared.

[0214] Example 19

[0215] Preparation of compound 19

[0216]

[0217] Phenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, dichloroacetyl chloride (0.15 mmol) was added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 19 was obtained by TLC, yielding 16.12 mg in 52% of the product. The structure of compound 19 was analyzed, and the structural confirmation data are as follows:

[0218] IR(KBr,cm -1 )3069,2960,2921,2853,1704,1583,1466,1345,1236,1163,1132,1034,913,807,759,706,664,616; 1 H NMR (400MHz, CDCl3 ppm) δ7.64 (s, 2H), 7.51 (d, J = 7.7Hz, 2H), 7.39 (dd, J = 7.8, 1.4Hz, 2H), 7.32 (t, J = 7.5Hz, 2H), 6.43 (s, 1H). 13C NMR (100MHz, CDCl3) 163.2, 137.2, 128.43, 128.42, 127.90, 127.89, 127.6, 126.4-126.2 (m), 126.0, 63.9. MS (EI, 70eV) m / z 310, 212, 198, 166, 140. HRMS (ESI) m / z [M+H]+ calcd for C14H9NOSCl2 290.04001, found 290.0408. Identification data indicate that compound 19 was successfully prepared.

[0219] Example 20

[0220] Preparation of compound 20

[0221]

[0222] Phenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, 2-chloropropionyl chloride (0.15 mmol) was added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 20 was isolated by TLC, yielding 16.10 mg in 55.7%. The structure of compound 20 was analyzed, and the structural confirmation data are as follows:

[0223] IR(KBr,cm -1 )3063,2933,1689,1462,1361,1260,1170,1068,965,763,654; 1 H NMR (400MHz, CDCl3 ppm) δ7.72(d,J=7.9Hz,2H),7.49(s,2H),7.39-7.37(m,2H),7.27(s,2H),4.81(q,J=6.2Hz,2H),1.65(s,3H). 13 C15H12NOSCl NMR (100MHz, CDCl3) 168.9, 138.1, 128.5, 128.1, 127.62, 127.61, 127.4, 127.3, 127.2, 126.4, 50.3, 21.7. MS (EI, 70eV) m / z 289, 226, 198, 166, 140. HRMS (ESI) m / z [M+H]+ calcd for C15H12NOSCl 290.0401, found 290.0418. Identification data indicate that compound 20 was successfully prepared.

[0224] Example 21

[0225] Preparation of compound 21

[0226]

[0227] Phenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, propionyl chloride (0.15 mmol) was added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 21 was obtained by TLC separation, with a yield of 81%. The structure of compound 21 was analyzed, and the structural confirmation data are as follows:

[0228] IR(KBr,cm -1 )3065,2977,2940,2884,2248,1910,1691,1590,1458,1359,1252,1182,1132,1077,1033,969,887,753,734,697,660,528,470; 1 H NMR (400MHz, CDCl3 ppm) δ7.58-7.16 (m, 7H), 2.49 (q, J = 7.3Hz, 2H), 1.18 (dt, J = 33.9, 7.2Hz, 3H). 13 C NMR(100MHz, CDCl3)173.1,138.9,133.2,128.0,127.4,127.0,126.8,27.96,9.6.MS(EI,70eV)m / z 255,226,198,180,171.HRMS(ESI)m / z[M+H]+calcd for C15H13NOS256.0791, found 256.0804.

[0229] The identification data indicate that compound 21 was successfully prepared.

[0230] Example 22

[0231] Preparation of compound 22

[0232]

[0233] Sodium hydride (0.3 mmol) and 1-bromopropane (0.1 mmol) were added to an ultradry N,N-dimethylformamide solution containing phenothiazine (0.1 mmol), and the reaction was carried out at 0 °C for 1 h. The mixture was then stirred at 35 °C for 1 h. Compound 22 was obtained by TLC, yielding 17.59 mg in 73% of the product. The structure of compound 22 was analyzed, and the structural confirmation data are as follows:

[0234] IR(KBr,cm -1)3070,3006,2958,2935,2834,1590,1467,1277,1211,1167,1132,1040,930,841,796,749; 1 HNMR (400MHz, CDCl3 ppm)δ7.23-7.05(m,4H),6.98(t,J=7.5Hz,1H),6.89(d,J=8.4Hz,1H),6.57-6.50(m,2H),4.23(t,J=7.3Hz,2H),3.82(d,J=2.8Hz,4H). 13 C NMR (100MHz, CDCl3) 159.9, 145.8, 144.2, 128.0, 127.7, 127.4, 125.9, 123.1, 116.2, 115.3, 107.4, 103.2, 55.6, 49.3, 40.0. MS (EI, 70eV) m / z 241, 226, 198, 180, 171. Identification data indicate that compound 22 was successfully prepared.

[0235] Example 23

[0236] Preparation of compound 23

[0237]

[0238] Diphenylamine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 23 was isolated by TLC, yielding 18.13 mg in 74% of the product. The structure of compound 23 was analyzed, and the structural confirmation data are as follows:

[0239] IR(KBr,cm -1 )3061,3010,2946,1679,1599,1493,1361,1266,1167,1077,784,765,734,701,662,610,571; 1 H NMR (400MHz, CDCl3 ppm) δ7.33 (d, J=7.3Hz, 10H), 4.06 (s, 2H). 13 C NMR (100MHz, CDCl3) 166.2, 141.8, 130.1, 129.2, 128.6, 126.8, 126.1, 42.9. MS (EI, 70eV) m / z 245, 196, 180, 169, 152. Identification data indicate that compound 23 was successfully prepared.

[0240] Example 24

[0241] Preparation of compound 24

[0242]

[0243] Iminostilbene (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the mixture was heated to 80 °C for 12 h. Compound 24 was isolated by TLC, yielding 15.63 mg in 58.1%. The structure of compound 24 was analyzed, and the structural confirmation data are as follows:

[0244] IR(KBr,cm -1 )3061,2927,1679,1491,1355,1254,1167,988,769,623; 1 H NMR (400MHz, CDCl3ppm) δ7.60-7.31 (m, 8H), 6.95 (q, J = 11.6Hz, 2H), 3.88 (dd, J = 103.5, 13.3Hz, 2H). 13 C NMR (100MHz, CDCl3)166.6,139.6,138.5,135.0,133.4,131.6,129.7,129.6 2,129.55,129.1,129.2,128.7,128.2,127.9,127.4,41.6.MS(EI,70eV)m / z 271,236,222,194,179.

[0245] The identification data indicate that compound 24 was successfully prepared.

[0246] Example 25

[0247] Preparation of compound 25

[0248]

[0249] Iminodibenzyl (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the mixture was heated to 80 °C for 12 h. Compound 25 was isolated by TLC, yielding 16.88 mg in 62.3%. The structure of compound 25 was analyzed, and the structural confirmation data are as follows:

[0250] IR(KBr,cm -1 )3057,3026,2946,1681,1489,1355,1264,1176,990,811,763,615; 1HNMR (400MHz, CDCl3 ppm) δ7.49-7.09(m,8H),4.17-3.92(m,2H),3.49-3.25(m,2H),2.90-2.71(m,2H). 13 C NMR (100MHz, CDCl3)166.2,140.9,139.7,137.9,134.6,130.9,130.4,129.3,128.3,128.0,127.7,127.2,126.7,42.1,30.8.MS(EI,70eV)m / z 269,192,165,152,140.

[0251] The identification data indicate that compound 25 was successfully prepared.

[0252] Example 26

[0253] Preparation of compound 26

[0254]

[0255] Phenyrazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the mixture was heated to 80 °C for 12 h. Compound 26 was obtained by TLC, yielding 21.32 mg in 83.2%. The structure of compound 26 was analyzed, and the structural confirmation data are as follows:

[0256] IR(KBr,cm -1 )2933,2706,1714,1640,1604,1460,1384,1323,1166,1122,1065,1013,1013,847,759; 1 H NMR (400MHz, CDCl3 ppm) δ7.61 (d, J = 7.7Hz, 2H), 7.30-7.26 (m, 2H), 7.22-7.18 (m, 4H), 4.35 (s, 2H). 13 C NMR (100MHz, CDCl3) 165.4, 151.0, 128.6, 127.7, 124.4, 123.8, 117.2, 41.6. MS (EI, 70eV) m / z 253, 182, 153, 127, 101. Identification data indicate that compound 26 was successfully prepared.

[0257] Example 27

[0258] Preparation of compound 27

[0259]

[0260] Carbazole (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Chloroacetyl chloride (0.15 mmol) was then added to the mixture, and the reaction was heated to 80 °C for 12 h. Compound 27 was isolated by TLC, yielding 16.36 mg in a 67.32% yield. The structure of compound 27 was analyzed, and the structural confirmation data are as follows:

[0261] IR(KBr,cm -1 )3730,3627,2952,1704,1578,1448,1330,1264,1238,1205,1161,1099,928,755,722; 1 HNMR (400MHz, CDCl3 ppm) δ8.12(t,J=7.0Hz,2H),7.96(d,J=7.6Hz,2H),7.50(s,1H),7.41(d,J=7.5Hz,2H),7.32-7.20(m,1H),4.78(s,2H). 13 C10 NMR (100MHz, CDCl3) 165.7, 138.0, 127.7, 126.7, 125.8, 124.4, 120.0, 116.2, 110.6, 45.0. MS (EI, 70eV) m / z 243, 180, 167, 152, 140. Identification data indicate that compound 27 was successfully prepared.

[0262] Example 28

[0263] Preparation of compound 28

[0264]

[0265] 0.1 mmol of 2-phenylthioaniline was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. Compound 28 was obtained by TLC, yielding 18.04 mg in 65.13%. The structure of compound 28 was analyzed, and the structural confirmation data are as follows:

[0266] IR(KBr,cm -1 )3323,3059,3012,2948,1689,1580,1524,1479,1440,1302,1231,1165,1025,918,763,745,693; 1H NMR (400MHz, CDCl3 ppm)δ9.46(s,1H),8.50(d,J=7.5Hz,1H),7.63(dd,J=7.7,1.6Hz,1H),7.47-7.41(m,1H),7.25-7.12(m,6H),4.04(s,2H).MS(EI,70eV)m / z 277,200,165,150,140. 13 C NMR (100MHz, CDCl3)164.0,138.9,136.7,135.4,131.0,129.4,127.7,126.6,125.3,121.5,120.8,43.2.

[0267] The identification data indicate that compound 28 was successfully prepared.

[0268] Example 29

[0269] Preparation of compound 29

[0270]

[0271] Using 2-methyldiphenylamine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (volume ratio 15:1) as the eluent to obtain 1-methylphenothiazine. 1-Methylphenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. 12.43 mg of compound 29 was obtained by TLC separation, with a yield of 43%. The structure of compound 29 was analyzed, and the structural confirmation data are as follows:

[0272] IR(KBr,cm -1 )3065,2962,2927,1687,1460,1337,1252,1182,1122,759,652; 1HNMR (400MHz, CDCl3 ppm)δ7.59(d,J=7.2Hz,1H),7.47-7.41(m,2H),7.34(dd,J=7.9,1.5Hz,1H),7.25(td, J=7.6,1.1Hz,1H),6.98(s,1H),6.88(dd,J=8.8,2.8Hz,1H),4.22(s,2H),3.80(s,3H). 13 C15H12NOSCl NMR (100MHz, CDCl3) δ 164.8, 138.5, 136.8, 133.1, 129.4, 128.6, 128.0, 127.6, 127.3, 126.1, 125.6, 41.7, 18.3. MS (EI, 70eV) m / z 289, 212, 180, 167, 152. HRMS (ESI) m / z [M+H]+ calcd for C15H12NOSCl 290.0401, found 290.0416. Identification data indicate that compound 29 was successfully prepared.

[0273] Example 30

[0274] Preparation of compound 30

[0275]

[0276] Aniline (0.1 mmol), 2-methoxyphenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 2-methoxy-N-phenylaniline. Using 2-methoxy-N-phenylaniline (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the crude product was extracted with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 1-methoxyphenothiazine. 0.1 mmol of 1-methoxyphenothiazine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 6.10 mg of compound 30 was obtained by TLC, with a yield of 21.01%. The structure of compound 30 was analyzed, and the structural confirmation data are as follows:

[0277] IR(KBr,cm -1 )3065,2960,2923,2851,1685,1605,1582,1493,1467,1442,1345,1250,1229,1176,1130,1062,1040,974,864,749; 1 HNMR (400MHz, CDCl3 ppm)δ7.61(d,J=7.5Hz,1H),7.53-7.44(m,2H),7.37(td,J=7.7,1.4Hz,1H),7.31-7.2 5(m,1H),7.01(d,J=2.7Hz,1H),6.90(dd,J=8.8,2.8Hz,1H),4.22(s,2H),3.84(s,3H). 13C15H12NO2SCl (100MHz, CDCl3) δ 165.7, 158.5, 138.3, 136.9, 130.7, 130.4, 128.1, 127.3, 126.6, 126.5, 113.7, 113.3, 112.8, 55.8, 41.9. MS (EI, 70eV) m / z 305, 229, 214, 199, 176. HRMS (ESI) m / z [M+H]+ calcd for C15H12NO2SCl 306.0350, found 306.0357. Identification data indicate that compound 30 was successfully prepared.

[0278] Example 31

[0279] Preparation of compound 31

[0280]

[0281] 0.1 mmol of 2-cyanophophorhizine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 26.46 mg of compound 31 was obtained by TLC, with a yield of 88.19%. The structure of compound 31 was analyzed, and the structural confirmation data are as follows:

[0282] IR(KBr,cm -1 )3068,2956,2232,1691,1597,1467,1409,1339,1256,1190,831,763,742,662,559; 1 HNMR (400MHz, CDCl3 ppm) δ7.95 (s, 1H), 7.62-7.25 (m, 6H), 4.41-4.02 (m, 2H). 13 C10 NMR (100MHz, CDCl3) 165.6, 138.2, 136.8, 132.2, 130.5, 130.4, 128.6, 128.3, 128.3, 126.1, 117.9, 110.8, 41.6. MS (EI, 70eV) m / z 300, 233, 199, 180, 167. Identification data indicate that compound 31 was successfully prepared.

[0283] Example 32

[0284] Preparation of compound 32

[0285]

[0286] 0.1 mmol of 2-chlorophenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 27.9 mg of compound 32 was obtained by TLC, with a yield of 90%. The structure of compound 32 was analyzed, and the structural confirmation data are as follows:

[0287] IR(KBr,cm -1 )2960,2929,2853,1693,1578,1457,1407,1339,1250,1168,1129,1095,815,759,739,661; 1 H NMR (400MHz, CDCl3 ppm) δ7.72-7.25(m,7H),4.41-4.15(m,2H). 13 C10 NMR (100MHz, CDCl3) 165.3, 138.9, 137.4, 133.1, 128.6, 128.4, 127.8, 127.7, 127.6, 127.1, 126.3, 41.8. MS (EI, 70eV) m / z 309, 232, 196, 188, 170. Identification data indicate that compound 32 was successfully prepared.

[0288] Example 33

[0289] Preparation of compound 33

[0290]

[0291] 0.1 mmol of 2-trifluoromethylphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 32.14 mg of compound 33 was obtained by TLC, with a yield of 93.7%. The structure of compound 33 was analyzed, and the structural confirmation data are as follows:

[0292] IR(KBr,cm -1 )3061,2963,2929,2853,1701,1609,1466,1421,1331,1241,1177,1121,1090,894,824,751; 1 H NMR (400MHz, CDCl3 ppm) δ7.95 (s, 1H), 7.62-7.46 (m, 4H), 7.38 (dtd, J = 30.2, 7.6, 1.2Hz, 2H), 4.32-4.10 (m, 2H). 13C NMR(100MHz, CDCl3)165.6,138.1,137.2,132.5,129.78,128.5,128.3,128.04,128.01,126.3,124.0,41.7.MS(EI,70eV)m / z343,266,247,234,222.

[0293] The identification data indicate that compound 33 was successfully prepared.

[0294] Example 34

[0295] Preparation of compound 34

[0296]

[0297] 0.1 mmol of 2-methylmercaptophenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 23.85 mg of compound 34 was obtained by TLC, with a yield of 74.3%. The structure of compound 34 was analyzed, and the structural confirmation data are as follows:

[0298] IR(KBr,cm -1 )3059,2923,1690,1458,1337,1250,1170,1100,1029,815,761,743,656,549; 1 H NMR (400MHz, CDCl3 ppm) δ7.61-7.45(m,2H),7.42-7.13(m,2H),4.21(s,1H),2.53(s,2H). 13 C10 NMR (100MHz, CDCl3) 165.5, 138.7, 138.5, 137.7, 128.2, 128.1, 127.5, 127.4, 125.6, 41.8, 41.0, 16.0. MS (EI, 70eV) m / z 321, 244, 199, 180, 167. Identification data indicate that compound 34 was successfully prepared.

[0299] Example 35

[0300] Preparation of compound 35

[0301]

[0302] 0.1 mmol of 2-methoxyphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 26.26 mg of compound 35 was obtained by TLC, with a yield of 86.1%. The structure of compound 35 was analyzed, and the structural confirmation data are as follows:

[0303] IR(KBr,cm -1 )2960,2924,2848,1687,1597,1474,1337,1261,1216,1129,1025,866,821,745,669; 1 H NMR (400MHz, CDCl3 ppm)δ7.58(d,J=7.8Hz,1H),7.46(d,J=7.7Hz,1H),7.34(t,J=7.4Hz,2H),7.29-7.22 (m,1H),7.20(d,J=2.1Hz,1H),6.85(dd,J=8.7,2.6Hz,1H),4.22(s,2H),3.83(s,3H). 13 C NMR (100MHz, CDCl3)165.5,159.3,139.1,137.9,128.6,128.2,127.4,127.2,126.5,114.1,112.2,55.8,42.0.MS(EI,70eV)m / z 305,229,214,199,176.

[0304] The identification data indicate that compound 35 was successfully prepared.

[0305] Example 36

[0306] Preparation of compound 36

[0307]

[0308] 0.1 mmol of 2-acetylphenothiazine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 24.50 mg of compound 36 was obtained by TLC, with a yield of 77.3%. The structure of compound 36 was analyzed, and the structural confirmation data are as follows:

[0309] IR(KBr,cm -1)3058,3008,2960,2924,1687,1592,1552,1463,1412,1337,1306,1264,1238,1160,1095,967,829,762,739,667; 1 H NMR (400MHz, CDCl3 ppm)δ8.20(s,1H),7.88(d,J=8.0Hz,1H),7.58(dd,J=21.0,7.9Hz,2H),7.49( d,J=7.6Hz,1H),7.37(dt,J=33.4,7.3Hz,2H),4.30-4.14(m,2H),2.64(s,3H). 13 C NMR (100MHz, CDCl3)196.5,165.6,137.9,137.3,136.2,128.3,128.0,127.9,127.0,126.6,126.4,41.7,26.7.MS(EI,70eV)m / z 317,240,199,180,167.

[0310] The identification data indicate that compound 36 was successfully prepared.

[0311] Example 37

[0312] Preparation of compound 37

[0313]

[0314] Using 3-methyldiphenylamine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 2-methylphenothiazine. 2-methylphenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. 24.10 mg of compound 37 was obtained by TLC separation, with a yield of 83.4%. The structure of compound 37 was analyzed, and the structural confirmation data are as follows:

[0315] IR(KBr,cm -1)3061,2954,2921,2855,1694,1588,1471,1343,1260,1203,1130,1060,1035,912,753; 1 H NMR (400MHz, CDCl3 ppm) δ7.66-7.10 (m, 7H), 4.23 (d, J = 13.1Hz, 2H), 2.45 (d, J = 20.6Hz, 3H). 13 C NMR (100MHz, CDCl3)165.5,138.1,138.0,137.9,137.4,128.6,128.4,128.2,127.9,127.4,127.3,126.9,42.2,21.2,20.1.MS(EI,70eV)m / z 289,212,197,180,167.C15 H12 NOS Cl HRMS(ESI)m / z[M+H]+calcd for C15H12NOSCl290.0401, found 290.0412.

[0316] The identification data indicate that compound 37 was successfully prepared.

[0317] Example 38

[0318] Preparation of compound 38

[0319]

[0320] 0.1 mmol of 2-propionylphenothiazine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the mixture was heated to 80 °C for 12 h. 23.21 mg of compound 38 was obtained by TLC, with a yield of 70.12%.

[0321] The structure of compound 38 was analyzed, and the structural confirmation data are as follows:

[0322] IR(KBr,cm -1 )3068,2973,2940,1691,1597,1465,1417,1341,1256,1209,1128,1066,802,763,740,656; 1H NMR (400MHz, CDCl3 ppm)δ8.21(s,1H),7.88(d,J=8.2Hz,1H),7.63-7.46(m,3H),7.36(dt,J=33.7,7. 5Hz,2H),4.29-4.14(m,2H),3.03(dq,J=13.9,7.1Hz,2H),1.25(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3)199.2,165.6,137.9,137.3,136.0,128.3,128.0,127.8,1 26.7,126.48,126.46,126.4,126.25,126.23,41.7,32.0,8.2.MS(EI,70eV)m / z 331,254,197,171,164.

[0323] The identification data indicate that compound 38 was successfully prepared.

[0324] Example 39

[0325] Preparation of compound 39

[0326]

[0327] 0.1 mmol of 2-ethylthiophenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 23.45 mg of compound 39 was obtained by TLC, with a yield of 70%. The structure of compound 39 was analyzed, and the structural confirmation data are as follows:

[0328] IR(KBr,cm -1 )3063,2977,2931,2867,1694,1578,1460,1339,1242,1174,1130,1104,813,757,740,662; 1 H NMR (400MHz, CDCl3 ppm)δ7.58(d,J=6.4Hz,2H),7.46(dd,J=7.7,1.3Hz,1H),7.39-7.34(m,2H),7.31- 7.20(m,2H),4.23(t,J=10.2Hz,2H),2.98(p,J=7.2Hz,2H),1.35(t,J=7.4Hz,3H). 13C NMR (100MHz, CDCl3) 165.5, 138.3, 137.7, 136.8, 128.2, 128.1, 127.7, 127.6, 127.4, 41.9, 27.8, 14.3. MS (EI, 70eV) m / z 355, 258, 2230, 185, 167.

[0329] The identification data indicate that compound 39 was successfully prepared.

[0330] Example 40

[0331] Preparation of compound 40

[0332]

[0333] Using 4-methyldiphenylamine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (volume ratio 15:1) as the eluent to obtain 3-methylphenothiazine. 3-methylphenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. 11.69 mg of compound 40 was obtained by TLC separation, with a yield of 40.45%. The structure of compound 40 was analyzed, and the structural confirmation data are as follows:

[0334] IR(KBr,cm -1 )3068,2950,1689,1586,1465,1339,1260,1200,1126,1033,817,786,755; 1 H NMR (400MHz, CDCl3 ppm) δ7.65-7.19(m,7H),4.24(s,2H),2.39(s,3H).MS(EI,70eV)m / z 289,212,180,167,152. 13C15H12NOSCl NMR (100MHz, CDCl3) 171.2, 165.6, 165.5, 138.1, 138.0, 137.9, 137.7, 137.4, 128.6, 128.3, 128.1, 127.8, 127.4, 127.3, 127.2, 126.8, 60.4, 42.0, 21.1, 20.0, 14.3. HRMS (ESI) m / z [M+H]+ calcd for C15H12NOSCl 290.0401, found 290.0408. Identification data indicate that compound 40 was successfully prepared.

[0335] Example 41

[0336] Preparation of compound 41

[0337]

[0338] Using 4-methoxydiphenylamine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 3-methoxyphenothiazine. 3-methoxyphenothiazine (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. 11.38 mg of compound 41 was obtained by TLC separation, with a yield of 37.3%. The structure of compound 41 was analyzed, and the structural confirmation data are as follows:

[0339] IR(KBr,cm -1 )2958,2923,2851,1681,1599,1491,1467,1337,1252,1225,1035,854,751; 1 H NMR (400MHz, CDCl3 ppm)δ7.59(d,J=7.2Hz,1H),7.45(dd,J=7.8,1.3Hz,2H),7.35(td,J=7.7,1.5Hz,1H),7.25(td, J=7.6,1.1Hz,1H),6.99(d,J=2.7Hz,1H),6.88(dd,J=8.8,2.8Hz,1H),4.22(s,2H),3.80(s,3H). 13C NMR (100MHz, CDCl3)165.7,158.4,138.3,136.9,130.6,128.3-127.9(m),127.3,113.7,113.3,112.8,55.7,42.0.MS(EI,70eV)m / z 305,229,214,199,176.HRMS(ESI)m / z[M+H]+calcd for C15H12NO2SCl306.0350, found 306.0355.

[0340] The identification data indicate that compound 41 was successfully prepared.

[0341] Example 42

[0342] Preparation of compound 42

[0343]

[0344] Using 2,4-dimethyldiphenylamine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (volume ratio 15:1) as the eluent to obtain 1,3-dimethylphenthiazide. 1,3-dimethylphenthiazide (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. Compound 42 was obtained by TLC separation, with a yield of 32% (9.70 mg). The structure of compound 42 was confirmed as follows:

[0345] IR(KBr,cm -1 )3061,2952,2919,2863,1689,1465,1345,1242,1172,1037,854,751,658,579; 1 H NMR (400MHz, CDCl3 ppm)δ7.65(s,1H),7.52(d,J=7.6Hz,1H),7.39-7.22(m,2H),7.12(d,J=37.9Hz,2H),4.22(dd,J=121.1,10.6Hz,2H),2.49(s,3H),2.33(s,3H). 13CNMR (100MHz, CDCl3) 164.9, 130.4, 128.59, 128.57, 127.8, 126.3, 126.0, 42.07, 42.0, 21.0, 21.0, 18.4. MS (EI, 70eV) m / z 303, 226, 210, 194, 180. HRMS (ESI) m / z [M+H]+ calcd for C16H14NOSCl 304.0557, found 304.0572. Identification data indicate that compound 42 was successfully prepared.

[0346] Example 43

[0347] Preparation of compound 43

[0348]

[0349] 3-Methylaniline (0.1 mmol), 3-fluorophenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 3-fluoro-N-(m-tolyl)aniline. Using 3-fluoro-N-(m-tolyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the crude product was extracted with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as eluent to obtain 2-fluoro,2'-methylphenthiazide. 0.1 mmol of 2-fluoro,2'-methylphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 12.44 mg of compound 43 was obtained by TLC, with a yield of 40.52%. The structure of compound 43 was analyzed, and the structural confirmation data are as follows:

[0350] IR(KBr,cm -1 )3063,2958,2921,2855,1689,1597,1467,1337,1264,1200,1134,1025,875,817,745,681; 1H NMR (400MHz, CDCl3 ppm) δ7.59-6.48 (m, 6H), 4.32-4.12 (m, 2H), 2.43 (d, J = 18.5Hz, 3H). 13 C NMR (100MHz, CDCl3)165.6,138.1,137.4,136.9,129.0,128.7,128.1,127.1,114.9,114.6,41.9,41.7,21.1,20.0.MS(EI,70eV)m / z 307,230,215,196,184.

[0351] The identification data indicate that compound 43 was successfully prepared.

[0352] Example 44

[0353] Preparation of compound 44

[0354]

[0355] 3-Methylaniline (0.1 mmol), 3-chlorophenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 3-chloro-N-(m-tolyl)aniline. Using 3-chloro-N-(m-tolyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL × 3) to obtain the crude product. The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as eluent to obtain 2-chloro,2'-methylphenthiazide. 0.1 mmol of 2-chloro,2'-methylphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 12.13 mg of compound 44 was obtained by TLC, with a yield of 37.67%. The structure of compound 44 was analyzed, and the structural confirmation data are as follows:

[0356] IR(KBr,cm -1)3068,2962,2925,2857,1694,1597,1446,1423,1335,1258,1211,1151,784,740; 1 H NMR (400MHz, CDCl3 ppm) δ.56-7.07(m,6H),4.22-4.12(m,2H),2.49-2.35(m,3H). 13 C NMR (100MHz, CDCl3) 165.9, 138.7, 138.3, 137.3, 132.2, 129.0, 128.9, 128.7, 128.1, 127.9, 127.5, 127.4, 127.3, 126.9, 41.8, 21.1. MS (EI, 70eV) m / z 323, 246, 210, 196, 184. HRMS (ESI) m / z [M+H]+ calcd for C15H11NOSCl2 324.0011, found 324.0016. Identification data indicate that compound 44 was successfully prepared.

[0357] Example 45

[0358] Preparation of compound 45

[0359]

[0360] 3-Methylaniline (0.1 mmol), 3-trifluoromethylphenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 3-trifluoromethyl-N-(m-tolyl)aniline. Using 3-trifluoromethyl-N-(m-tolyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL × 3) to obtain the crude product. The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as eluent to obtain 2-trifluoromethyl,2'-methylphenthiazide. 0.1 mmol of 2-trifluoromethyl,2'-methylphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 10.43 mg of compound 45 was obtained by TLC, with a yield of 29.22%. The structure of compound 45 was analyzed, and the structural confirmation data are as follows:

[0361] IR(KBr,cm -1 )2956,2925,2853,1687,1436,1324,1258,1176,1130,1097,811,745; 1 H NMR (400MHz, CDCl3 ppm) δ7.79(d,J=7.9Hz,1H),7.64(d,J=7.8Hz,1H),7.48-7.41(m,3H),7.15(d,J=8.9Hz,1H),4.29-4.16(m,2H),2.43(s,3H). 13 C16H11NOF3SCl (100MHz, CDCl3) 165.5, 139.5, 138.8, 138.0, 130.4, 129.1, 128.8, 128.3, 126.8, 126.6, 125.1, 125.0, 124.6, 121.9, 41.7, 21.1. MS (EI, 70eV) m / z 357, 338, 280, 248, 235. HRMS (ESI) m / z [M+H]+ calcd for C16H11NOF3SCl 358.0274, found 358.0274. Identification data indicate that compound 45 was successfully prepared.

[0362] Example 46

[0363] Preparation of compound 46

[0364]

[0365] Using di(m-tolyl)amine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (volume ratio 15:1) as the eluent to obtain 2,2'-dimethylphenthiazide. 2,2'-dimethylphenthiazide (0.1 mmol) was added to 2 mL of toluene and cooled to 0 °C. Then, chloroacetyl chloride (0.15 mmol) was added to the mixture, and the mixture was heated at 80 °C for 12 h. 12.57 mg of compound 46 was obtained by TLC separation, with a yield of 41.5%. The structure of compound 46 was analyzed, and the structural confirmation data are as follows:

[0366] IR(KBr,cm -1 )3063,2950,2921,2857,1691,1578,1465,1339,1266,1215,1143,1062,811,778,749; 1 H NMR (400MHz, CDCl3 ppm) δ7.49-7.10 (m, 6H), 4.23 (q, J = 14.0, 13.1Hz, 2H), 2.52-2.41 (m, 6H). 13 C NMR (100MHz, CDCl3)165.6,138.1,137.7,137.6,136.9,128.5,128.2,127.8,127.2,126.8,126 .7,124.0,42.0,21.12,20.0.MS(EI,70eV)m / z303261,226,210,194.HRMS(ESI)m / z[M+H]+calcd for C16H14NOSCl 304.0557,found304.0572.

[0367] The identification data indicate that compound 46 was successfully prepared.

[0368] Example 47

[0369] Preparation of compound 47

[0370]

[0371] Using di(p-tolyl)amine (0.1 mmol) as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, with 1,2-dichlorobenzene (2.0 mL) as the solvent. The reaction was carried out at 175 °C under nitrogen for 12 h. After the reaction was completed, 15.0 mL of water was added to the reaction mixture, and the crude product was obtained by extraction with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (volume ratio 15:1) as the eluent to obtain 3,3'-dimethylphenthiazide. 3,3'-dimethylphenthiazide (0.1 mmol) was added to 2 mL of toluene, cooled to 0 °C, and then chloroacetyl chloride (0.15 mmol) was added to the mixture. The mixture was heated at 80 °C for 12 h. 10.1 mg of compound 47 was obtained by TLC separation, with a yield of 33.3%. The structure of compound 47 was analyzed, and the structural confirmation data are as follows:

[0372] IR(KBr,cm -1 )2957,2926,2851,1687,1597,1477,1337,1252,1168,1132,1081,981,818,683,580; 1 H NMR (400MHz, CDCl3 ppm) δ7.47(d,J=7.8Hz,2H),7.28(s,2H),7.16(d,J=8.0Hz,2H),4.21(s,2H),2.38(s,6H). 13 C16H14NOSCl (100MHz, CDCl3) 165.6, 137.5, 135.6, 128.44, 128.0, 126.14, 126.09, 126.0, 41.9, 21.0. MS (EI, 70eV) m / z 303261, 226, 210, 194. HRMS (ESI) m / z [M+H]+ calcd for C16H14NOSCl 304.0557, found 304.0572. Identification data indicate that compound 47 was successfully prepared.

[0373] Example 48

[0374] Preparation of compound 48

[0375]

[0376] 2-Methoxyaniline (0.1 mmol), 3-methoxyphenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 2-methoxy-N-(3-methoxyphenyl)aniline. Using 2-methoxy-N-(3-methoxyphenyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the crude product was extracted with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 1,2'-dimethoxyphenothiazine. 0.1 mmol of 1,2'-dimethoxyphenothiazine was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 10.72 mg of compound 48 was obtained by TLC, with a yield of 32%. The structure of compound 48 was analyzed, and the structural confirmation data are as follows:

[0377] IR(KBr,cm -1 )3397,3190,2963,2923,2850,1698,1600,1474,1443,1348,1272,1224,1188,1157,1087,1039,966,871,809,779,714; 1 H NMR (400MHz, CDCl3 ppm) δ7.29(s,4H),7.12(d,J=7.9Hz,1H),6.92(d,J=8.2Hz,1H),4.35(d,J=12.5Hz,2H),3.95(s,3H),3.86(s,3H). 13C16H14NO3SCl (100MHz, CDCl3) 166.1, 159.1, 153.6, 139.8, 137.4, 128.5, 127.9, 120.9, 113.9, 113.2, 110.4, 55.7, 42.4. MS (EI, 70eV) m / z 335, 259, 244, 229, 176. HRMS (ESI) m / z [M+H]+ calcd for C16H14NO3SCl 336.0456, found 336.0472. Identification data indicate that compound 48 was successfully prepared.

[0378] Example 49

[0379] Preparation of compound 49

[0380]

[0381] 3-Methoxyaniline (0.1 mmol), 3-methoxyphenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 2-methoxy-N-(3-methoxyphenyl)aniline. Using 3-methoxy-N-(3-methoxyphenyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL × 3) to obtain the crude product. The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 2,2'-dimethoxyphenthiazide. 0.1 mmol of 2,2'-dimethoxyphenthiazide was added to 2 mL of toluene and cooled to 0°C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80°C for 12 h. 13.97 mg of compound 49 was obtained by TLC, with a yield of 41.7%. The structure of compound 49 was analyzed, and the structural confirmation data are as follows:

[0382] IR(KBr,cm -1 )3084,3010,2938,2834,1704,1597,1475,1442,1345,1273,1151,1048,864,773,718; 1H NMR (400MHz, CDCl3 ppm) δ7.04 (dd, J=141.9, 64.1Hz, 6H), 4.41-3.70 (m, 8H). 13 C16H14NO3SCl (100MHz, CDCl3) 166.2, 159.1, 139.7, 137.4, 128.5, 127.9, 120.8, 113.9, 113.2, 110.4, 56.2, 55.7, 42.4. MS (EI, 70eV) m / z 335, 259, 244, 229, 176. HRMS (ESI) m / z [M+H]+ calcd for C16H14NO3SCl 336.0456, found 336.0475. Identification data indicate that compound 49 was successfully prepared.

[0383] Example 50

[0384] Preparation of Compound 50

[0385]

[0386] 4-Methoxyaniline (0.1 mmol), 3-methoxyphenylboronic acid (0.3 mmol), copper acetate (20 mol%), potassium carbonate (0.1 mmol), and benzoic acid (0.05 mmol) were sequentially added to ethyl acetate (5.0 mL), and the mixture was reacted at 80 °C for 4 h. After the reaction was complete, water (15 mL) was added to the reaction mixture to extract the resulting mixture. The crude product was purified by thin-layer chromatography (TLC) to obtain 3-methoxy-N-(4-methoxyphenyl)aniline. Using 3-methoxy-N-(4-methoxyphenyl)aniline as a starting material, sulfur (0.2 mmol) and iodine (0.2 mmol) were added sequentially to the reaction mixture, and 1,2-dichlorobenzene (2.0 mL) was used as a solvent. The mixture was reacted at 175 °C under nitrogen for 12 h. After the reaction was complete, 15.0 mL of water was added to the reaction mixture, and the crude product was extracted with ethyl acetate (5.0 mL × 3). The crude product was purified by thin-layer chromatography (TLC) using a petroleum ether / ethyl acetate mixture (15:1 v / v) as the eluent to obtain 2,3'-dimethoxyphenthiazide. 0.1 mmol of 2,3'-dimethoxyphenthiazide was added to 2 mL of toluene and cooled to 0 °C. Then, 0.15 mmol of chloroacetyl chloride was added to the mixture, and the reaction was heated to 80 °C for 12 h. 5.77 mg of compound 50 was obtained by TLC, with a yield of 17.23%. The structure of compound 50 was analyzed, and the structural confirmation data are as follows:

[0387] IR(KBr,cm -1)3037,2997,2935,2834,1588,1502,1460,1271,1242,1180,1114,1035,829,759,588,518; 1 H NMR (400MHz, CDCl3 ppm) δ7.42-6.74 (m, 8H), 4.19 (d, J = 93.0Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H). 13 C16H14NO3SCl (100MHz, CDCl3) 155.4, 154.5, 142.0, 136.7, 128.9, 125.6, 123.1, 121.6, 114.1, 113.4, 56.0, 55.5. MS (EI, 70eV) m / z 335, 259, 244, 229, 176. HRMS (ESI) m / z [M+H]+ calcd for C16H14NO3SCl 336.0456, found 336.0474. Identification data indicate that compound 50 was successfully prepared.

[0388] Test Example 1

[0389] In vitro adult insecticidal activity test

[0390] (1) In vitro activity test against adult insects

[0391] Prepared RPMI-1640 culture medium was added to sterile 24-well plates, 2 mL per well. Then, 2 μL of each compound (1–50) was added to each well, with a final concentration of 0.1 mmol / L for each compound. The control group received 2 μL of DMSO. After adding the drugs, the plates were thoroughly mixed. Active adult Schistosoma japonicum collected at 45 days old were then placed in RPMI-1640 culture medium (10 schistosomes / 2 mL / well). The plates were then incubated at 37°C in a 5% CO2 incubator for 72 h. The viability of the schistosomes was observed using a stereomicroscope and an inverted microscope at specified time intervals after 24–72 h of incubation. Praziquantel served as the positive control group (2 μL of 100 μmol / mL praziquantel solution was added to 2 mL of culture medium to obtain a 100 μmol / L praziquantel solution); the negative control group received 2 μL of DMSO solvent in the culture medium; and the blank control group received no reagents added to the culture medium. The results are shown in Tables 1–4.

[0392] Table 1. In vitro anti-Schistosoma japonicum adult worm activity of compounds 1-11 at a concentration of 1100 μmol / L.

[0393]

[0394]

[0395] In Table 1, the blank control group consisted of culture medium only, the negative control group consisted of 2 μL LDMSO, and the positive control group consisted of 2 μL 100 μmol / L PZQ. The values ​​correspond to three independent experiments (n=3).

[0396] Table 2 shows the in vitro anti-Schistosoma japonicum adult activity of compounds 12–18 at a concentration of 100 μmol / L.

[0397]

[0398] In Table 2, the blank control group consisted of culture medium only, the negative control group consisted of 2 μL DMSO, and the positive control group consisted of 2 μL 100 μmol / LPZQ. The values ​​correspond to three independent experiments (n=3).

[0399] Table 3 shows the in vitro anti-Schistosoma japonicum adult activity of compounds 19–28 at a concentration of 100 μmol / L.

[0400]

[0401]

[0402] In Table 3, the blank control group consisted of culture medium only, the negative control group consisted of 2 μL LDMSO, and the positive control group consisted of 2 μL 100 μmol / L PZQ. The values ​​correspond to three independent experiments (n=3).

[0403] Table 4. In vitro anti-Schistosoma japonicum adult worm activity of compounds 29–50 at 100 μmol / L.

[0404]

[0405] In Table 4, the blank control group consisted of culture medium only, the negative control group consisted of 2 μL LDMSO, and the positive control group consisted of 2 μL 100 μmol / LPZQ. The values ​​correspond to three independent experiments (n=3).

[0406] Test Example 2

[0407] In vivo anti-schistosomiasis effect

[0408] Twenty-five mice infected with 60 cercariae were cultured for 9 / 35 days (the in vivo experiment was divided into administration during the juvenile stage and administration during the adult stage, with day 9 and day 35 corresponding to the administration time during the juvenile stage and the administration time during the adult stage, respectively). They were then divided into five groups (A, B, C, D, and E), with five mice in each group. Their body weight was measured, and compounds 35, 37, and 46 were weighed and dissolved in edible oil. They were then administered orally at a dose of 100 mg / kg for 5 consecutive days.

[0409] Mice in group A were administered compound 35 by gavage at a dose of 100 mg / kg; mice in group B were administered compound 37 by gavage at a dose of 100 mg / kg; mice in group C were administered compound 46 by gavage at a dose of 100 mg / kg; mice in group D were administered the corresponding volume of edible oil as a negative control group; and mice in group E were administered the same dose of praziquantel as a positive control group. The administration was repeated for 5 consecutive days. Mice were sacrificed on day 45 post-infection for autopsy to observe the worm-reducing effect and the pathological characteristics of the liver and spleen. The results are shown in Tables 5 and 6. Tables 5 and 6 show the anti-schistosomiasis effects of the compounds during the juvenile and adult stages in vivo.

[0410] Table 5. In vivo larval and egg-reducing effects of the compounds.

[0411]

[0412]

[0413] In Table 5, the negative control group 1 a : Corresponding to compound 35 and the positive control group (untreated control group); negative control group 2 b : The untreated control group corresponding to compound 37; the negative control group 3 c d represents the untreated control group corresponding to compound 46; d represents the praziquantel group corresponding to negative control group 1; e represents the group where no adult worms were found in mice, which is then recorded as the fully treated group; f represents the number of mice that died from the start of gavage to the time of dissection; g indicates that the corresponding average value was used in the calculation. Worm reduction rate = (average number of surviving worms in the negative control group - average number of surviving worms in the experimental group) / average number of surviving worms in the negative control group × 100%.

[0414] Table 6. In vivo insect and egg reduction effects of compounds during the adult stage.

[0415]

[0416] In Table 6, the negative control group 1 a : Corresponding to compound 35 and the positive control group (untreated control group); negative control group 2 b : The untreated control group corresponding to compound 37; the negative control group 3 c : The untreated control group corresponding to compound 46; d represents the fully treated group if no adult worms were found in mice; e represents the number of mice that died from the start of gavage to dissection; f indicates that the corresponding average value was used in the calculation. Worm reduction rate = (average number of surviving worms in the negative control group - average number of surviving worms in the experimental group) / average number of surviving worms in the negative control group × 100%.

[0417] As shown in Tables 5 and 6, compounds 35, 37 and 46 achieved insect reduction rates of 82.35%, 44% and 56% respectively during the juvenile stage, and 63.63%, 55.32% and 70.59% respectively during the adult stage, demonstrating high in vivo activity against adult insects.

[0418] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A covalent small molecule compound or a pharmaceutically acceptable salt thereof, said covalent small molecule compound having the structure shown in any one of Formulas I to IV: In the structures shown in Formulas I to IV, R1 is a group containing a carbonyl group, a carbon-carbon unsaturated bond, an ester group, an epoxy group, a cyano group, an alkyl group, a haloalkyl group, an aryl group, or a heteroaryl group; R2 and R3 are independently -H, halogen, alkyl, alkoxy, cyano, haloalkyl, thioalkyl, or alkylacyl; and R4 is sulfur, oxygen, -CH2-CH2-, or -CH=CH-.

2. The covalent small molecule compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, The carbonyl-containing group has any of the following structures:

3. The covalent small molecule compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, The group containing carbon-carbon unsaturated bonds is The ester-containing group is The epoxy-containing group is The cyano-containing group is The alkyl-containing group is The alkyl-containing group is The aryl-containing group is The heteroaryl group is 4. The covalent small molecule compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, In R2 and R3, the halogen is -F or -Cl, the alkyl group is -CH3, the alkoxy group is -OCH3, the haloalkyl group is -CF3, the thioalkyl group is -SCH3 or -SC2H5, and the alkylacyl group is -COCH3 or -COC2H5.

5. The covalent small molecule compound or its pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that, The covalent small molecule compound has any of the following structures:

6. The use of the covalent small molecule compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5 in the preparation of a medicament for treating schistosomiasis.

7. The application according to claim 6, characterized in that, The drug is used to kill both juvenile and adult schistosomes.

8. The application according to claim 7, characterized in that, The schistosomiasis mentioned includes Schistosoma japonicum.

9. A pharmaceutical composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is a covalent small molecule compound as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition comprises a covalent small molecule compound or a pharmaceutically acceptable salt thereof in a mass percentage of 0.05–99%; the dosage form of the pharmaceutical composition is tablets, granules, powders, solutions, emulsions, suspensions, syrups, injections, or capsules.

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