An indoline compound, a preparation method and application thereof

Abstract

The application discloses an indoline compound and a preparation method and application thereof, and belongs to the fields of medicinal chemistry and pharmacotherapy. The compound shown in the formula I, isomers or pharmaceutically acceptable salts thereof have good anti-HBV activity, can effectively inhibit the replication of HBV DNA, can be applied to the preparation of anti-HBV drugs, and have excellent potential application prospect.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and pharmacotherapeutic science, specifically to a class of indoline compounds. These compounds can be used to prepare drugs with anti-hepatitis B virus activity. This invention also relates to methods for preparing these compounds and drug combinations containing them. Background Technology

[0002] Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) and is a chronic carrier state.

[0003] Currently approved HBV treatments fall into two main categories: interferon-alpha (IFN-α) and nucleoside(s)ide analogues (NAs). Interferon-alpha has direct antiviral and immunomodulatory effects, providing a sustained virologic response (SVR) after discontinuation, but with a low response rate and numerous adverse reactions. Nucleoside(s) are derived from nucleosides through structural changes in bases or pentose rings, resulting in a series of drugs such as lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir. These drugs directly competitively inhibit HBV polymerase activity, blocking DNA replication. They are convenient to take orally with few side effects, but they are less effective against HBV covalently closed circular DNA (CCC) transcription template DNA. While it does not affect DNA, it cannot completely eliminate HBV, and relapse ("rebound phenomenon") is common after stopping medication. Furthermore, long-term use can lead to viral mutations and drug resistance. Therefore, the development of anti-HBV drugs with high response rates, low relapse rates, and resistance is urgently needed.

[0004] Since current clinical drugs cannot completely eliminate HBV, pharmaceutical researchers both domestically and internationally have been exploring the HBV life cycle and immunotherapy methods, discovering a series of novel antiviral drugs, including entry inhibitors MyrcludexB, ccc DNA synthesis inhibitors CCC-0975, viral transcription inhibitors ONIS-HBVRx (GSK3228836), capsid assembly inhibitors GLS4, hepatitis B surface antigen (HBsAg)-targeting drug REP2055, immune checkpoint inhibitors Nivolumab, and innate immune response Toll-like receptor 8 activator GS-9688, etc. It is hoped that this series of drugs can solve the "rebound" and drug resistance phenomena of existing anti-HBV drugs. Summary of the Invention

[0005] The purpose of this invention is to provide a class of indoline compounds based on existing technology. Pharmacological experiments have shown that these compounds have good anti-HBV activity.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned compound.

[0007] Another object of the present invention is to provide a use of the above-mentioned compound in medicine.

[0008] The technical solution of the present invention is as follows:

[0009] This invention relates to compounds with structures as shown in general formula I, isomers, including pharmaceutically acceptable salts thereof.

[0010]

[0011] in,

[0012] R 1 Represents phenyl, substituted phenyl, pyridine, substituted pyridine, pyrrole, piperidine, substituted piperidine, thiophene, substituted thiophene, furan, tetrahydrofuran, tetrahydropyran, cyclopentane, or cyclohexane;

[0013] The substituted phenyl, substituted pyridine, substituted piperidine, or substituted thiophene may be mono- or poly-substituted by the following substituents: halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, amino, cyano, or C1-C6 ester.

[0014] R 2 Represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, trifluoromethyl, cyano, or nitro;

[0015] R 3 Represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, trifluoromethyl, or trifluoromethoxy;

[0016] X represents -NH-, S atom, or O atom;

[0017] m represents an integer between 0 and 3;

[0018] n represents an integer between 0 and 3.

[0019] In a preferred embodiment, R 1 Represents a phenyl or substituted phenyl group, wherein the substituted phenyl group may be mono- or poly-substituted by the following substituents: fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or nitro.

[0020] In a more preferred embodiment, R 1Represents a phenyl or substituted phenyl group, wherein the substituted phenyl group may be mono- or poly-substituted by the following substituents: fluorine, chlorine, bromine, methyl, methoxy, or trifluoromethyl.

[0021] In a preferred embodiment, R 2 It represents hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano, or nitro.

[0022] In a more preferred embodiment, R 2 It represents hydrogen or methyl.

[0023] In a preferred embodiment, R 3 It represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, cyano, nitro, or trifluoromethyl.

[0024] In a more preferred embodiment, R 3 It represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, cyano, or nitro.

[0025] In a preferred embodiment, X represents either -NH- or O atoms.

[0026] In a more preferred embodiment, X represents an O atom.

[0027] In a preferred embodiment, m represents an integer from 1 to 2.

[0028] In a more preferred embodiment, m represents 1.

[0029] In a preferred embodiment, n represents an integer from 1 to 2.

[0030] In a more preferred embodiment, n represents 1.

[0031] In a particularly preferred embodiment, R 1 Represents a phenyl or substituted phenyl group, wherein the substituted phenyl group may be mono- or poly-substituted by the following substituents: fluorine, chlorine, bromine, methyl, methoxy, or trifluoromethyl; R 2 Represents hydrogen or methyl; R 3 Represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, cyano, or nitro; X ​​represents an O atom; m represents 1; n represents 1.

[0032] Furthermore, the compound of general formula I is preferably selected from the following compounds:

[0033] 2-(2-(2-fluorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I1);

[0034] 2-(2-(3-fluorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I2);

[0035] 2-(2-(4-fluorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I3);

[0036] 2-(2-(2-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I4);

[0037] 2-(2-(3-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I5);

[0038] 2-(2-(4-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I6);

[0039] 2-(2-(2-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I7);

[0040] 2-(2-(3-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I8);

[0041] 2-(2-(4-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I9);

[0042] 2-(2-(2-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 10 );

[0043] 2-(2-(3-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 11 );

[0044] 2-(2-(4-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 12 );

[0045] 2-(2-(2-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 13 );

[0046] 2-(2-(3-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 14 );

[0047] 2-(2-(4-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 15 );

[0048] 2-(2-(2-trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 16 );

[0049] 2-(2-(3-(trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 17 );

[0050] 2-(2-(4-trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 18 );

[0051] 1-(4-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 19 );

[0052] 1-(5-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 20 );

[0053] 1-(6-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 21 );

[0054] 1-(7-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 22 );

[0055] 1-(4-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 23 );

[0056] 1-(5-chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 24 );

[0057] 1-(6-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 25 );

[0058] 1-(7-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 26 );

[0059] 1-(4-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 27 );

[0060] 1-(5-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 28 );

[0061] 1-(6-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 29 );

[0062] 1-(7-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 30 );

[0063] 1-(2-Methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 31 );

[0064] 1-(4-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 32 );

[0065] 1-(5-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 33 );

[0066] 1-(6-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 34 );

[0067] 1-(7-Methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 35 );

[0068] 1-(4-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 36 );

[0069] 1-(5-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 37 );

[0070] 1-(6-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 38 );

[0071] 1-(7-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 39 );

[0072] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-4-carboxynitrile (I 40 );

[0073] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-5-carboxynitrile (I 41 );

[0074] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-6-carboxynitrile (I 42 );

[0075] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-7-carboxynitrile (I 43 );

[0076] 1-(5-nitroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 44 );

[0077] 1-(6-nitroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 45 ).

[0078] The structural formulas of the compounds mentioned above are shown below:

[0079]

[0080]

[0081] This invention discloses a method for preparing the compound of general formula I, wherein when X represents an O atom, m represents 1, and n represents 1, it includes the following steps:

[0082]

[0083] In a preferred embodiment, when X represents an O atom, m represents 1, and n represents 1, the method for preparing the compound of general formula I includes the following steps:

[0084]

[0085] The specific preparation method of the above synthetic route includes the following steps:

[0086] Bromoacetonitrile undergoes a nucleophilic substitution reaction with a hydroxyl derivative to generate intermediate 1. Intermediate 1 reacts with a thioacetamide ring to synthesize intermediate 2. Intermediate 2 undergoes a nucleophilic substitution reaction with methyl 4-chloroacetoacetate to generate intermediate 3. Intermediate 3 is hydrolyzed with NaOH to generate intermediate 4. Indole and its derivatives undergo a reduction reaction with sodium cyanoborohydride under acidic conditions to generate indoline and its derivatives. Intermediate 4 undergoes a nucleophilic substitution reaction with indoline and its derivatives to generate the target compound.

[0087] These intermediates or target compounds can be purified using conventional separation techniques and, if necessary, converted into addition salts with pharmaceutically acceptable acids.

[0088] The present invention also provides a pharmaceutical composition having the above-mentioned compounds, isomers, or pharmaceutically acceptable salts thereof as the active ingredient or main active ingredient, supplemented with pharmaceutically acceptable excipients. In this composition, in addition to the above-mentioned compounds, isomers, or pharmaceutically acceptable salts thereof, the active ingredient may also include other anti-HBV drugs or nucleoside anti-HBV drugs, such as lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir in combination, and may also be used in combination with interferon, etc.

[0089] Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below:

[0090] "Halogen" refers to fluorine, chlorine, and bromine, with fluorine or chlorine being preferred.

[0091] "Trifluoromethyl" represents the -CF3 group.

[0092] "Trifluoromethoxy" indicates the -OCF3 group.

[0093] "Hydroxy" represents the -OH group.

[0094] “Cyano” represents the -CN group.

[0095] "Nitro" represents the -NO2 group.

[0096] "Amino" indicates the -NH2 group.

[0097] "alkyl" refers to a saturated aliphatic hydrocarbon group with 1-20 carbon atoms, including straight-chain and branched groups (the numerical range mentioned in this application, such as "1-20", refers to the group, which is an alkyl group and can contain 1, 2, 3, etc., up to 20 carbon atoms). Alkyl groups containing 1-4 carbon atoms are called lower alkyl groups. When a lower alkyl group has no substituents, it is called an unsubstituted lower alkyl group. More preferably, the alkyl group is a medium-sized alkyl group with 1-10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. Preferably, the alkyl group is a lower alkyl group with 1-4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, etc. The alkyl group can be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably 1-3, and most preferably 1 or 2 substituents.

[0098] "Alkoxy" refers to -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0099] "Ester group" represents -C(O)O-alkyl group.

[0100] "Pharmaceutically acceptable salts" refer to those salts that retain the bioavailability and properties of the parent compound. These salts include:

[0101] (1) It forms salts with acids, which are obtained by reacting the free base of the parent compound with inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc. Organic acids include acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecyl sulfate, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid, etc.

[0102] (2) Salts formed by replacing acidic protons in the parent compound with metal ions or by coordinating with organic bases. Examples of metals include alkali metal ions, alkaline earth metal ions, or aluminum ions. Examples of organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, quinine, etc.

[0103] "Pharmaceutical composition" refers to the mixing of one or more of the compounds of this invention, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, with other chemical components, such as a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate the administration of the drug to animals.

[0104] The advantages of using the technical solution of this invention are as follows:

[0105] The indoline compounds provided by this invention exhibit good anti-HBV activity. Studies have found that these compounds not only possess good anti-HBV activity but also effectively inhibit HBV DNA replication. The indoline compounds, their isomers, or pharmaceutically acceptable salts provided by this invention can be used in the preparation of anti-HBV drugs, demonstrating excellent potential application prospects. Detailed Implementation

[0106] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention. They should not be construed as limiting the present invention.

[0107] Example 1

[0108] 2-(2-(2-fluorophenoxy)methyl)-4-yl)-1-(indoline-1-yl)acet-1-one (I1)

[0109] 2-Fluorophenol (4 g, 35.7 mmol) was dissolved in N,N-dimethylformamide, and then 1,4-dioxane (8 mL), potassium hydroxide (4.00 g, 71.4 mmol), potassium iodide (500 mg), bromoacetonitrile (12.4 mL, 178.5 mmol), and 200 μL of water were added. The mixture was stirred at 90 °C for 4 h, and the reaction was monitored by TLC. After the reaction was complete, water was added to stop the reaction. The mixture was allowed to cool naturally to room temperature and then extracted with ethyl acetate. The extract was washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain 2-fluorophenoxyacetonitrile. 2-Fluorophenoxyacetonitrile (4 g, 26.5 mmol) was dissolved in N,N-dimethylformamide, and then 1,4-dioxane (8 mL), thioacetamide (6.0 g, 79.5 mmol), and 4 mL of dilute hydrochloric acid (4 mol / L) were added. The mixture was stirred at 100 °C for 6 h.TLC monitoring was performed, followed by the addition of a large amount of water to stop the reaction. After natural cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to 8, causing solid precipitation. The filter cake obtained was 2-(2-fluorophenoxy)thioacetamide. 2-(2-fluorophenoxy)thioacetamide (2.5 g, 13.5 mmol) was dissolved in an appropriate amount of ethanol, and 8 mL of dioxane, 5.7 mL of triethylamine (40.5 mmol), 7.86 mL of 4-chloroacetoacetate (54 mmol), and 200 μL of water were added. The mixture was reacted at room temperature for half an hour, then gradually heated to 75 °C and stirred for 8 hours. TLC monitoring was performed, and the reaction was stopped by adding a large amount of water. After natural cooling to room temperature, the mixture was concentrated under reduced pressure to remove ethanol, and ethyl acetate was added for extraction. Take, wash successively with distilled water and saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain methyl 2-(4-(2-fluorophenoxy)methyl)-1,3-thiazolyl-2-yl)acetate; dissolve methyl 2-(4-(2-fluorophenoxy)methyl)-1,3-thiazolyl-2-yl)acetate (1.5 g, 5.3 mmol) in N,N-dimethylformamide, add in portions of sodium hydroxide solution (856 mg, 21.4 mmol), react at room temperature for 3 hours under TLC monitoring, stop the reaction by adding a large amount of water, cool naturally to room temperature, extract with ethyl acetate, wash successively with distilled water and saturated brine, adjust the pH of the aqueous layer to 2 with hydrochloric acid, extract again with ethyl acetate, and distill... Washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(4-(2-fluorophenoxy)methyl)-1,3-thiazolyl-2-yl)acetic acid; indole (0.35 g, 3 mmol) was dissolved in an appropriate amount of N,N-dimethylformamide, and glacial acetic acid (2 mL) was added under ice bath conditions, followed by the addition of sodium cyanoborohydride (0.94 g, 15 mmol) in portions. The temperature was gradually raised to 25 °C, and the mixture was stirred for 24 h. The reaction was monitored by TLC, and the reaction was stopped by adding a large amount of water. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution under ice bath conditions, and the mixture was extracted with ethyl acetate. Washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain indoline; 2-(4-fluorophenoxy)methyl)-1,3-thiazolyl-2-yl)acetic acid was dissolved in ... (4-Chlorophenoxy)methyl)-1,3-thiazolyl-2-yl)acetic acid (800 mg, 2.8 mmol) was dissolved in dichloromethane, and N-methylmorpholine (934 μL, 8.4 mmol) and indoline (1.35 mL, 8.4 mmol) were added. Isobutyl chloroformate (1.05 mL, 8.4 mmol) was slowly added dropwise under ice bath. After stirring for 4 h, the reaction was monitored by TLC. After the reaction was complete, a large amount of water was added to stop the reaction. Dichloromethane was added for extraction, and the mixture was washed successively with distilled water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the organic phase was concentrated under reduced pressure to obtain the crude target compound. The crude compound was obtained by silica gel column chromatography (dichloromethane: ethyl acetate = 300:1, V / V).

[0110] Yellow powder, yield 28%; mp 81.8-82.1℃. Analytical data for I1: 1 H NMR (400MHz, DMSO-d6) δppm: 8.05 (t, J=8.0Hz, 1H, Ar-H), 7.54 (d, J=8.0Hz, 1H, Ar-H), 7.30-7.21 (m, 3H, Ar-H), 7.14-7.08 (m, 2H, Ar -H),7.00-6.94(m,2H,Ar-H),5.46(s,2H,CH2),4.21-4.17(t,J=8.0Hz,2H,CH2),3.99(s,2H,CH2),3.15-3.11(t,J=8.0Hz,2H,CH2); 13 CNMR(100MHz,DMSO-d6)δppm:168.2,165.5,153.6(d, 1 J CF =242.9Hz), 150.3, 145.9 (d, 2 J CF =11.0Hz),143.5,132.4,127.5,125.4,125.3,123.9,122.7(d, 3 J CF =6.7Hz), 118.6, 116.9 (d, 2 J CF =17.2Hz),116.6,116.3,67.9,48.3,38.8,28.0; ESI-HRMS(TOF):m / z[M+Na] + calcdfor C 20 H 17 FN2NaO2S, 391.0887, found 391.0911; HPLC purity 97.6%.

[0111] Example 2

[0112] 2-(2-(3-fluorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I2)

[0113] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 3-fluorophenol, and the rest was the same as in Example 1.

[0114] White powder, yield 14%; mp 224.5-225.1℃. Analytical data for I2: 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7.32-7.26 (m, 1H, Ar-H), 7.21 (d, J=7.2Hz, 1H, Ar-H), 7.13-7.09 (t, J=8.0Hz, 1H, Ar-H), 6.98-6.92 (m, 2H, Ar-H),6.88(dd,J=8.4Hz,2.4Hz,1H,Ar-H),6.80(td,J=8.4Hz,2.0Hz,1H,Ar-H),5.39(s,2H ,CH2),4.20-4.16(t,J=8.8Hz,2H,CH2),3.97(s,2H,CH2),3.14-3.10(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.4,164.6(d, 1 J CF =222.1Hz), 159.6(d, 3 J CF =11.0Hz),150.3,143.4,132.4,131.4(d, 3 J CF =10.1Hz),127.5,125.4,123.9,118.6,116.5,111.8,108.7(d, 2 J CF =20.9Hz), 103.2(d, 2 J CF =25.0Hz),67.3,48.3,38.8,27.9; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 FN2NaO2S,391.0887,found 391.0861;HPLCpurity 96.7%

[0115] Example 3

[0116] 2-(2-(4-fluorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I3)

[0117] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 4-fluorophenol, and the rest was the same as in Example 1.

[0118] White powder, yield 25%; mp 110.8-111.2℃. Analytical data for I3: 1 H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.21 (d, J=7.2Hz, 1H, Ar-H), 7.12-7.02 (m, 5H, Ar-H), 6.9 8-6.94(t,J=7.6Hz,1H,Ar-H),5.34(s,2H,CH2),4.19-4.15(t,J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.13-3.09(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.9,158.6(d, 1 J CF =234.8Hz),1594.4,150.2,143.4,132.4,127.5,125.4,123.9,118.4,116. 9,116.8,116.6,116.5,116.4,67.6,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 FN2NaO2S,391.0887, found391.0882; HPLC purity 99.3%.

[0119] Example 4

[0120] 2-(2-(2-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I4)

[0121] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 2-chlorophenol, and the rest was the same as in Example 1.

[0122] Brown powder, yield 16%; mp 138.0-138.3℃. Analytical data for I4: 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7.4 3(d,J=8.0Hz,1H,Ar-H),7.28-7.24(m,2H,Ar-H),7.21(d,J=7.2Hz,1H,Ar-H),7 .12-7.09(t,J=7.6Hz,1H,Ar-H),6.98-6.94(m,2H,Ar-H),5.46(s,2H,CH2),4.1 9-4.15(t,J=8.0Hz,2H,CH2),3.96(s,2H,CH2),3.13-3.09(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.3,165.6,153.4,150.2,143.4,132.4,130.6,128.9,127.5, 125.4,123.9,123.0,122.1,118.5,116.5,115.1,67.9,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 20 H 17 ClN2NaO2S, 407.0591, found 407.0586; HPLC purity 99.1%.

[0123] Example 5

[0124] 2-(2-(3-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I5)

[0125] Similar to Example 1, except that 2-fluorophenol is replaced with 3-chlorophenol, and the rest is the same as in Example 1.

[0126] Yellow powder, yield 35%; mp 99.7-100.6℃. Analytical data for I5: 1H NMR (400MHz, CDCl3) δppm: 8.24 (d, J = 7.6Hz, 1H, Ar-H), 7.29 (s, 1H, Ar-H), 7.21-7.16 (m, 3H, Ar-H), 7.04-6.97 (m, 2H, Ar-H), 6.98 (d, J = 8.0Hz, 1H, Ar-H),6.89(dd,J=8.4Hz,2.4Hz,1H,Ar-H),5.31(s,2H,CH2),4.22-4.18(t,J=8.4Hz,2H,CH2),3.98(s,2H,CH2),3.22-3.18(t,J=8.4Hz,2H,CH2); 13 C NMR (100MHz, CDCl3) δppm:167.7,165.9,158.6,149.6,143.0,135.1,131.4,130.5,127.7,1 24.8,124.0,122.1,117.5,117.3,115.7,113.3,67.5,48.5,39.1,28.1; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 ClN2NaO2S,407.0591,found407.0565; HPLC purity 98.9%.

[0127] Example 6

[0128] 2-(2-(4-chlorophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I6)

[0129] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 4-chlorophenol, and the rest was the same as in Example 1.

[0130] Yellow powder, yield 16%; mp 110.8-111.2℃. Analytical data for I6:1H NMR (400MHz, CDCl3): δppm: 8.24 (d, J = 8.4Hz, 1H, Ar-H), 7.28-7.16 (m, 5H, Ar-H), 7.04-7.00 (t, J = 7.2Hz, 1H, Ar-H), 6.92 (d, J = 8.4Hz, 2H, Ar-H), 5.29 (s, 2H, CH2), 4.20-4.15 (t, J = 8.4Hz, 2H, CH2), 3.97 (s, 2H, CH2), 3.21-3.17 (t, J = 8.4Hz, 2H, CH2); 13C NMR (100MHz, CDCl3) δppm:167.7,166.2,156.5,149.5,142.9,131.4,129.6(2C),127.7,1 26.8,124.7,124.1,117.4,117.3,116.4(2C),67.6,48.5,39.1,28.1; ESI-HRMS(TOF):m / z + [M+Na] + calcdfor C 20 H 17 ClN2NaO2S, 407.0591, found 407.0561; HPLC purity 98.1%.

[0131] Example 7

[0132] 2-(2-(2-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I7)

[0133] The procedure was similar to that in Example 1, except that 2-fluorophenol was replaced with 2-bromophenol, and the rest was the same as in Example 1.

[0134] Brown powder, yield 16%; mp 140.0-140.3℃. Analytical data for I7: 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.59 (d, J=7.6Hz, 1H, Ar -H),7.52(s,1H,Ar-H),7.32-7.28(t,J=7.6Hz,1H,Ar-H),7.23-7.19(m,2H,Ar-H) ,7.12-7.09(t,J=7.2Hz,1H,Ar-H),6.98-6.89(m,2H,Ar-H),5.46(s,2H,CH2),4. 20-4.16(t,J=8.4Hz,2H,CH2),3.97(s,2H,CH2),3.14-3.10(t,J=7.6Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.3,165.7,154.3,150.1,143.4,133.7,132.4,129.6,127.5, 125.4,123.9,123.5,118.5,116.5,115.0,111.6,68.0,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 20 H 17 BrN2NaO2S, 451.0086, found 451.0078; HPLC purity 98.8%.

[0135] Example 8

[0136] 2-(2-(3-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I8)

[0137] The procedure was similar to that in Example 1, except that 2-fluorophenol was replaced with 3-bromophenol, and the rest was the same as in Example 1.

[0138] White powder, yield 15%; mp 103.0-103.8℃. Analytical data for I8: 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.28-7.20 (m, 3H, Ar-H), 7.15-7.09 (m, 2H, Ar-H), 7.05 (dd, J=8.0Hz, 2.5H z,1H,Ar-H),6.98-6.94(t,J=8.0Hz,1H,Ar-H),5.40(s,2H,CH2),4.21-4.1 6(t,J=8.8Hz,2H,CH2),3.97(s,2H,CH2),3.14-3.10(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.4,159.1,150.3,143,5,132.4,131.8,127.5,125.4,124 .9,123.9,122.7,118.6,118.4,116.5,115.0,67.3,48.3,38.8,28.0; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 BrN2NaO2S, 451.0086, found 451.0058; HPLC purity 95.2%.

[0139] Example 9

[0140] 2-(2-(4-bromophenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)acet-1-one (I9)

[0141] The procedure was similar to that in Example 1, except that 2-fluorophenol was replaced with 4-bromophenol, and the rest was the same as in Example 1.

[0142] Brown powder, yield 14%; mp 101.6-102.3℃. Analytical data for I9 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J = 8.0Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.43 (d, J = 8.8Hz, 2H, Ar-H), 7.21 (d, J = 7.2Hz, 1H, Ar-H), 7.12-7.09 (t, J=7.6Hz,1H,Ar-H),7.01-6.94(m,3H,Ar-H),5.36(s,2H,CH2),4.19-4.14(t,J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.13-3.09(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.6,157.4,150.2,143.4,132.8(2C),132.4,127.5, 125.4,123.9,118.5,117.8(2C),116.5,113.4,67.2,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 BrN2NaO2S, 451.0086, found 451.0073; HPLC purity 95.2%.

[0143] Example 10

[0144] 2-(2-(2-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 10 )

[0145] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 2-methylphenol, and the rest was the same as in Example 1.

[0146] Yellow powder, yield 19%; mp 111.5-112.0℃. Analytical data for I 10 : 1H NMR (400MHz, DMSO-d6) δppm: 8.03 (d, J=8.0Hz, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.21 (d, J=7 .6Hz,1H,Ar-H),7.15-7.09(m,3H,Ar-H),7.02-7.00(d,J=8.0Hz,1H,Ar-H),6.98-6.94( t,J=7.6Hz,1H,Ar-H),6.87-6.83(t,J=7.2Hz,1H,Ar-H),5.36(s,2H,CH2),4.20-4.15(t ,J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.13-3.09(t,J=8.0Hz,2H,CH2),2.18(s,3H,CH3); 13 C NMR (100MHz, DMSO-d6) δppm: 168.3, 166.9, 156.2, 150.1, 143.4, 132.4, 131.1, 127.5 (2C), 126. 5,125.4,123.9,121.7,118.0,116.5,112.5,67.4,48.3,38.9,28.0,16.5; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO2S,387.1138,, found 387.1148; HPLC purity 96.1%.

[0147] Example 11

[0148] 2-(2-(3-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 11 )

[0149] Similar to Example 1, except that 2-fluorophenol is replaced with 3-methylphenol, and the rest is the same as in Example 1.

[0150] Yellow crystals, yield 16%; mp 69.3-70.2℃. Analytical data for I 11 : 1H NMR (400MHz, CDCl3) δppm: 8.25 (d, J=8.0Hz, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.20-7.14 (m, 3H, Ar-H), 7.03-7.00 (t, J=7.6Hz, 1H, Ar-H), 6.81- 6.78(m,3H,Ar-H),5.31(s,2H,CH2),4.21-4.17(t,J=8.4Hz,2H,CH2),3.98(s,2H,CH2),3.21-3.17(t,J=8.4Hz,2H,CH2),2.32(s,3H,CH3); 13 C NMR (100MHz, CDCl3) δppm: 167.7, 167.1, 158.0, 149.4, 143.0, 139.8, 131.4, 129.4, 127.7, 124. 6,124.0,122.7,117.4,117.1,116.0,111.8,67.4,48.5,39.2,28.2,21.6; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO2S, 387.1138, found 387.1128; HPLC purity 97.6%.

[0151] Example 12

[0152] 2-(2-(4-methylphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 12 )

[0153] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 4-methylphenol, and the rest was the same as in Example 1.

[0154] White powder, yield 23%; mp 91.5-92.5℃. Analytical data for I 12 : 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.21 (d, J= 7.2Hz,1H,Ar-H),7.12-7.09(d,J=7.6Hz,1H,Ar-H),7.06(d,J=8.4Hz,2H,Ar-H),6.98-6 .94(t,J=7.6Hz,1H,Ar-H),6.91(d,J=8.4Hz,2H,Ar-H),5.30(s,2H,CH2),4.19-4.15(t, J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.13-3.09(t,J=8.4Hz,2H,CH2),2.18(s,3H,CH3); 13 CNMR(100MHz,DMSO-d6)δppm:168.3,166.4,156.0,150.1,143.4,132.4,130.7,130.4(2C),12 7.5.125.4,123.9,118.3,116.5,115.3(2C),67.1,48.3,38.8,27.9,20.6; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO2S, 387.1138, found 387.1136; HPLC purity95.4%.

[0155] Example 13

[0156] 2-(2-(2-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 13 )

[0157] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 2-methoxyphenol, and the rest was the same as in Example 1.

[0158] Yellow powder, yield 22%; mp 100.5-101.5℃. Analytical data for I 13 : 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.21 (d, J= 7.2Hz,1H,Ar-H),7.13-7.09(t,J=7.6Hz,1H,Ar-H),7.05(d,J=8.0Hz,1H,Ar-H),6.98- 6.90(m,3H,Ar-H),6.83-6.80(t,J=7.6Hz,1H,Ar-H),5.30(s,2H,CH2),4.19-4.15(t,J =8.4Hz,2H,CH2),3.95(s,2H,CH2),3.74(s,3H,CH3),3.13-3.09(t,J=8.0Hz,2H,CH2); 13 CNMR(100MHz,DMSO-d6)δppm:168.3,166.3,150.1,149.9,147.5,143.4,132.4,127.5,125.4,12 3.9,122.7,121.2,118.4,116.5,115.2,113.1,68.0,56.1,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO3S, 403.1087, found 403.1078; HPLC purity97.9%.

[0159] Example 14

[0160] 2-(2-(3-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 14 )

[0161] The same method was used as in Example 1, except that 2-fluoro was replaced with 3-methoxyphenol, and the rest was the same as in Example 1.

[0162] Yellow powder, yield 20%; mp 92.9-93.9℃. Analytical data for I 14 : 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7 .21-7.09(m,3H,Ar-H),6.98-6.94(t,J=7.2Hz,1H,Ar-H),6.60-6.59(m,2H,A r-H),6.53(d,J=8.4Hz,1H,Ar-H),5.34(s,2H,CH2),4.20-4.16(t,J=8.4Hz,2 H,CH2),3.96(s,2H,CH2),3.68(s,3H,CH3),3.14-3.09(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,166.1,161.0,159.3,150.1,143.4,132.4,130.6,127.5,125 .4,123.9,118.4,116.5,107.7,107.6,101.6,67.1,55.7,48.3,38.3,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 21 H 20 N2NaO3S, 403.1087, found 403.1077; HPLC purity 99.4%.

[0163] Example 15

[0164] 2-(2-(4-methoxyphenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)ethyl-1-one (I 15 )

[0165] The same method as in Example 1 was used, except that 2-fluorophenol was replaced with 4-methoxyphenol, and the rest was the same as in Example 1.

[0166] Brown powder, yield 15%; mp 76.7-77.6℃. Analytical data for I 15 : 1H NMR (400MHz, CDCl3) δppm: 8.25 (d, J=8.0Hz, 1H, Ar-H), 7.26-7.16 (m, 3H, Ar-H), 7.03-6.99 (t, J=7.2Hz, 1H, Ar-H), 6.93 (d, J=9.2Hz, 2H, Ar-H), 6. 83(d,J=9.2Hz,2H,Ar-H),5.27(s,2H,CH2),4.19-4.15(t,J=8.4Hz,2H,CH2),3.97(s,2H,CH2),3.75(s,3H,CH3),3.20-3.16(t,J=8.8Hz,2H,CH2); 13 C NMR (100MHz, CDCl3) δppm:167.8,167.2,154.6,152.1,149.3,143.0,131.4,127.7,124.7,12 4.0,117.3,117.1,116.2(2C),114.8(2C),68.2,55.8,48.5,39.2,28.1; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO3S,403.1087, found403.1063; HPLC purity 97.9%.

[0167] Example 16

[0168] 2-(2-(2-trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 16 )

[0169] Following a similar method to Example 1, 2-fluorophenol was replaced with 2-trifluoromethylphenol, and the rest was the same as in Example 1.

[0170] Yellow powder, yield 20%; mp 99.0-100.0℃. Analytical data for I 16 : 1H NMR (400MHz, DMSO-d6) δppm: 8.05 (d, J=8.0Hz, 1H, Ar-H), 7.69-7.58 (m, 2H, 2×Ar-H) ,7.55(s,1H,SCH),7.39(d,J=8.4Hz,1H,Ar-H),7.24(d,J=7.4Hz,1H,Ar-H),7.15(t d,J=7.7,2.9Hz,2H,2×Ar-H),6.99(tt,J=7.4,1.3Hz,1H,Ar-H),5.56(s,2H,CH2),4 .23-4.19(t,J=8.4Hz,2H,CH2),4.00(s,2H,CH2),3.17-3.13(t,J=8.4Hz,2H,CH2); 13 C NMR (100MHz, DMSO-d6) δppm:167.8,165.1,155.2,149.6,143.0,134.3,131.9,127.0,126.9(d, 3 J CF =5.00Hz), 125.1(d, 1 J CF =273.23Hz),124.9,123.4,121.3,118.0,117.5(d, 2 J CF =30.26Hz),116.0,114.2,67.4,47.8,38.3,27.4; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 21 H 17 F3N2NaO2S, 441.0855, found 441.0854; HPLC purity 96.3%.

[0171] Example 17

[0172] 2-(2-(3-(trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 17 )

[0173] Similar to Example 1, except that 2-fluorophenol is replaced with 3-fluoromethylphenol, and the rest is the same as in Example 1.

[0174] Brown powder, yield 16%; mp 109.5-111.4℃. Analytical data for I 17 : 1H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J=8.0Hz, 1H, Ar-H), 7.53-7.49 (m, 2H, A r-H),7.37-7.30(m,3H,Ar-H),7.21(d,J=7.2Hz,1H,Ar-H),7.13-7.09(t,J=8 .0Hz,1H,Ar-H),6.98-6.95(t,J=7.2Hz,1H,Ar-H),5.48(s,2H,CH2),4.21-4 .16(t,J=8.4Hz,2H,CH2),3.97(s,2H,CH2),3.14-3.10(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.2,158.4,150.3,143.5,132.4,131.4,131.1(d, 2 J CF =27Hz), 127.5, 125.8 (d, 1 J CF =270.7Hz),125.4,123.9,119.8,118.7,118.5,116.5,112.2,67.3,48.3,38.8,28.0; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 21 H 17 F3N2NaO2S, 441.0855, found 441.0835; HPLC purity 98.5%.

[0175] Example 18

[0176] 2-(2-(4-trifluoromethyl)phenoxy)methyl)thiazolyl-4-yl)-1-(indoline-1-yl)aceto-1-one (I 18 )

[0177] Following a similar method to Example 1, 2-fluorophenol was replaced with 4-trifluoromethylphenol, and the rest was the same as in Example 1.

[0178] Brown powder, yield 22%; mp 97.6-98.4℃. Analytical data for I 18 : 1H NMR (400MHz, DMSO-d6) δppm: 8.04(d,J=8.1Hz,1H,Ar-H),7.67(d,J=8.4Hz,2H,2×Ar-H),7.56(s,1H,SCH),7.25(d,J=8.4Hz,3H,3×Ar-H),7.12-7.16(t,J =7.6Hz,1H,Ar-H),7.02-6.98(t,J=7.4Hz,1H,Ar-H),5.51(s,2H,CH2),4.24 -4.19(t,J=8.4Hz,CH2),4.01(s,2H,CH2),3.17-3.13(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,165.2,160.9,150.3,143.4,132.4,127.6(2C),127.5, (2C),125.4,123.9,118.7,116.5,116.0(3C),67.2,48.3,38.8,27.9; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 17 F3N2NaO2S, 441.0855, found 441.0832; HPLC purity 96.6%.

[0179] Example 19

[0180] 1-(4-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 19 )

[0181] Phenol (3g, 31.2mmol) was dissolved in N,N-dimethylformamide, and then 1,4-dioxane (8mL), potassium hydroxide (2.5g, 62.4mmol), potassium iodide (500mg), bromoacetonitrile (10.8mL, 156mmol), and water (200μL) were added. The mixture was stirred at 90℃ for 4h, and the reaction was monitored by TLC.After the reaction was complete, water was added to stop the reaction. The mixture was allowed to cool naturally to room temperature and then extracted with ethyl acetate. The extract was washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain phenoxyacetonitrile. Phenoxyacetonitrile (2 mL, 16.2 mmol) was dissolved in N,N-dimethylformamide, and then dioxane (8 mL), thioacetamide (3.65 g, 48.6 mmol), and 4 mL (4 mol / L) dilute hydrochloric acid were added. The mixture was stirred at 100 °C for 6 h, monitored by TLC, and then a large amount of water was added to stop the reaction. The mixture was allowed to cool naturally to room temperature. After adding the saturated sodium bicarbonate solution at room temperature, the pH was adjusted to 8, and a solid precipitated. The filter cake obtained by filtration was 4-chlorophenoxythioacetamide. Phenoxythioacetamide (4 g, 31.6 mmol) was dissolved in an appropriate amount of ethanol, and 8 mL of dioxane, 13.2 mL of triethylamine (94.8 mmol), methyl 4-chloroacetoacetate (13.8 mL, 94.8 mmol), and 200 μL of water were added. The reaction was carried out at room temperature for half an hour, then gradually heated to 75 °C and stirred for 8 hours. TLC monitoring was performed, and the reaction was stopped by adding a large amount of water. The mixture was then allowed to cool naturally to room temperature. Ethanol was removed by concentration under reduced pressure, followed by extraction with ethyl acetate. The mixture was washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain methyl 2-(4-(4-phenoxy)methyl)-1,3-thiazolyl-2-yl)acetate. 3 g (12 mmol) of methyl 2-(4-(4-phenoxy)methyl)-1,3-thiazolyl-2-yl)acetate was dissolved in N,N-dimethylformamide, and sodium hydroxide solution (1.92 g, 48 mmol) was added in portions. The reaction was carried out at room temperature for 3 hours under TLC monitoring. A large amount of water was then added. The reaction was stopped, and the mixture was allowed to cool naturally to room temperature. It was then extracted with ethyl acetate, washed successively with distilled water and saturated brine. The aqueous layer was adjusted to pH 2 with hydrochloric acid, and extracted again with ethyl acetate. The mixture was washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under reduced pressure to obtain 2-(4-(4-phenoxy)methyl)-1,3-thiazol-2-yl)acetic acid. 2-(4-(4-phenoxy)methyl)-1,3-thiazol-2-yl)acetic acid (800 mg, 3.2 mmol) was dissolved in dichloromethane, and then N-methylmorpholine (1.06 mg) was added. 2-Methylindoline (1.25 mL, 9.6 mmol) was added dropwise with isobutyl chloroformate (1.21 mL, 9.6 mmol) under ice bath. After stirring for 4 h, the reaction was monitored by TLC. After the reaction was complete, a large amount of water was added to stop the reaction. Dichloromethane was added for extraction. The mixture was washed successively with distilled water and saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound I. 19 The crude product was subjected to silica gel column chromatography (dichloromethane:ethyl acetate = 300:1, V / V) to give the title compound I. 19 .

[0182] White powder, yield 20%; mp 106.7-107.5℃. Analytical data for I 19 : 1 H NMR (400MHz, DMSO-d6) δppm: 7.85 (d, J=8.0Hz, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7.2 9-7.25(m,2H,Ar-H),7.20-7.15(m,1H,Ar-H),7.03-7.01(m,2H,Ar-H),6.96-6.9 3(t,J=7.2Hz,1H,Ar-H),6.84-6.79(t,J=8.8Hz,1H,Ar-H),5.36(s,2H,CH2),4.2 7-4.23(t,J=8.0Hz,2H,CH2),3.98(s,2H,CH2),3.16-3.12(t,J=8.0Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.5,166.2,160.2(d, 1 J CF =241.5Hz),158.1,149.9,146.1(d, 3 J CF =8.6Hz), 130.1(2C), 130.0(d, 3 J CF =8.0Hz),122.0,118.5,118.3,115.4(2C),112.7,110.7(d, 2 J CF =20.1Hz),67.0,48.9,38.8,24.2; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 FN2NaO2S, 391.0887, found391.0863; HPLC purity 95.8%.

[0183] Example 20

[0184] 1-(5-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 20 )

[0185] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-fluoroindoline, and the rest was the same as in Example 19.

[0186] Yellow powder, yield 17%; mp 103.2-104.0℃. Analytical data for I 20 : 1 H NMR (400MHz, DMSO-d6) δppm: 8.03 (dd, J=8.8Hz, 4.8Hz, 1H, Ar-H), 7.29 (s, 1H, Ar-H), 7.29-7.25 (m, 2H, Ar-H), 7.07-7.00 (m, 3H, Ar- H),6.96-6.90(m,2H,Ar-H),5.35(s,2H,CH2),4.22-4.18(t,J=8.0Hz,2H,CH2),3.96(s,2H,CH2),3.14-3.09(t,J=8.0Hz,2H,CH2); 13 CNMR(100MHz,DMSO-d6)δppm:168.1,166.2,160.1(d, 1 J CF =238.2Hz),158.1,150.1,139.9,135.0,130.1(2C),122.0,118.4,117.3(d, 3 J CF =8.1Hz), 115.4(2C), 113.7(d, 2 J CF =22.5Hz), 112.0(d, 2 J CF =23.9Hz),67.0,48.7,38.6,28.0; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 FN2NaO2S, 391.0887, found 391.0894; HPLC purity 98.7%.

[0187] Example 21

[0188] 1-(6-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 21 )

[0189] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-fluoroindoline, and the rest was the same as in Example 19.

[0190] White powder, yield 18%; mp 84.6-85.1℃. Analytical data for I 21 : 1H NMR (400MHz, DMSO-d6) δppm: 7.78 (dd, J=11.2Hz, 2.4Hz, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7. 29-7.25(m,2H,Ar-H),7.22-7.19(t,J=8.0Hz,1H,Ar-H),7.02(d,J=8.0Hz,2H,Ar-H),6. 96-6.92(t,J=7.2Hz,1H,Ar-H),6.81-6.76(td,J=8.8Hz,2.4Hz,1H,Ar-H),5.35(s,2H,C H2),4.26-4.21(t,J=8.8Hz,2H,CH2),3.98(s,2H,CH2),3.11-3.07(t,J=8.4Hz,2H,CH2); 13 CNMR(100MHz,DMSO-d6)δppm:168.8,166.2,162.9(d, 1 J CF =237.2Hz),158.1,149.8,144.8(d, 3 J CF =12.5Hz),130.1(2C),128.2,126.2(d, 3 J CF =9.9Hz),122.0,118.5,115.4(2C),110.1(d, 2 J CF =22.3Hz), 104.3(d, 2 J CF =28.9Hz),67.0,49.2,38.6,27.3; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 FN2NaO2S, 391.0887, found 391.0862; HPLC purity 99.8%.

[0191] Example 22

[0192] 1-(7-fluoroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 22 )

[0193] Following a similar method to Example 19, 4-fluoroindoline was replaced with 7-fluoroindoline, and the rest was the same as in Example 19.

[0194] White powder, yield 15%; mp 72.9-73.6℃. Analytical data for I 22 : 1 H NMR (400MHz, DMSO-d6) δppm: 7.49 (s, 1H, Ar-H), 7.29-7.25 (m, 2H, Ar-H), 7.10-6.98 (m, 5H, Ar-H), 6.96-6.93 (t, J = 8.0 Hz,1H,Ar-H),5.35(s,2H,CH2),4.18-4.14(t,J=8.0Hz,2H,CH2),4.00(s,2H,CH2),3.08-3.04((t,J=8.0Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:167.8,166.2,158.1,152.70(d, 1 J CF =233Hz),150.2,138.5,130.2(2C),129.5(d, 3 J CF =11Hz), 126.5(d, 3 J CF =7Hz),122.0,121.3,118.4,115.8(d, 2 J CF =20Hz),115.4(2C),67.0,50.8,38.2,29.8; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 FN2NaO2S,391.0887, found391.0890; HPLC purity 97.0%.

[0195] Example 23

[0196] 1-(4-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 23 )

[0197] Following a similar method to Example 19, 4-fluoroindoline was replaced with 4-chloroindoline, and the rest was the same as in Example 20.

[0198] Yellow powder, yield 24%; mp 103.5-104.5℃. Analytical data for I 23 : 1H NMR (400MHz, DMSO-d6) δppm: 7.97 (d, J=8.0Hz, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7.29-7.25 (t, J=8.0Hz, 2H, Ar-H), 7.19-7.15 (t, J=8.0Hz, 1H, Ar-H), 7.05-7. 01(m,3H,Ar-H),6.96-6.93(t,J=8.0Hz,1H,Ar-H),5.36(s,2H,CH2),4.26-4 .22(t,J=8.0Hz,2H,CH2),3.98(s,2H,CH2),3.15-3.11(t,J=8.0Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.7,166.2,158.1,149.9,145.0,130.7,130.1(2C),130.0,129 .7,123.5,122.0,118.5,115.4(2C),115.1,67.0,48.2,38.7,27.5; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 ClN2NaO2S, 407.0591, found 407.0580; HPLC purity 95.4%.

[0199] Example 24

[0200] 1-(5-chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 24 )

[0201] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-chloroindoline, and the rest was the same as in Example 19.

[0202] Brown powder, yield 22%; mp 120.7-121.7℃. Analytical data for I 24 : 1H NMR (400MHz, DMSO-d6) δppm: 8.00 (d, J=8.0Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.29-7.25(m,3H,Ar-H),7.18-7.16(d,J=8.0Hz,2H,Ar-H),7.03-7.01(d,J=8 .0Hz,2H,Ar-H),6.97-6.93(t,J=8.0Hz,1H,Ar-H),5.36(s,2H,CH2),4.23-4 .19(t,J=8.0Hz,2H,CH2),3.97(s,2H,CH2),3.15-3.11(t,J=8.0Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.5,166.2,158.1,150.0,142.5,135.1,130.2(2C),127.4,127 .3,125.4,122.0,118.4,117.5,115.4(2C),67.0,48.6,38.6,27.8; ESI-HRMS(TOF):m / z[M+H] + calcd for C 20 H 17 ClN2O2S, 385.0772, found 385.0759; HPLC purity 97.3%.

[0203] Example 25

[0204] 1-(6-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 25 )

[0205] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-chloroindoline, and the rest was the same as in Example 19.

[0206] Yellow powder, yield 30%; mp 117.2-118.0℃. Analytical data for I 25 : 1 H NMR (400MHz, CDCl3) δppm: 8.27 (s, 1H, Ar-H), 7.80-7.25 (m, 3H, Ar-H), 7.06-6.95 (m, 5H, Ar-H), 5.3 2(s,2H,CH2),4.21-4.17(t,J=8.4Hz,2H,CH2),3.95(s,2H,CH2),3.15-3.11(t,J=8.4Hz,2H,CH2); 13C NMR (100MHz, CDCl3) δppm:168.0,167.0,157.9,149.0,144.0,133.1,129.8,129.7(2C),1 25.2,123.9,121.8,117.6,117.3,115.0(2C),67.3,49.0,39.0,27.7; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 ClN2NaO2S, 407.0591, found 407.0592; HPLC purity 95.9%.

[0207] Example 26

[0208] 1-(7-Chloroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 26 )

[0209] Following a similar method to Example 19, 4-fluoroindoline was replaced with 7-chloroindoline, and the rest was the same as in Example 19.

[0210] Yellow oil, yield 16%; mp 153.9-155.1℃. Analytical data for I 26 : 1 H NMR (400MHz, CDCl3) δppm: 7.31-7.23 (m, 3H, Ar-H), 7.22-7.20 (d, J=7.6Hz, 1H, Ar-H), 7.13 (d, J=7.6Hz, 2H, Ar-H), 7.04 (d, J=7.2Hz, 1H, Ar-H), 7.00 -6.96(m,3H,Ar-H),7.01-6.94(m,3H,Ar-H),5.30(s,2H,CH2),4.26-4.22(t,J=7.2Hz,2H,CH2),4.09(s,2H,CH2),3.03-3.00(t,J=7.6Hz,2H,CH2); 13 C NMR (100MHz, CDCl3) δppm:168.8,167.7,157.9,149.7,140.3,137.9,129.7(2C),129.1,1 26.4,124.5,123.1,121.8,117.1,115.0(2C),67.3,51.7,38.8,30.4; ESI-HRMS(TOF):m / z + [M+Na] +calcd for C 20 H 17 ClN2NaO2S, 407.0591, found 407.0564; HPLC purity 96.1%.

[0211] Example 27

[0212] 1-(4-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 27 )

[0213] Following a similar method to Example 19, 4-fluoroindoline was replaced with 4-bromoindoline, and the rest was the same as in Example 19.

[0214] Yellow powder, yield 11%; mp 94.6-95.3℃. Analytical data for I 27 : 1 H NMR (400MHz, DMSO-d6) δppm: 8.01 (d, J=8.0Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.28-7 .24(m,2H,Ar-H),7.18(d,J=8.0Hz,1H,Ar-H),7.11-7.01(t,J=8.0Hz,1H,Ar-H),7.0 2-7.00(d,J=8.4Hz,2H,Ar-H),6.96-6.92(t,J=8.0Hz,1H,Ar-H),5.35(s,2H,CH2), 4.25-4.21(t,J=8.4Hz,2H,CH2),3.97(s,2H,CH2),3.10-3.06(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.7,166.2,158.1,149.9,144.7,132.8,130.1(2C),129.9, 126.4,122.0,119.3,119.4,115.5,115.4(2C),67.0,47.8,38.7,29.6; ESI-HRMS(TOF):m / z + [M+Na] + calcdfor C 20 H 17 BrN2NaO2S, 451.0086, found 451.0056; HPLC purity 97.7%.

[0215] Example 28

[0216] 1-(5-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 28 )

[0217] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-bromoindoline, and the rest was the same as in Example 19.

[0218] White powder, yield 13%; mp 70.5-71.3℃. Analytical data for I 28 : 1 H NMR(400MHz,DMSO-d6)δppm:7.94(d,J=8.8Hz,1H,Ar-H),7.49(s,1H,Ar-H),7.40(s,1H,Ar-H),7.30-7.25(m,3H,Ar-H),7.02-7.00(d,J=8.4Hz,2 H,Ar-H),6.96-6.92(t,J=7.2Hz,1H,Ar-H),5.35(s,2H,CH2),4.21-4.17(t,J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.15-3.11(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.5,166.2,158.1,149.9,142.9,135.5,130.2,130.1(2C), 128.3,122.0,118.4,118.0,115.4(2C),115.3,67.0,48.5,38.6,27.7; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 BrN2NaO2S, 451.0086, found 451.0060; HPLC purity 95.0%.

[0219] Example 29

[0220] 1-(6-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 29 )

[0221] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-bromoindoline, and the rest was the same as in Example 19.

[0222] Yellow powder, yield 16%; mp 107.3-107.8℃. Analytical data for I 29 : 1 H NMR(400MHz,DMSO-d6)δppm:8.17(s,1H,Ar-H),7.51(s,1H,Ar-H),7.29-7.25(m,2H,Ar-H),7.18-7.13(m,2H,Ar-H),7.02-7.00(d,J=8.0Hz,2H, Ar-H),6.96-6.92(d,J=8.0Hz,1H,Ar-H),5.35(s,2H,CH2),4.23-4.18(t,J=8.4Hz,2H,CH2),3.98(s,2H,CH2),3.10-3.06(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.9,166.2,158.1,149.8,145.0,132.1,130.1(2C),127.1,126 .4,122.0,119.9,119.0,118.5,115.4(2C),113.2,67.0,48.8,38.7,27.6; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 20 H 17 BrN2NaO2S,451.0086, found451.0094; HPLC purity 96.7%.

[0223] Example 30

[0224] 1-(7-bromoindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 30 )

[0225] Following a similar method to Example 19, 4-fluoroindoline was replaced with 7-bromoindoline, and the rest was the same as in Example 19.

[0226] Yellow oil, yield 31%; Analytical data for I 30 : 1H NMR (400MHz, DMSO-d6) δppm: 7.40 (s, 1H, Ar-H), 7.36 (d, J = 8.0Hz, 1H, Ar-H), 7.29-7.25 (m, 3H, Ar-H), 7.03-6.93 (m ,4H,Ar-H),5.36(s,2H,CH2),4.18-4.14(t,J=8.0Hz,2H,CH2),4.03(s,2H,CH2),3.05-3.01(t,J=8.0Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.4,166.3,158.1,150.3,142.7,139.1,131.8,130.1(2C),127 .0,124.4,122.0,118.2,115.4(2C),113.2,67.0,51.6,38.8,30.7; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 20 H 17 BrN2NaO2S, 451.0086, found 451.0057; HPLC purity 96.4%.

[0227] Example 31

[0228] 1-(2-Methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 31 )

[0229] Following a similar method to Example 19, 4-fluoroindoline was replaced with 2-methylindoline, and the rest was the same as in Example 19.

[0230] Brown oily substance, yield 29%; Analytical data for I 31 : 1 H NMR (400MHz, DMSO-d6) δppm: 8.00 (d, J=8.1Hz, 1H, Ar-H), 7.55 (s, 1H, SCH), 7.32-7.26 (m, 3H, Ar-H), 7.18-7.14 (t, J=7.7Hz, 1H, Ar-H), 7.06-6.96 (m, 4H, Ar-H), 5.39 (s, 2H, CH2), 4.15-3.95 (q, J = 15.8Hz, 1H, CH2), 3.40 (s, 1H, CH2),3.37(s,1H,CH2),2.68(d,J=15.9Hz,1H,CH),1.37-1.28(m,3H,CH3); 13C NMR(100MHz,Chloroform-d)δpmm:167.5,166.8,158.0,149.8,141.6,130.7,129.7(2C),127.6, 125.1,124.3,121.8,118.3,117.2,115.0(2C),67.4,56.1,38.2,36.6,22.1; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO2S, 387.1138, found 387.1133; HPLC purity 98.2%.

[0231] Example 32

[0232] 1-(4-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 32 )

[0233] The same method was used as in Example 19, except that 4-fluoroindoline was replaced with 4-methylindoline, and the rest was the same as in Example 19.

[0234] White powder, yield 13%; mp 107.5-108.1℃. Analytical data for I 32 : 1 H NMR(400MHz,DMSO-d6)δppm:8.02(d,J=8.0Hz,1H,Ar-H),7.50(s,1H,Ar-H),7.21-7.09(m,3H,Ar-H),6.98(d,J=7.2Hz,1H,Ar-H),6.60-6 .51(m,3H,Ar-H),5.34(s,2H,CH2),4.20-4.16(t,J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.68(s,3H,CH3),3.14-3.09(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,166.2,158.1,150.2,143.1,134.3,131.1,130.1(2C),127 .6,124.8,121.9,118.3,115.4(2C),114.0,67.0,48.2,38.8,26.8,18.8; ESI-HRMS(TOF):m / z + [M+Na]+ calcd for C 21 H 20 N2NaO2S, 387.1138, found 387.1128; HPLC purity 97.2%.

[0235] Example 33

[0236] 1-(5-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 33 )

[0237] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-methylindoline, and the rest was the same as in Example 19.

[0238] Yellow powder, yield 12%; mp 95.9-96.9℃. Analytical data for I 33 : 1 H NMR (400MHz, CDCl3) δppm: 8.12 (d, J=8.4Hz, 1H, Ar-H), 7.31-7.27 (m, 3H, Ar-H), 7.00-6.98 (m, 5H, Ar-H), 5.33 (s ,2H,CH2),4.19-4.15(t,J=8.4Hz,2H,CH2),3.97(s,2H,CH2),3.17-3.13(t,J=8.4Hz,2H,CH2),2.29(s,3H,CH3); 13 C NMR (100MHz, CDCl3) δppm: 167.4, 166.9, 157.9, 149.5, 140.6, 133.7, 131.5, 129.7 (2C), 128. 1,125.3,121.8,117.1,117.0,115.0(2C),67.3,48.6,39.1,28.1,21.1; ESI-HRMS(TOF):m / z + [M+H] + calcd for C 21 H 20 N2O2S, 365.1318, found 365.1296; HPLC purity 98.8%.

[0239] Example 34

[0240] 1-(6-methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 34 )

[0241] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-methylindoline, and the rest was the same as in Example 19.

[0242] Yellow powder, yield 19%; mp 132.8-133.5℃. Analytical data for I 34 : 1 H NMR (400MHz, DMSO-d6) δppm: 7.91 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.33-7.28 (m, 2H, Ar-H), 7.12-6.95 (m, 4H, Ar-H), 6.83-6.69 (t, J=8. 0Hz,1H,Ar-H),5.39(s,2H,CH2),4.22-4.18(t,J=8.0Hz,2H,CH2),3.99(s,2H,CH2),3.11-3.07(t,J=8.0Hz,2H,CH2),2.25(s,3H,CH3); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,166.2,158.1,150.2,143.6,136.6,130.2(2C),129.4,125.0, 124.5,122.0,118.3,117.3,115.4(2C),67.0,48.7,38.3,27.6,21.9; ESI-HRMS(TOF):m / z[M+Na] + calcd for C 21 H 20 N2NaO2S, 387.1138, found 387.1117; HPLC purity 95.2%.

[0243] Example 35

[0244] 1-(7-Methylindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 35 )

[0245] Following a similar method to Example 19, 4-fluoroindoline was replaced with 7-methylindoline, and the rest was the same as in Example 19.

[0246] Brown oily substance, yield 28%; Analytical data for I 35 : 1H NMR (400MHz, CDCl3) δppm:7.31-7.26(m,3H,Ar-H),7.04-6.97(m,1H,Ar-H),5.33(s,2H,CH2),4.2 0-4.16(t,J=7.2Hz,2H,CH2),4.05(s,2H,CH2),3.01-2.97(t,J=7.6Hz,2H,CH2),2.23(s,3H,CH3); 13 CNMR (100MHz, CDCl3) δppm:167.9,166.9,158.0,150.1,141.5,134.7,129.9,129.7(2C),12 9.2,125.5,121.8(2C),116.8,115.0(2C),67.3,51.2,39.3,30.2,20.8; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2O2S, 365.1318, found 365.1321; HPLC purity 96.2%.

[0247] Example 36

[0248] 1-(4-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 36 )

[0249] The same method was used as in Example 19, except that 4-fluoroindoline was replaced with 4-methoxyindoline, and the rest was the same as in Example 19.

[0250] Brown powder, yield 25%; mp 89.0-89.4℃. Analytical data for I 36 : 1H NMR (400MHz, DMSO-d6) δppm: 7.65 (d, J=8.0Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.1 2-7.08(t,J=8.0Hz,1H,Ar-H),7.03-7.00(m,2H,Ar-H),6.96-6.92(t,J=7.6Hz, 1H, Ar-H), 6.65 (d, J = 8.0Hz, 1H, Ar-H), 5.35 (s, 2H, CH2), 4.21-4.16 (t, J = 8.4Hz ,2H,CH2),3.94(s,2H,CH2),3.75(s,3H,CH3),3.01-2.96(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.2,166.2,158.1,156.0,150.1,144.7,130.1,129.2,121.9,1 18.8,118.3,115.4,109.7(2C),106.8(2C),67.0,55.7,48.7,38.8,28.2; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 21 H 20 N2NaO3S, 403.1087, found 403.1060; HPLC purity 95.1%.

[0251] Example 37

[0252] 1-(5-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 37 )

[0253] The same method was used as in Example 19, except that 4-fluoroindoline was replaced with 5-methoxyindoline, and the rest was the same as in Example 19.

[0254] Yellow powder, yield 18%; mp 105.3-105.9℃. Analytical data for I 37 : 1H NMR (400MHz, DMSO-d6) δppm: 7.93 (d, J=8.8Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.29- 7.25(m,2H,Ar-H),7.03(d,J=8.0Hz,1H,Ar-H),6.96-6.93(t,J=7.2Hz,1H,Ar-H),7 .82(s,1H,Ar-H),6.68(d,J=8.8Hz,1H,Ar-H),5.35(s,2H,CH2),4.19-4.14(t,J=8. 0Hz,2H,CH2),3.93(s,2H,CH2),3.67(s,3H,CH3),3.11-3.07(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:167.4,166.1,158.1,156.2,150.3,137.1,134.0,130.1(2C),121 .9,118.2,117.1,115.4(2C),112.2,111.3,67.0,55.8,48.5,38.6,28.2; ESI-HRMS(TOF):m / z + [M+Na] + calcdfor C 21 H 20 N2NaO3S, 403.1087, found 403.1074; HPLC purity 98.9%.

[0255] Example 38

[0256] 1-(6-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 38 )

[0257] The same method was used as in Example 19, except that 4-fluoroindoline was replaced with 6-methoxyindoline, and the rest was the same as in Example 19.

[0258] White powder, yield 19%; mp 108.6-109.4℃. Analytical data for I 38 : 1H NMR (400MHz, DMSO-d6) δppm: 7.68 (d, J=2.0Hz, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.29-7.25 (m,2H,Ar-H),7.09(d,J=8.4Hz,1H,Ar-H),7.03(d,J=8.4Hz,2H,Ar-H),6.96-6.93(t,J= 7.2Hz,1H,Ar-H),6.55(dd,J=8.4Hz,2.4Hz,1H,Ar-H),5.36(s,2H,CH2),4.21-4.17(t, J=8.4Hz,2H,CH2),3.96(s,2H,CH2),3.66(s,3H,CH3),3.05-3.01(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:168.4,166.1,159.1,158.1,150.1,144.5,130.1(2C),125.5,124 .1,121.9,118.4,115.4(2C),109.2,103.1,67.0,55.7,49.1,38.7,27.2; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO3S, 403.1087; HPLC purity 98.9%.

[0259] Example 39

[0260] 1-(7-methoxyindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)ethyl-1-one (I 39 )

[0261] The same method was used as in Example 19, except that 4-fluoroindoline was replaced with 7-methoxyindoline, and the rest was the same as in Example 19.

[0262] Yellow oil, yield 24%; Analytical data for I 39 : 1H NMR (400MHz, DMSO-d6) δppm: 7.36 (s, 1H, Ar-H), 7.29-7.25 (m, 2H, Ar-H), 7.05-6.98 (m, 3H, Ar-H), 6.96-6.92 (t, J=7.6Hz, 1H, Ar-H), 6.89-6 .86(m,2H,Ar-H),5.30(s,2H,CH2),4.08-4.05(t,J=7.2Hz,2H,CH2),3.91(s,2H,CH2),3.75(s,3H,OCH3),2.91-2.88(t,J=7.6Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:169.6,165.8,158.1,150.9,149.4,137.8,131.0,130.1(2C),126 .5,121.9,117.8,117.7,115.4(2C),112.0,67.0,56.0,51.8,38.0,29.6; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 20 N2NaO3S, 403.1087, found 403.1098; HPLC purity96.9%.

[0263] Example 40

[0264] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-4-carboxynitrile (I 40 )

[0265] Following a similar method to Example 19, 4-fluoroindoline was replaced with 4-cyanoindoline, and the rest was the same as in Example 19.

[0266] Yellow powder, yield 17%; mp 136.4-137.3℃. Analytical data for I 40 : 1H NMR (400MHz, DMSO-d6) δppm: 8.27 (d, J=8.0Hz, 2H, Ar-H), 7.51 (s, 1H, Ar-H), 7.40 (d,J=7.6Hz,2H,Ar-H),7.34-7.30(t,J=8.0Hz,1H,Ar-H),7.28-7.24(t,J=8.0Hz, 2H,Ar-H),7.02-7.00(m,2H,Ar-H),6.96-6.92(t,J=7.2Hz,1H,Ar-H),5.35(s,2H ,CH2),4.29-4.25(t,J=8.4Hz,2H,CH2),4.00(s,2H,CH2),3.27-3.30(m,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:169.0,166.3,158.1,149.7,144.4,137.3,130.1(2C),129.1,126 .6,122.0,120.6,118.5,117.6,115.4(2C),108.7,67.0,48.3,38.7,27.7; ESI-HRMS(TOF):m / z + [M+Na] + calcdfor C 21 H 17 N3NaO2S, 398.0934, found 398.0918; HPLC purity 97.5%.

[0267] Example 41

[0268] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-5-carboxynitrile (I 41 )

[0269] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-cyanoindoline, and the rest was the same as in Example 19.

[0270] Yellow powder, yield 20%; mp 136.8-137.7℃. Analytical data for I 41 : 1 H NMR(400MHz,CDCl3)δppm:8.30(br,1H,Ar-H),7.49(d,2H,Ar-H),7.27(br,3H,Ar-H),6.9 8(br,3H,Ar-H),5.32(s,2H,CH2),4.28(br,2H,CH2),3.99(s,2H,CH2),3.23(br,2H,CH2);13 C NMR (100MHz, CDCl3) δppm: 168.6, 167.3, 157.9, 148.6, 146.7, 132.9, 132.5, 129.7 (2C), 128 .2,121.9,119.3,117.5(2C),115.0(2C),106.8,67.3,48.7,39.2,27.7; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 17 N3NaO2S, 398.0934, found 398.0919; HPLC purity 95.8%.

[0271] Example 42

[0272] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-6-carboxynitrile (I 42 )

[0273] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-cyanoindoline, and the rest was the same as in Example 19.

[0274] Brown powder, yield 21%; mp 129.3-130.1℃. Analytical data for I 42 : 1 H NMR(400MHz,DMSO-d6)δppm:8.23(s,1H,Ar-H),7.52(s,1H,Ar-H),7.46-7.41(m,2H,Ar-H),7.29-7.25(m,2H,Ar-H),7.03-7.00(m,2H,Ar-H ),6.96-6.92(t,J=7.6Hz,1H,Ar-H),5.35(s,2H,CH2),4.26-4.22(t,J=8.4Hz,2H,CH2),4.00(s,2H,CH2),3.24-3.20(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:169.2,166.3,158.1,149.7,144.0,139.0,130.1(2C),128.3,12 6.7,122.0,119.7,118.6(2C),115.4(2C),110.0,67.0,48.5,38.6,28.3; ESI-HRMS(TOF):m / z + [M+Na] +calcd for C 21 H 17 N3NaO2S, 398.0934, found 398.0910; HPLC purity 97.6%.

[0275] Example 43

[0276] 1-(2-(2-phenoxymethyl)thiazolyl-4-yl)acetyl)indoline-7-carboxynitrile (I 43 )

[0277] Following a similar method to Example 19, 4-fluoroindoline was replaced with 7-cyanoindoline, and the rest was the same as in Example 19.

[0278] Brown oily substance, yield 25%; Analytical data for I 43 : 1 H NMR(400MHz,DMSO-d6)δppm:7.55-7.49(m,2H,Ar-H),7.28-7.24(m,2H,Ar-H),7.18-7.14(t,J=7.6Hz,1H,Ar-H),7.03(s,1H,Ar-H),7.01(s,1H, Ar-H),6.95-6.92(t,J=7.2Hz,1H,Ar-H),5.37(s,2H,CH2),4.25-4.21(t,J=8.0Hz,2H,CH2),4.08(s,2H,CH2),3.12-3.08(t,J=8.0Hz,2H,CH2); 13 CNMR(100MHz,DMSO-d6)δppm:168.4,166.4,158.1,149.7,143.5,136.7,132.2,130.1(2C),130 .1,125.2,122.0,118.5,117.6,115.4(2C),102.1,67.1,50.0,38.5,28.8; ESI-HRMS(TOF):m / z + [M+Na] + calcd for C 21 H 17 N3NaO2S, 398.0934, found 398.0906; HPLC purity99.5%.

[0279] Example 44

[0280] 1-(5-nitroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 44 )

[0281] Following a similar method to Example 19, 4-fluoroindoline was replaced with 5-nitrochloroindoline, and the rest was the same as in Example 19.

[0282] Yellow oil, yield 23%; Analytical data for I 44 : 1 H NMR(400MHz,DMSO-d6)δppm:8.14-8.08(m,3H,Ar-H),7.53(s,1H,Ar-H),7.29-7.25(t,J=8.0Hz,2H,Ar-H),7.02(d,J=8.8Hz,1H,Ar-H), 6.96-6.92(t,J=7.2Hz,1H,Ar-H),5.35(s,2H,CH2),4.32-4.28(t,J=8.4Hz,2H,CH2),4.05(s,2H,CH2),3.24-3.20(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:169.7,166.3,158.1,149.5,149.2,143.2,134.6,130.1(2C), 124.9,122.0,121.0,118.7,115.7,115.4(2C),67.0,49.3,38.7,27.4; ESI-HRMS(TOF):m / z + [M+Na] + calcdfor C 20 H 17 N3NaO4S, 418.0832, found 418.0820; HPLC purity 95.6%.

[0283] Example 45

[0284] 1-(6-nitroindoline-1-yl)-2-(2-(phenoxymethyl)thiazolyl-4-yl)aceto-1-one (I 45 )

[0285] Following a similar method to Example 19, 4-fluoroindoline was replaced with 6-nitroindoline, and the rest was the same as in Example 19.

[0286] Brown powder, yield 20%; mp 118.2-119.2℃. Analytical data for I 45 : 1H NMR (400MHz, DMSO-d6) δppm: 8.76 (d, J=2.0Hz, 1H, Ar-H), 7.90 (dd, J=8.0Hz, 2.0H z,1H,Ar-H),7.54(s,1H,Ar-H),7.47(d,J=8.4Hz,1H,Ar-H),7.29(m,2H,Ar-H),7. 02(d,J=8.4Hz,2H,Ar-H),6.96-6.92(t,J=7.6Hz,1H,Ar-H),5.36(s,2H,CH2),4. 32-4.27(t,J=8.8Hz,2H,CH2),4.02(s,2H,CH2),3.27-3.23(t,J=8.4Hz,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δppm:169.4,166.3,158.1,149.6,147.4,144.3,141.1,130.1(2C), 126.0,121.9,119.6,118.6,115.4(2C),110.5,67.0,49.0,38.6,28.1; ESI-HRMS(TOF):m / z + [M+Na] + calcd forC 20 H 17 N3NaO4S, 418.0832, found 418.0819; HPLC purity 99.2%.

[0287] The following are some of the pharmacological tests and results of representative compounds of this invention:

[0288] Anti-HBV DNA activity

[0289] Based on the results of the compound's cytotoxicity against HepG2 2.2.15 cells (CC... 50 >20 μM), the non-toxic concentration of each compound was used as the high-dose group, and medium- and low-dose groups were also set up. The drug solution was prepared using DMEM containing 2% FBS. A positive control group for the anti-HBV drug lamivudine (LAM) (structure shown below) and a virus control group were also set up. 0.5 mL / well was added to each well of a 24-well cell culture plate, with 3 wells per concentration. The medium was changed every 2 days, and the cell supernatant was collected on day 6. Cells were lysed using 0.5% NP-40. Total DNA was extracted from the cell lysate using DNA Extraction Soln 1.0, and the HBV DNA load in the cells was detected by RT-PCR. The experimental results are shown in Tables 1 and 2.

[0290]

[0291]

[0292] Table 1. Inhibitory activity of the representative compounds of this invention against HBV DNA replication in HepG2 2.2.15 cells.

[0293]

[0294] Table 1 shows that these compounds have certain inhibitory activity against HBV DNA replication, among which compound I... 24 I 28 and I 42 The inhibition rates at 4 μM were 80.02%, 94.04%, and 92.81%, respectively, demonstrating good anti-HBV activity. Other compounds in this application also showed similar inhibition rate data, exhibiting good inhibitory activity.

[0295] Table 2 shows the IC50 values ​​of the representative compounds of this invention against HBV DNA replication in HepG2 2.2.15 cells. 50

[0296]

[0297]

[0298] Table 2 shows that these compounds have certain inhibitory activity against HBV DNA replication, among which compounds I1 and I... 24 and I 28 It exhibits strong anti-HBV activity. Other compounds in this application also possess similar IC50 activity. 50 The data showed good inhibitory activity.

[0299] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

2. A pharmaceutical composition comprising, as the main active ingredient, the compound of claim 1 or a pharmaceutically acceptable salt thereof, supplemented by a pharmaceutically acceptable carrier.

3. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-HBV drug.

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