CN117886810A - Indoline compound and preparation method and application thereof - Google Patents
Indoline compound and preparation method and application thereof Download PDFInfo
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Abstract
本发明公开了一种吲哚啉类化合物及其制备方法和应用，属于药物化学和药物治疗学领域。本发明提供的式I所示的化合物、异构体或其药学上可接受的盐，具有良好的抗HBV活性，能有效抑制HBV DNA的复制，可应用在制备抗HBV药物中，具有优异的潜在应用前景。 The present invention discloses an indoline compound and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry and pharmacotherapy. The compound, isomer or pharmaceutically acceptable salt thereof shown in formula I provided by the present invention has good anti-HBV activity, can effectively inhibit the replication of HBV DNA, can be used in the preparation of anti-HBV drugs, and has excellent potential application prospects.
Description
Technical Field
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to indoline compounds. The compounds can be used for preparing medicines with anti-hepatitis B virus effect. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Hepatitis B is an infectious disease caused by hepatitis B virus (Hepatitis B virus, HBV) and in a chronic carrying state.
Currently approved HBV therapeutic drugs are two major classes, interferon- α (IFN- α) which has direct antiviral and immunomodulatory effects, and Nucleotide Analogs (NAs) which can achieve sustained virologic response (Sustained virologic response, SVR) after withdrawal, but with lower response rates and multiple adverse effects; the latter is based on nucleoside, and a series of medicaments are derived through structural change of base or pentose ring, such as Lamivudine (Lamivudine), adefovir dipivoxil (Adefovir dipivoxil), entecavir (Entecavir), telbivudine (Telbivudine), tenofovir (Tenofovir) and the like, which can directly compete to inhibit HBV polymerase activity, block DNA replication, have little convenient side effect after oral administration, but have no influence on HBV transcription template covalent closed loop DNA (covalently closed circular DNA, ccc DNA), can not completely clear HBV, and is easy to relapse after drug withdrawal, namely "rebound phenomenon", and the long-time administration is easy to cause virus mutation to generate medicament resistance. Therefore, development of anti-HBV drugs with high response rate, difficult 'rebound' and drug resistance is urgent.
Because the clinically used drugs can not thoroughly clear HBV, pharmaceutical workers at home and abroad search for life cycle and immunotherapy methods of HBV, a series of novel antiviral drugs including an entry inhibitor Myrcludex B, CCC DNA synthesis inhibitor CCC-0975, a viral transcription inhibitor ONIS-HBVRx (GSK 3228836), a capsid assembly inhibitor GLS4, a hepatitis B surface antigen (HBsAg) targeting drug REP2055, an immune checkpoint inhibitor Nivolumab, an innate immune response Toll-like receptor 8 activator GS-9688 and the like are discovered, and the problem of 'rebound' and drug resistance of the existing anti-HBV drugs is expected to be solved through the series of drugs.
Disclosure of Invention
The invention aims to provide indoline compounds based on the prior art, and pharmacological experiments prove that the compounds have good anti-HBV activity.
It is another object of the present invention to provide a process for the preparation of the above compounds.
It is a further object of the present invention to provide a pharmaceutical use of the above-mentioned compounds.
The technical scheme of the invention is as follows:
the invention relates to a compound with a structure shown in a general formula I, isomers, including pharmaceutically acceptable salts thereof,
wherein,
R 1 represents phenyl, substituted phenyl, pyridine, substituted pyridine, pyrrole, piperidine, substituted piperidine, thiophene, substituted thiophene, furan, tetrahydrofuran, tetrahydropyran, cyclopentane or cyclohexane;
the substituted phenyl, substituted pyridine, substituted piperidine or substituted thiophene may be optionally mono-or polysubstituted with the following substituents: halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, amino, cyano or C 1 -C 6 An ester group;
R 2 represents hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, trifluoromethyl, cyano or nitro;
R 3 represents hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, nitro, trifluoromethyl or trifluoromethoxy;
x represents-NH-, an S atom or an O atom;
m represents an integer of 0 to 3;
n represents an integer of 0 to 3.
In a preferred embodiment, R 1 Represents phenyl or substituted phenyl, said extractionThe substituted phenyl group may be optionally mono-or polysubstituted with the following substituents: fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or nitro.
In a more preferred embodiment, R 1 Represents phenyl or substituted phenyl, which may be optionally mono-or polysubstituted by the following substituents: fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl.
In a preferred embodiment, R 2 Represents hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro.
In a more preferred embodiment, R 2 Represents hydrogen or methyl.
In a preferred embodiment, R 3 Represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, cyano, nitro or trifluoromethyl.
In a more preferred embodiment, R 3 Represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, cyano or nitro.
In a preferred embodiment, X represents an-NH-or O atom.
In a more preferred embodiment, X represents an O atom.
In a preferred embodiment, m represents an integer from 1 to 2.
In a more preferred embodiment, m represents 1.
In a preferred embodiment, n represents an integer from 1 to 2.
In a more preferred embodiment, n represents 1.
In a particularly preferred embodiment, R 1 Represents phenyl or substituted phenyl, which may be optionally mono-or polysubstituted by the following substituents: fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl; r is R 2 Represents hydrogen or methyl; r is R 3 Represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, cyano or nitro; x represents an O atom; m represents 1; n represents 1.
Further, the compound of formula I is preferably selected from the following compounds:
2- (2- (2-fluorophenoxy) methyl group) Thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 1 )；
2- (2- (3-fluorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 2 )；
2- (2- (4-fluorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 3 )；
2- (2- (2-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 4 )；
2- (2- (3-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 5 )；
2- (2- (4-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 6 )；
2- (2- (2-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 7 )；
2- (2- (3-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 8 )；
2- (2- (4-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 9 )；
2- (2- (2-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 10 )；
2- (2- (3-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 11 )；
2- (2- (4-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 12 )；
2- (2- (2-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 13 )；
2- (2- (3-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 14 )；
2- (2- (4-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 15 )；
2- (2- (2-trifluoromethyl) phenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 16 )；
2- (2- (3- (trifluoromethyl) phenoxy) methyl) thiazole-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 17 )；
2- (2- (4-trifluoromethyl) phenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 18 )；
1- (4-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 19 )；
1- (5-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 20 )；
1- (6-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 21 )；
1- (7-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 22 )；
1- (4-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 23 )；
1- (5-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 24 )；
1- (6-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 25 )；
1- (7-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 26 )；
1- (4-bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 27 )；
1- (5-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 28 )；
1- (6-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 29 )；
1- (7-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 30 )；
1- (2-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 31 )；
1- (4-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 32 )；
1- (5-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 33 )；
1- (6-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 34 )；
1- (7-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 35 )；
1- (4-methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 36 )；
1- (5-Methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 37 )；
1- (6-methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 38 )；
1- (7-Methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 39 )；
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-4-carbonitrile (I) 40 )；
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-5-carbonitrile (I) 41 )；
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-6-carbonitrile (I) 42 )；
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-7-carbonitrile (I) 43 )；
1- (5-Nitroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 44 )；
1- (6-Nitroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 45 )。
The structural formulae of the above-mentioned compounds are shown below, respectively:
the invention discloses a preparation method of a compound shown in a general formula I, wherein when X represents O atom, m represents 1, n represents 1, the preparation method comprises the following steps:
in a preferred embodiment, when X represents an O atom, m represents 1, n represents 1, a process for the preparation of the compounds of formula I comprising the steps of:
the specific preparation method of the synthetic route comprises the following steps:
the bromoacetonitrile and the hydroxy derivative undergo nucleophilic substitution reaction to generate an intermediate product 1, the intermediate product 1 and the thioacetamide are cyclized to synthesize an intermediate product 2, the intermediate product 2 and the methyl 4-chloroacetoacetate undergo nucleophilic substitution reaction to generate an intermediate product 3, the intermediate product 3 undergoes NaOH hydrolysis to generate an intermediate product 4, indole and the derivative thereof undergo reduction reaction with sodium cyanoborohydride under an acidic condition to generate indoline and the derivative thereof, and the intermediate product 4 and the indoline and the derivative thereof undergo nucleophilic substitution to generate the target compound.
These intermediates or target compounds can each be purified by conventional isolation techniques and converted, if desired, to addition salts with pharmaceutically acceptable acids.
The invention also provides a pharmaceutical composition, which takes the compound, the isomer or the pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient and is assisted with pharmaceutically acceptable auxiliary materials. In the composition, the active ingredient may include other anti-HBV drugs or nucleoside anti-HBV drugs, for example, lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir in combination with interferon or the like, in addition to the above-mentioned compounds, isomers or pharmaceutically acceptable salts thereof.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"halogen" means fluorine, chlorine, bromine, preferably fluorine or chlorine.
"trifluoromethyl" means-CF 3 A group.
"trifluoromethoxy" means-OCF 3 Radicals (C)
"hydroxy" means an-OH group.
"cyano" means a-CN group.
"nitro" means-NO 2 A group.
"amino" means-NH 2 Radicals (C)
"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain groups (the numerical ranges mentioned herein, e.g., "1 to 20", refer to such groups, which in this case are alkyl groups, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups containing 1 to 4 carbon atoms are referred to as lower alkyl groups. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group. More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.
"ester" means a-C (O) O-alkyl group.
"pharmaceutically acceptable salts" means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) Salified with acids obtained by reacting the free base of the parent compound with an inorganic acid including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or an organic acid including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic 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, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion or a salt formed by complexation with an organic base such as alkali metal ion, alkaline earth metal ion or aluminum ion, and an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, etc.
"pharmaceutical composition" means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is admixed with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
By adopting the technical scheme of the invention, the advantages are as follows:
the indoline compound provided by the invention has better anti-HBV activity. The research shows that the compounds not only have better anti-HBV activity, but also can effectively inhibit the replication of HBV DNA. The indoline compound, the isomer or the pharmaceutically acceptable salt thereof provided by the invention can be applied to preparation of anti-HBV drugs, and has excellent potential application prospects.
Detailed Description
In order to further illustrate the invention, the following examples are set forth which are purely illustrative and are intended to be a detailed description of the invention and should not be taken as limiting the invention.
Example 1
2- (2- (2-fluorophenoxy) methyl) -4-yl) -1- (indolin-1-yl) ethan-1-oneI 1 )
After 2-fluorophenol (4 g,35.7 mmol) was dissolved in N, N-dimethylformamide, 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 water 200. Mu.L were added and stirred for 4h at 90℃and the reaction was monitored by TLC. After the reaction is completed, adding water to stop the reaction, naturally cooling to room temperature, extracting with ethyl acetate, washing with distilled water and saturated saline water in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to obtain 2-fluorophenoxyacetonitrile; after 2-fluorophenoxyacetonitrile (4 g,26.5 mmol) was dissolved in N, N-dimethylformamide, dioxane (8 mL), thioacetamide (6.0 g,79.5 mmol) and diluted hydrochloric acid (4 mL/L) were added, and the mixture was stirred at 100℃for 6 hours. TLC monitoring, stopping the reaction with a large amount of water, naturally cooling to room temperature, adding saturated sodium bicarbonate aqueous solution to adjust the pH to 8, precipitating solid, and carrying out suction filtration to obtain a filter cake which is 2- (2-fluorophenoxy) thioacetamide; dissolving 2- (2-fluorophenoxy) thioacetamide (2.5 g,13.5 mmol) with a proper amount of ethanol, adding 8mL of dioxane, adding triethylamine (5.7 mL,40.5 mmol), methyl 4-chloroacetoacetate (7.86 mL,54 mmol), reacting with 200 mu L of water at room temperature for half an hour, gradually heating to 75 ℃ and stirring for 8h, TLC monitoring, adding large amount of water to stop the reaction, naturally cooling to room temperature, concentrating under reduced pressure to remove ethanol, adding ethyl acetate for extraction, washing with distilled water, saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to obtain 2- (4- (2-fluorophenoxy) methyl) -1, 3-thiazole-2-yl) methyl acetate; methyl 2- (4- (2-fluorophenoxy) methyl) -1, 3-thiazol-2-yl) acetate (1.5 g,5.3 mmol) was dissolved in N, N-dimethylformamide, sodium hydroxide solution (850 mg,21.4 mmol) was added in portions, the reaction was stopped at room temperature for 3 hours by TLC monitoring, water was added to stop the reaction, and after naturally cooling to room temperature, ethyl acetate was used for extraction, distilled water was used in turn, saturated saline solution was used for washing, the aqueous layer was used for adjusting pH to 2 with hydrochloric acid, ethyl acetate was used again for extraction, distilled water was used for washing, saturated saline solution was used in turn, anhydrous sodium sulfate was used for drying, suction filtration was used, and the filtrate was concentrated under reduced pressure to obtain 2- (4- (2-fluorophenoxy) methyl) -1, 3-thiazol-2-yl) acetic acid; dissolving indole (0.35 g,3 mmol) with appropriate amount of N, N-dimethylformamide, adding glacial acetic acid (2 mL) under ice bath, then adding sodium cyanoborohydride (0.94 g,15 mmol) in batches, gradually heating to 25deg.C, stirring for 24 hr, monitoring by TLC, stopping reaction with large amount of water, adding saturated sodium bicarbonate solution under ice bath to adjust pH to 8, extracting with ethyl acetate, sequentially washing distilled water, saturated saline solution, drying over anhydrous sodium sulfate, suction filtering, and concentrating the organic phase under reduced pressure to obtain indoline; after 2- (4- (4-chlorophenoxy) methyl) -1, 3-thiazol-2-yl) acetic acid (800 mg,2.8 mmol) was dissolved in dichloromethane, N-methylmorpholine (934. Mu.L, 8.4 mmol), indoline (1.35 mL,8.4 mmol) were added, isobutyl chloroformate (1.05 mL,8.4 mmol) was slowly added dropwise under ice bath, TLC was monitored after stirring for 4h, after completion of the reaction, the reaction was stopped with an increased amount of water, dichloromethane extraction was added, anhydrous sodium sulfate was washed successively with distilled water, saturated brine, dried, suction filtered, and the organic phase was concentrated under reduced pressure to give crude title compound, which was purified by silica gel column chromatography (dichloromethane: ethyl acetate=300:1, V/V) to give the title compound.
Yellow powder, yield 28%; m.p.81.8-82.1 ℃ Analytical data for I 1 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.21-4.17(t,J＝8.0Hz,2H,CH 2 ),3.99(s,2H,CH 2 ),3.15-3.11(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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] + calcd for C 20 H 17 FN 2 NaO 2 S,391.0887,found 391.0911；HPLC purity 97.6％.
Example 2
2- (2- (3-fluorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 2 )
The procedure was analogous to that in example 1, except that 2-fluorophenol was changed to 3-fluorophenol.
White powderYield 14%; m.p.224.5-225.1 ℃ Analytical data for I 2 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.20-4.16(t,J＝8.8Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.14-3.10(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0861；HPLC purity 96.7％
Example 3
2- (2- (4-fluorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 3 )
The procedure was analogous to that in example 1, except that 2-fluorophenol was changed to 4-fluorophenol.
White powder, yield 25%; m.p.110.8-111.2 ℃ Analytical data for I 3 : 1 H NMR(400MHz,DMSO-d 6 )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),6.98-6.94(t,J＝7.6Hz,1H,Ar-H),5.34(s,2H,CH 2 ),4.19-4.15(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.13-3.09(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0882；HPLC purity 99.3％.
Example 4
2- (2- (2-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 4 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 2-chlorophenol.
Brown powder, 16% yield; m.p.138.0-138.3 ℃ Analytical data for I 4 : 1 H NMR(400MHz,DMSO-d 6 )δppm:8.02(d,J＝8.0Hz,1H,Ar-H),7.51(s,1H,Ar-H),7.43(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,CH 2 ),4.19-4.15(t,J＝8.0Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.13-3.09(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 for C 20 H 17 ClN 2 NaO 2 S,407.0591,found 407.0586；HPLC purity 99.1％.
Example 5
2- (2- (3-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 5 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 3-chlorophenol and the remainder was identical to that used in example 1.
Yellow powder, yield 35%; m.p.99.7-100.6 ℃ Analytical data for I 5 : 1 H NMR(400MHz,CDCl 3 )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,CH 2 ),4.22-4.18(t,J＝8.4Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.22-3.18(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:167.7,165.9,158.6,149.6,143.0,135.1,131.4,130.5,127.7,124.8,124.0,122.1,117.5,117.3,115.7,113.3,67.5,48.5,39.1,28.1；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 20 H 17 ClN 2 NaO 2 S,407.0591,found 407.0565；HPLC purity 98.9％.
Example 6
2- (2- (4-chlorophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 6 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 4-chlorophenol.
Yellow powder, 16% yield; m.p.110.8-111.2 ℃ Analytical data for I 6 :1H NMR(400MHz,CDCl 3 )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,CDCl 3 )δppm:167.7,166.2,156.5,149.5,142.9,131.4,129.6(2C),127.7,126.8,124.7,124.1,117.4,117.3,116.4(2C),67.6,48.5,39.1,28.1；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 20 H 17 ClN 2 NaO 2 S,407.0591,found 407.0561；HPLC purity 98.1％.
Example 7
2- (2- (2-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 7 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 2-bromophenol.
Brown powder, 16% yield; m.p.140.0-140.3 ℃ Analytical data for I 7 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.20-4.16(t,J＝8.4Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.14-3.10(t,J＝7.6Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 for C 20 H 17 BrN 2 NaO 2 S,451.0086,found 451.0078；HPLC purity 98.8％.
Example 8
2- (2- (3-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 8 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 3-bromophenol.
White powder, 15% yield; m.p.103.0-103.8 ℃ Analytical data for I 8 : 1 H NMR(400MHz,DMSO-d 6 )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,2.5Hz,1H,Ar-H),6.98-6.94(t,J＝8.0Hz,1H,Ar-H),5.40(s,2H,CH 2 ),4.21-4.16(t,J＝8.8Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.14-3.10(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 BrN 2 NaO 2 S,451.0086,found 451.0058；HPLC purity 95.2％.
Example 9
2- (2- (4-bromophenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 9 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 4-bromophenol.
Brown powder, 14% yield; m.p.101.6-102.3 ℃ Analytical data for I 9 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.19-4.14(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.13-3.09(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 BrN 2 NaO 2 S,451.0086,found 451.0073；HPLC purity 95.2％.
Example 10
2- (2- (2-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 10 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 2-methylphenol.
Yellow powder, yield 19%; m.p.111.5-112.0 ℃ Analytical data for I 10 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.20-4.15(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.13-3.09(t,J＝8.0Hz,2H,CH 2 ),2.18(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 2 NaO 2 S,387.1138,,found 387.1148；HPLC purity 96.1％.
Example 11
2- (2- (3-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 11 )
The procedure was analogous to that in example 1 except that 2-fluorophenol was changed to 3-methylphenol, and the remainder was identical to that in example 1.
Yellow crystals, yield 16%; m.p.69.3-70.2 ℃ Analytical data for I 11 : 1 H NMR(400MHz,CDCl 3 )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,CH 2 ),4.21-4.17(t,J＝8.4Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.21-3.17(t,J＝8.4Hz,2H,CH 2 ),2.32(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 )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 N 2 NaO 2 S,387.1138,found 387.1128；HPLC purity 97.6％.
Example 12
2- (2- (4-methylphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 12 )
The procedure was analogous to that used in example 1, except that 2-fluorophenol was changed to 4-methylphenol.
White powder, 23% yield; m.p.91.5-92.5 ℃ Analytical data for I 12 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.19-4.15(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.13-3.09(t,J＝8.4Hz,2H,CH 2 ),2.18(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:168.3,166.4,156.0,150.1,143.4,132.4,130.7,130.4(2C),127.5.125.4,123.9,118.3,116.5,115.3(2C),67.1,48.3,38.8,27.9,20.6；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 21 H 20 N 2 NaO 2 S,387.1138,found 387.1136；HPLC purity 95.4％.
Example 13
2- (2- (2-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 13 )
In a similar manner to example 1, 2-fluorophenol was changed to 2-methoxyphenol, and the remainder was identical to example 1.
Yellow powder, 22% yield; m.p.100.5-101.5 ℃ Analytical data for I 13 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.19-4.15(t,J＝8.4Hz,2H,CH 2 ),3.95(s,2H,CH 2 ),3.74(s,3H,CH 3 ),3.13-3.09(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:168.3,166.3,150.1,149.9,147.5,143.4,132.4,127.5,125.4,123.9,122.7,121.2,118.4,116.5,115.2,113.1,68.0,56.1,48.3,38.8,27.9；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 21 H 20 N 2 NaO 3 S,403.1087,found 403.1078；HPLC purity 97.9％.
Example 14
2- (2- (3-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 14 )
In a similar manner to example 1, 2-fluoro was changed to 3-methoxyphenol, and the remainder was the same as in example 1.
Yellow powder, yield 20%; m.p.92.9-93.9 ℃ Analytical data for I 14 : 1 H NMR(400MHz,DMSO-d 6 )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,Ar-H),6.53(d,J＝8.4Hz,1H,Ar-H),5.34(s,2H,CH 2 ),4.20-4.16(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.68(s,3H,CH 3 ),3.14-3.09(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 for C 21 H 20 N 2 NaO 3 S,403.1087,found 403.1077；HPLC purity 99.4％.
Example 15
2- (2- (4-methoxyphenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 15 )
In a similar manner to example 1, 2-fluorophenol was changed to 4-methoxyphenol, and the remainder was identical to example 1.
Brown powder, 15% yield; m.p.76.7-77.6 ℃ Analytical data for I 15 : 1 H NMR(400MHz,CDCl 3 )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,CH 2 ),4.19-4.15(t,J＝8.4Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.75(s,3H,CH 3 ),3.20-3.16(t,J＝8.8Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:167.8,167.2,154.6,152.1,149.3,143.0,131.4,127.7,124.7,124.0,117.3,117.1,116.2(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 N 2 NaO 3 S,403.1087,found 403.1063；HPLC purity 97.9％.
Example 16
2- (2- (2-trifluoromethyl) phenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 16 )
In a similar manner to example 1, 2-fluorophenol is changed to 2-trifluoromethylphenol, the remainder being the same as in example 1
Yellow powder, yield 20%; m.p.99.0-100.0 ℃ Analytical data for I 16 : 1 H NMR(400MHz,DMSO-d 6 )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(td,J＝7.7,2.9Hz,2H,2×Ar-H),6.99(tt,J＝7.4,1.3Hz,1H,Ar-H),5.56(s,2H,CH 2 ),4.23-4.19(t,J＝8.4Hz,2H,CH 2 ),4.00(s,2H,CH 2 ),3.17-3.13(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 for C 21 H 17 F 3 N 2 NaO 2 S,441.0855,found 441.0854；HPLC purity 96.3％.
Example 17
2- (2- (3- (trifluoromethyl) phenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 17 )
The procedure was analogous to that in example 1 except that 2-fluorophenol was changed to 3-fluoromethylphenol.
Brown powder, 16% yield; m.p.109.5-111.4 ℃ Analytical data for I 17 : 1 H NMR(400MHz,DMSO-d 6 )δppm:8.02(d,J＝8.0Hz,1H,Ar-H),7.53-7.49(m,2H,Ar-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,CH 2 ),4.21-4.16(t,J＝8.4Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.14-3.10(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 F 3 N 2 NaO 2 S,441.0855,found 441.0835；HPLC purity 98.5％.
Example 18
2- (2- (4-trifluoromethyl) phenoxy) methyl) thiazol-4-yl) -1- (indolin-1-yl) ethan-1-one (I) 18 )
In a similar manner to example 1, 2-fluorophenol was changed to 4-trifluoromethylphenol, the remainder being the same as in example 1
Brown powder, 22% yield; m.p.97.6-98.4 ℃ Analytical data for I 18 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.24-4.19(t,J＝8.4Hz,CH 2 ),4.01(s,2H,CH 2 ),3.17-3.13(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 F 3 N 2 NaO 2 S,441.0855,found 441.0832；HPLC purity 96.6％.
Example 19
1- (4-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 19 )
After phenol (3 g,31.2 mmol) was dissolved in N, N-dimethylformamide, 1, 4-dioxane (8 mL), potassium hydroxide (2.5 g,62.4 mmol), potassium iodide (500 mg), bromoacetonitrile (10.8 mL,156 mmol) and 200. Mu.L of water were added, and the reaction was monitored by TLC under stirring at 90℃for 4 hours. After the reaction is completed, adding water to stop the reaction, naturally cooling to room temperature, extracting with ethyl acetate, washing with distilled water and saturated saline water in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to obtain phenoxyacetonitrile; phenoxyacetonitrile (2 mL,16.2 mmol) is dissolved by N, N-dimethylformamide, dioxane (8 mL) is added, thioacetamide (3.65 g,48.6 mmol) and diluted hydrochloric acid (4 mL/L) are stirred for 6h at 100 ℃, TLC monitoring is carried out, then water is added to stop the reaction, saturated sodium bicarbonate aqueous solution is added to adjust the pH to 8 after the reaction is naturally cooled to room temperature, solid is separated out, and filter cake is obtained by suction filtration, namely 4-chlorophenoxythioacetamide; after phenoxythioacetamide (4 g,31.6 mmol) is dissolved by proper amount of ethanol, 8mL of dioxane is added, triethylamine (13.2 mL,94.8 mmol) and 4-chloroacetoacetic acid methyl ester (13.8 mL,94.8 mmol) are added, 200 mu L of water is reacted for half an hour at room temperature, the temperature is gradually raised to 75 ℃ and stirred for 8 hours, TLC monitoring is carried out, the reaction is stopped by adding large amount of water, the water is naturally cooled to room temperature, the ethanol is removed by decompression concentration, ethyl acetate is added for extraction, distilled water and saturated saline water are sequentially used for washing, anhydrous sodium sulfate is used for drying, suction filtration is carried out, and the organic phase is decompressed and concentrated to obtain 2- (4- (4-phenoxy) methyl) -1, 3-thiazole-2-yl) methyl acetate; methyl 2- (4- (4-phenoxy) methyl) -1, 3-thiazol-2-yl) acetate (3 g,12 mmol) was dissolved in N, N-dimethylformamide, and sodium hydroxide solution (1.92 g,48 mmol) was added in portions to react at room temperature for 3 hoursTLC monitoring, stopping the reaction with a large amount of water, naturally cooling to room temperature, extracting with ethyl acetate, washing the water layer with distilled water and saturated saline water in sequence, adjusting the pH value of the water layer to 2 with hydrochloric acid, extracting the water layer with ethyl acetate again, washing the distilled water and saturated saline water in sequence, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the organic layer under reduced pressure to obtain 2- (4- (4-phenoxy) methyl) -1, 3-thiazole-2-yl) acetic acid; dissolving 2- (4- (4-phenoxy) methyl) -1, 3-thiazol-2-yl) acetic acid (800 mg,3.2 mmol) in dichloromethane, adding N-methylmorpholine (1.06 mL,9.6 mmol), 2-methylindoline (1.25 mL,9.6 mmol), slowly dropwise adding isobutyl chloroformate (1.21 mL,9.6 mmol) under ice bath, stirring for 4 hr, monitoring by TLC, stopping the reaction with large amount of water after the reaction is complete, adding dichloromethane, extracting, washing with distilled water, saturated saline solution, drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate under reduced pressure to obtain the target compound I 19 The crude product was chromatographed on a column of silica gel (dichloromethane: ethyl acetate=300:1, V/V) to give the title compound I 19 。
White powder, yield 20%; m.p.106.7-107.5 ℃ Analytical data for I 19 : 1 H NMR(400MHz,DMSO-d 6 )δppm:7.85(d,J＝8.0Hz,1H,Ar-H),7.51(s,1H,Ar-H),7.29-7.25(m,2H,Ar-H),7.20-7.15(m,1H,Ar-H),7.03-7.01(m,2H,Ar-H),6.96-6.93(t,J＝7.2Hz,1H,Ar-H),6.84-6.79(t,J＝8.8Hz,1H,Ar-H),5.36(s,2H,CH 2 ),4.27-4.23(t,J＝8.0Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.16-3.12(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0863；HPLC purity 95.8％.
Example 20
1- (5-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 20 )
In a similar manner to the process in example 19, 4-fluoroindoline was changed to 5-fluoroindoline, and the rest was the same as in example 19.
Yellow powder, 17% yield; m.p.103.2-104.0 ℃ Analytical data for I 20 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.22-4.18(t,J＝8.0Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.14-3.09(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0894；HPLC purity 98.7％.
Example 21
1- (6-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 21 )
In a similar manner to the process in example 19, 4-fluoroindoline was changed to 6-fluoroindoline, and the rest was the same as in example 19.
White powder, 18% yield; m.p.84.6-85.1 ℃ Analytical data for I 21 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.26-4.21(t,J＝8.8Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.11-3.07(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0862；HPLC purity 99.8％.
Example 22
1- (7-fluoroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 22 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-fluoroindoline, and the rest was the same as in example 19.
White powder, 15% yield; m.p.72.9-73.6 ℃ Analytical data for I 22 : 1 H NMR(400MHz,DMSO-d 6 )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＝8.0Hz,1H,Ar-H),5.35(s,2H,CH 2 ),4.18-4.14(t,J＝8.0Hz,2H,CH 2 ),4.00(s,2H,CH 2 ),3.08-3.04((t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 NaO 2 S,391.0887,found 391.0890；HPLC purity 97.0％.
Example 23
1- (4-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 23 )
In a similar manner to the process in example 19, 4-fluoroindoline was changed to 4-chloroindoline, and the rest was the same as in example 20.
Yellow powder, 24% yield; m.p.103.5-104.5 ℃ Analytical data for I 23 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.26-4.22(t,J＝8.0Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.15-3.11(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 ClN 2 NaO 2 S,407.0591,found 407.0580；HPLC purity 95.4％.
Example 24
1- (5-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 24 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-chloroindoline, and the rest was the same as in example 19.
Brown powder, 22% yield; m.p.120.7-121.7 ℃ Analytical data for I 24 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.23-4.19(t,J＝8.0Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.15-3.11(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 ClN 2 O 2 S,385.0772,found 385.0759；HPLC purity 97.3％.
Example 25
1- (6-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 25 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-chloroindoline, and the rest was the same as in example 19.
Yellow powder, yield 30%; m.p.117.2-118.0 ℃ Analytical data for I 25 : 1 H NMR(400MHz,CDCl 3 )δppm:8.27(s,1H,Ar-H),7.80-7.25(m,3H,Ar-H),7.06-6.95(m,5H,Ar-H),5.32(s,2H,CH 2 ),4.21-4.17(t,J＝8.4Hz,2H,CH 2 ),3.95(s,2H,CH 2 ),3.15-3.11(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:168.0,167.0,157.9,149.0,144.0,133.1,129.8,129.7(2C),125.2,123.9,121.8,117.6,117.3,115.0(2C),67.3,49.0,39.0,27.7；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 20 H 17 ClN 2 NaO 2 S,407.0591,found 407.0592；HPLC purity 95.9％.
Example 26
1- (7-chloroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 26 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-chloroindoline, and the rest was the same as in example 19.
Yellow oil, yield 16%; m.p.153.9-155.1 ℃ Analytical data for I 26 : 1 H NMR(400MHz,CDCl 3 )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,CH 2 ),4.26-4.22(t,J＝7.2Hz,2H,CH 2 ),4.09(s,2H,CH 2 ),3.03-3.00(t,J＝7.6Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:168.8,167.7,157.9,149.7,140.3,137.9,129.7(2C),129.1,126.4,124.5,123.1,121.8,117.1,115.0(2C),67.3,51.7,38.8,30.4；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 20 H 17 ClN 2 NaO 2 S,407.0591,found 407.0564；HPLC purity 96.1％.
Example 27
1- (4-bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 27 )
In a similar manner to example 19, 4-fluoroindoline was changed to 4-bromoindoline, and the rest was the same as in example 19.
Yellow powder, 11% yield; m.p.94.6-95.3 ℃ Analytical data for I 27 : 1 H NMR(400MHz,DMSO-d 6 )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),7.02-7.00(d,J＝8.4Hz,2H,Ar-H),6.96-6.92(t,J＝8.0Hz,1H,Ar-H),5.35(s,2H,CH 2 ),4.25-4.21(t,J＝8.4Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.10-3.06(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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] + calcd for C 20 H 17 BrN 2 NaO 2 S,451.0086,found 451.0056；HPLC purity 97.7％.
Example 28
1- (5-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 28 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-bromoindoline, and the rest was the same as in example 19.
White powder, 13% yield; m.p.70.5-71.3 ℃ Analytical data for I 28 : 1 H NMR(400MHz,DMSO-d 6 )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,2H,Ar-H),6.96-6.92(t,J＝7.2Hz,1H,Ar-H),5.35(s,2H,CH 2 ),4.21-4.17(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.15-3.11(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 BrN 2 NaO 2 S,451.0086,found 451.0060；HPLC purity 95.0％.
Example 29
1- (6-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 29 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-bromoindoline, and the rest was the same as in example 19.
Yellow powder, 16% yield; m.p.107.3-107.8 ℃ Analytical data for I 29 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.23-4.18(t,J＝8.4Hz,2H,CH 2 ),3.98(s,2H,CH 2 ),3.10-3.06(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 BrN 2 NaO 2 S,451.0086,found 451.0094；HPLC purity 96.7％.
Example 30
1- (7-Bromoindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 30 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-bromoindoline, and the rest was the same as in example 19.
Yellow oil, 31% yield; analytical data for I 30 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.18-4.14(t,J＝8.0Hz,2H,CH 2 ),4.03(s,2H,CH 2 ),3.05-3.01(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 BrN 2 NaO 2 S,451.0086,found 451.0057；HPLC purity 96.4％.
Example 31
1- (2-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 31 )
In a similar manner to example 19, 4-fluoroindoline was changed to 2-methylindoline, and the rest was the same as in example 19.
Brown oil, 29% yield; analytical data for I 31 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.15-3.95(q,J＝15.8Hz,1H,CH 2 ),3.40(s,1H,CH 2 ),3.37(s,1H,CH 2 ),2.68(d,J＝15.9Hz,1H,CH),1.37-1.28(m,3H,CH 3 )； 13 C 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 N 2 NaO 2 S,387.1138,found 387.1133；HPLC purity 98.2％.
Example 32
1- (4-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 32 )
In a similar manner to example 19, 4-fluoroindoline was changed to 4-methylindoline, and the rest was the same as in example 19.
White powder, 13% yield; m.p.107.5-108.1 ℃ Analytical data for I 32 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.20-4.16(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.68(s,3H,CH 3 ),3.14-3.09(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 2 NaO 2 S,387.1138,found 387.1128；HPLC purity 97.2％.
Example 33
1- (5-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 33 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-methylindoline, and the rest was the same as in example 19.
Yellow powder, 12% yield; m.p.95.9-96.9 ℃ Analytical data for I 33 : 1 H NMR(400MHz,CDCl 3 )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,CH 2 ),4.19-4.15(t,J＝8.4Hz,2H,CH 2 ),3.97(s,2H,CH 2 ),3.17-3.13(t,J＝8.4Hz,2H,CH 2 ),2.29(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 )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 N 2 O 2 S,365.1318,found 365.1296；HPLC purity 98.8％.
Example 34
1- (6-methylindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 34 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-methylindoline, and the rest was the same as in example 19.
Yellow powder, yield 19%; m.p.132.8-133.5 ℃ Analytical data for I 34 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.22-4.18(t,J＝8.0Hz,2H,CH 2 ),3.99(s,2H,CH 2 ),3.11-3.07(t,J＝8.0Hz,2H,CH 2 ),2.25(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 2 NaO 2 S,387.1138,found 387.1117；HPLC purity 95.2％.
Example 35
1- (7-methylindoline)-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 35 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-methylindoline, and the rest was the same as in example 19.
Brown oil, 28% yield; analytical data for I 35 : 1 H NMR(400MHz,CDCl 3 )δppm:7.31-7.26(m,3H,Ar-H),7.04-6.97(m,1H,Ar-H),5.33(s,2H,CH 2 ),4.20-4.16(t,J＝7.2Hz,2H,CH 2 ),4.05(s,2H,CH 2 ),3.01-2.97(t,J＝7.6Hz,2H,CH 2 ),2.23(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 )δppm:167.9,166.9,158.0,150.1,141.5,134.7,129.9,129.7(2C),129.2,125.5,121.8(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 N 2 O 2 S,365.1318,found 365.1321；HPLC purity 96.2％.
Example 36
1- (4-methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 36 )
In a similar manner to example 19, 4-fluoroindoline was changed to 4-methoxyindoline, and the rest was the same as in example 19.
Brown powder, yield 25%; m.p.89.0-89.4 ℃ Analytical data for I 36 : 1 H NMR(400MHz,DMSO-d 6 )δppm:7.65(d,J＝8.0Hz,1H,Ar-H),7.48(s,1H,Ar-H),7.12-7.08(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,CH 2 ),4.21-4.16(t,J＝8.4Hz,2H,CH 2 ),3.94(s,2H,CH 2 ),3.75(s,3H,CH 3 ),3.01-2.96(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:168.2,166.2,158.1,156.0,150.1,144.7,130.1,129.2,121.9,118.8,118.3,115.4,109.7(2C),106.8(2C),67.0,55.7,48.7,38.8,28.2；ESI-HRMS(TOF):m/z + [M+Na] + calcd for C 21 H 20 N 2 NaO 3 S,403.1087,found 403.1060；HPLC purity 95.1％.
Example 37
1- (5-Methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 37 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-methoxyindoline, and the rest was the same as in example 19.
Yellow powder, 18% yield; m.p.105.3-105.9 ℃ Analytical data for I 37 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.19-4.14(t,J＝8.0Hz,2H,CH 2 ),3.93(s,2H,CH 2 ),3.67(s,3H,CH 3 ),3.11-3.07(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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] + calcd for C 21 H 20 N 2 NaO 3 S,403.1087,found 403.1074；HPLC purity 98.9％.
Example 38
1- (6-methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 38 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-methoxyindoline, and the rest was the same as in example 19.
White powder, yield 19%; m.p.108.6-109.4 ℃ Analytical data for I 38 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.21-4.17(t,J＝8.4Hz,2H,CH 2 ),3.96(s,2H,CH 2 ),3.66(s,3H,CH 3 ),3.05-3.01(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 2 NaO 3 S,403.1087；HPLC purity 98.9％.
Example 39
1- (7-Methoxyindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 39 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-methoxyindoline, and the rest was the same as in example 19.
Yellow oil, 24% yield; analytical data for I 39 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.08-4.05(t,J＝7.2Hz,2H,CH 2 ),3.91(s,2H,CH 2 ),3.75(s,3H,OCH 3 ),2.91-2.88(t,J＝7.6Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 2 NaO 3 S,403.1087,found 403.1098；HPLC purity 96.9％.
Example 40
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-4-carbonitrile (I) 40 )
In a similar manner to example 19, 4-fluoroindoline was changed to 4-cyanoindoline, and the rest was the same as in example 19.
Yellow powder, 17% yield; m.p.136.4-137.3 ℃ Analytical data for I 40 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.29-4.25(t,J＝8.4Hz,2H,CH 2 ),4.00(s,2H,CH 2 ),3.27-3.30(m,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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] + calcd for C 21 H 17 N 3 NaO 2 S,398.0934,found 398.0918；HPLC purity 97.5％.
Example 41
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-5-carbonitrile (I) 41 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-cyanoindoline, and the rest was the same as in example 19.
Yellow powder, yield 20%; m.p.136.8-137.7 ℃ Analytical data for I 41 : 1 H NMR(400MHz,CDCl 3 )δppm:8.30(br,1H,Ar-H),7.49(d,2H,Ar-H),7.27(br,3H,Ar-H),6.98(br,3H,Ar-H),5.32(s,2H,CH 2 ),4.28(br,2H,CH 2 ),3.99(s,2H,CH 2 ),3.23(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )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 N 3 NaO 2 S,398.0934,found 398.0919；HPLC purity 95.8％.
Example 42
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-6-carbonitrile (I) 42 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-cyanoindoline, and the rest was the same as in example 19.
Brown powder, 21% yield; m.p.129.3-130.1 ℃ Analytical data for I 42 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.26-4.22(t,J＝8.4Hz,2H,CH 2 ),4.00(s,2H,CH 2 ),3.24-3.20(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.2,166.3,158.1,149.7,144.0,139.0,130.1(2C),128.3,126.7,122.0,119.7,118.6(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 N 3 NaO 2 S,398.0934,found 398.0910；HPLC purity 97.6％.
Example 43
1- (2- (2-phenoxymethyl) thiazol-4-yl) acetyl) indoline-7-carbonitrile (I) 43 )
In a similar manner to example 19, 4-fluoroindoline was changed to 7-cyanoindoline, and the rest was the same as in example 19.
Brown oil, yield 25%; analytical data for I 43 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.25-4.21(t,J＝8.0Hz,2H,CH 2 ),4.08(s,2H,CH 2 ),3.12-3.08(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 N 3 NaO 2 S,398.0934,found 398.0906；HPLC purity 99.5％.
Example 44
1- (5-Nitroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 44 )
In a similar manner to example 19, 4-fluoroindoline was changed to 5-nitrochloroindoline, and the rest was the same as in example 19.
Yellow oil, 23% yield; analytical data for I 44 : 1 H NMR(400MHz,DMSO-d 6 )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,CH 2 ),4.32-4.28(t,J＝8.4Hz,2H,CH 2 ),4.05(s,2H,CH 2 ),3.24-3.20(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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] + calcd for C 20 H 17 N 3 NaO 4 S,418.0832,found 418.0820；HPLC purity 95.6％.
Example 45
1- (6-Nitroindolin-1-yl) -2- (2- (phenoxymethyl) thiazol-4-yl) ethan-1-one (I) 45 )
In a similar manner to example 19, 4-fluoroindoline was changed to 6-nitroindoline, and the rest was the same as in example 19.
Brown powder, yield 20%; m.p.118.2-119.2 ℃ Analytical data for I 45 : 1 H NMR(400MHz,DMSO-d 6 )δppm:8.76(d,J＝2.0Hz,1H,Ar-H),7.90(dd,J＝8.0Hz,2.0Hz,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,CH 2 ),4.32-4.27(t,J＝8.8Hz,2H,CH 2 ),4.02(s,2H,CH 2 ),3.27-3.23(t,J＝8.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )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 for C 20 H 17 N 3 NaO 4 S,418.0832,found 418.0819；HPLC purity 99.2％.
The following are some of the pharmacological tests and results of representative compounds of the present invention:
anti-HBV DNA Activity
Based on the results of cytotoxicity of the compounds against HepG 2.2.15 (CC 50 >20 mu M), respectively taking nontoxic concentration of each compound as high dose group, setting medium and low dose groups, preparing into medicinal liquid with DMEM containing 2% FBS, additionally setting positive control group and virus control group of anti-HBV drug Lamivudine (LAM) (structure shown below), respectively adding into 24-well cell culture plate, 0.5 mL/well,3 wells per concentration. Cell supernatants were collected every 2 days and cells were lysed with 0.5% NP-40 on day 6. The cell lysate is used for extracting total DNA of cells by using DNA Extraction Soln 1.0 extracting solution, and the HBV DNA loading in the cells is detected by using an RT-PCR method. The experimental results are shown in tables 1 and 2.
Table 1 the present invention represents the inhibitory activity of the compounds on replication of HBV DNA in HepG 2.2.15 cells
Table 1 shows that the compounds have certain inhibitory activity on HBV DNA replication, wherein the compounds I 24 、I 28 And I 42 The inhibition rate at 4 mu M is 80.02%, 94.04% and 92.81%, respectively, and the anti-HBV activity is good. Other compounds of the present application also have similar inhibition rate data and exhibit good inhibition activity.
Table 2 the present invention represents the IC of compounds for replication of HBV DNA in HepG 2.2.15 cells 50
Table 2 shows that the compounds have certain inhibitory activity on HBV DNA replication, wherein the compound I 1 、I 24 And I 28 Has strong anti-HBV activity. Other compounds of the present application also have similar ICs 50 Data, which show good inhibitory activity.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
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