CN115109011B - Benzothiazole compound, preparation method and application - Google Patents

Benzothiazole compound, preparation method and application Download PDF

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CN115109011B
CN115109011B CN202210954718.9A CN202210954718A CN115109011B CN 115109011 B CN115109011 B CN 115109011B CN 202210954718 A CN202210954718 A CN 202210954718A CN 115109011 B CN115109011 B CN 115109011B
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李文燕
王丽
刘洪涛
洪斌
许艳妮
司书毅
李文雅
马志欣
朱香荣
李玥
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Institute of Medicinal Biotechnology of CAMS
Hebei Normal University
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Hebei Normal University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a benzothiazole compound, a preparation method and application thereof. The invention provides a series of benzothiazole compounds, and activity researches show that the benzothiazole compounds have better inhibition effect on PCSK9, can be used for developing and preparing PCSK9 inhibitor medicines and are used for preparing medicines for treating diseases which are treated or relieved by blocking PCSK9, such as hypercholesterolemia.

Description

Benzothiazole compound, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a benzothiazole compound, a preparation method and application thereof.
Background
Cardiovascular diseases (Cardiovascular disease, CVD) with Atherosclerosis (AS) AS a main pathological feature are the most life-threatening diseases in modern society, causing about 1770 thousands of deaths worldwide, and bringing huge economic burden to countries each year because of the mortality rate of CVD exceeding 40% in our country.
Numerous studies have shown that low density lipoprotein cholesterol (Low density lipoprotein cholesterol, LDL-C) in the blood is closely related to the development and progression of AS cardiovascular disease. Low density lipoprotein receptor (LDLreceptor, LDLR) -mediated low density lipoprotein (Low density lipoprotein, LDL) clearance is a major factor in determining circulating LDL-C levels, which can significantly reduce the rate of disability and mortality of cardiovascular disease.
Proprotein convertase subtilisin 9 (Proprotein convertase subtilisin kexin type, PCSK9) encodes a liver secreted protein whose mutations are closely related to LDL-C levels. The study proves that PCSK9 directly interacts with LDLR on the surface of cells, the PCSK9 and the LDLR enter the cells together through the internalization of clathrin pits, a compact complex is formed by the PCSK9 and the LDLR, and the PCSK9 and the LDLR enter a lysosome for degradation, so that the level of LDLR on the surface of liver cells is reduced, the clearance of LDL-C by the liver is reduced, and the process plays an important role in maintaining the LDL in plasma at a relatively constant level. Thus, blocking PCSK9 function has become a new strategy for treating hypercholesterolemia.
Based on the synthesis development research result of the PCSK9 inhibitor, the invention is particularly provided.
Disclosure of Invention
The invention aims to provide benzothiazole compounds, a preparation method and application thereof.
The above object of the present invention is achieved by the following technical scheme:
a benzothiazole compound which is a compound shown in a general formula I, II or III or pharmaceutically acceptable salt thereof:
wherein n in the general formula I is 0 or 1, R 1 3-methyl-1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-t-butoxycarbonyl-1-piperazinyl, 1-morpholinyl, or 1-piperazinyl;
wherein in the general formula II, R 2 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl;
wherein in the general formula III, the A ring moiety represents
R 4 Is 2, 3-dichloro, 2, 4-dichloro, 3, 4-dichloro, 2, 6-dichloro, 3-trifluoromethyl or 2-trifluoromethoxy.
The preparation method, the synthesis method and the synthesis route of the compound shown in the general formula I are as follows: 4-chlorosulfonyl benzoic acid is taken as a raw material, triethylamine is added, and the mixture is acylated with 3-aminopropionitrile to obtain an intermediate 2a; then condensing with HATU, DIEA and intermediate 1 at normal temperature to obtain the final product;
wherein n is 0 or 1, R 1 Is 3-methyl-1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-t-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl.
The preparation method, the synthesis method and the synthesis route of the compound shown in the general formula II are as follows: sequentially adding 2-amino-6-n-butylbenzothiazole (1 a), DIEA, HATU and single-substituted or multi-substituted benzoic acid into DMF, and reacting at normal temperature to obtain the compound;
wherein in the general formula II, R 2 Is 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl.
The preparation method, the synthesis method and the synthesis route of the compound shown in the general formula III are as follows: anhydrous CuCl 2 Adding tert-butyl nitrite into a reaction bottle, acetonitrile as a solvent, then adding 2-aminobenzothiazole-6-ethyl formate, reacting at normal temperature to obtain an intermediate 3, carrying out hydrocarbonylation reaction on the intermediate 3 and 4-Boc aminopiperidine to obtain an intermediate 4, deprotecting the intermediate 4, and condensing with benzoic acid with different substituents to obtain the product;
wherein in the general formula III, the dotted line is in the frameWhen the 4-Boc aminopiperidine is replaced by 1-Boc piperazine;
R 4 is 2, 3-dichloro, 2, 4-dichloro, 3, 4-dichloro, 2, 6-dichloro, 3-trifluoromethyl or 2-trifluoromethoxy.
The benzothiazole compound is used for preparing PCSK9 inhibitor medicaments.
The use of the benzothiazole compounds for preparing a medicament for treating a disease treated or alleviated by blocking PCSK 9.
Further, the disease includes hypercholesterolemia.
The beneficial effects are that:
the invention provides a series of benzothiazole compounds, and activity researches show that the benzothiazole compounds have better inhibition effect on PCSK9, can be used for developing and preparing PCSK9 inhibitor medicines and are used for preparing medicines for treating diseases which are treated or relieved by blocking PCSK9, such as hypercholesterolemia.
Detailed Description
The following describes the essential aspects of the present invention in detail with reference to examples, but is not intended to limit the scope of the present invention.
Example 1: synthesis of intermediates
(1) Synthesis of 2-aminobenzothiazole intermediate 1:
(1) synthesis of 2-amino-6-n-butylbenzothiazole: adding 4-n-butylaniline and potassium thiocyanate into glacial acetic acid in sequence, slowly dropwise adding a mixed solution of bromine and glacial acetic acid under the condition of ice water bath, and reacting at 75 ℃ after dropwise adding to obtain an intermediate 1a, wherein the yield is 88.2%.
Preparation of 2-amino-6-n-butylbenzothiazole (1 a): potassium thiocyanate (4.92 g,50.66 mmoL) was dissolved in 25mL of glacial acetic acid, 4-n-butylaniline (2 mL,12.67 mmoL) was added to the reaction flask after 10min, stirred at room temperature for 10min, and a solution of liquid bromine (0.71 mL,13.93 mmoL) dissolved in 2mL of glacial acetic acid was slowly added dropwise to the reaction solution in an ice bath, after the dropwise addition was completed, the ice bath was removed and warmed to room temperature, and then transferred to an oil bath pot at 75 ℃ for heating reaction, TLC was used to monitor the reaction progress, and after 5h the reaction was completed. The reaction solution was cooled to room temperature, naOH solution was added, pH was adjusted to 9, EA was extracted, the organic phase was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated and subjected to column chromatography (PE: ea=3:1) to give 2.3g of a white solid with a yield of 88.2%. The melting point is 113.7-114.5 ℃. 1 H NMR(400MHz,DMSO)δ7.44(s,1H),7.32(s,2H),7.22(d,J＝8.1Hz,1H),7.01(d,J＝8.1Hz,1H),2.57(t,J＝7.6Hz,2H),1.59-1.49(m,2H),1.35-1.24(m,2H),0.88(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO)δ166.20,151.30,135.47,131.41,126.26,120.58,117.80,35.04,34.03,22.17,14.35,14.18.ESI-MS,m/z:207.7[M+H] + .
(2) Synthesis of (2-aminobenzothiazol-6-yl) tert-butyl carbonate: 2-amino-6-hydroxy benzothiazole is used as a raw material, naOH is used as a base to react with di-tert-butyl dicarbonate in ice bath to generate an intermediate 2-amino benzothiazole-6-tert-butyl carbonate 1b, and the yield is 79.4%.
Preparation of (2-aminobenzothiazol-6-yl) tert-butyl carbonate (1 b): to 10mL of THF was added successively 2-amino-6-hydroxybenzothiazole (0.2 g,1.20 mmoL), di-t-butyl dicarbonate (0.33 mL,1.44 mmoL), and to the reaction mixture was slowly added dropwise 5mL of 2N NaOH solution, the reaction was carried out at room temperature, and the progress of the reaction was monitored by thin layer chromatography, after 2 hours, the reaction was completed. The reaction solution was distilled off under reduced pressure to remove most of the solvent, 25mL of distilled water was added to the reaction solution, the mixture was extracted 3 times with EA, and the organic layer was washed with saturated brine and then dried over anhydrous MgSO 4 Drying, suction filtration and concentration of the filtrate to obtain a crude product, and eluting the crude product by silica gel column chromatography (PE: EA=2:1) to obtain 0.25g of white solid. The yield was 79.4%. The melting point is 159.0-160.1 ℃. 1 HNMR(400MHz,DMSO)δ7.54(d,J＝2.4Hz,1H),7.51(s,2H),7.30(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,2.4Hz,1H),1.48(s,9H). 13 C NMR(101MHz,DMSO)δ167.32,152.28,151.15,145.13,131.74,119.55,118.02,114.64,83.44,27.74.ESI-MS,m/z:266.8[M+H] + ,288.9[M+Na] + .
(3) Synthesis of 2-aminobenzothiazol-6-yl acetate: sequentially adding 2-amino-6-hydroxybenzothiazole, triethylamine and acetic anhydride into a reaction bottle, and reacting under the condition of ice water bath to obtain an intermediate 2-aminobenzothiazole-6-acetate 1c, wherein the yield is 48.0%.
Acetic acid (2-aminobenzothiazole)-6-yl) preparation of ester (1 c): 2-amino 6-hydroxybenzothiazole (0.5 g,3.01 mmoL), acetic anhydride (3.15 mL,3.31 mmoL) and triethylamine (0.63 mL,4.51 mmoL) were sequentially added to methylene chloride (15 mL) in an ice bath, the reaction was allowed to proceed at room temperature, TLC was performed to check the reaction, after the completion of the reaction, the mixture was extracted 3 times with DCM, washed successively with distilled water and saturated brine, and the organic phase was washed with anhydrous Na 2 SO 4 Drying, distillation under reduced pressure the next day and column chromatography (PE: ea=1:1) gave 0.31g of a white solid. The yield was 48.0%. The melting point is 151.2-153.6 ℃. 1 H NMR(400MHz,DMSO)δ7.54(s,2H),7.52(d,J＝2.4Hz,1H),7.36(d,J＝8.6Hz,1H),7.00(dd,J＝8.6,2.4Hz,1H),2.31(s,3H). 13 C NMR(101MHz,DMSO)δ170.11,167.14,151.11,144.89,131.76,119.85,118.08,114.86,21.31.ESI-MS,m/z:209.5[M+H] + ,231.3[M+Na] + .
(4) Synthesis of intermediate 1 d-k: 4-nitrobenzyl bromide or 4-nitrobenzyl bromide is used as a starting material, and is alkylated with secondary amine firstly, then nitro at the 4-position is reduced to amino, and finally cyclized with potassium thiocyanate and liquid bromine to obtain an intermediate 1d-k.
Preparation of 2-amino-6- (dimethylaminomethyl) benzothiazole (1 d): dimethylamine hydrochloride (0.57 g,6.99 mmoL) was weighed and dissolved in 20mL of acetonitrile, then p-nitrobenzyl bromide (1.0 g,4.63 mmoL) was added in three portions, once every 30min at intervals, and reacted at room temperature. After completion of the reaction, the solvent was distilled off, extracted three times with DCM and the organic phase was dried over anhydrous MgSO 4 After drying, suction filtration, concentration of the filtrate under reduced pressure gave the intermediate as a yellow oil, which was then dissolved in methanol (0.81 g,4.50 mmoL): ethanol: to a solvent (25 mL) of water=6:3:1, ammonium chloride (1.43 g,26.99 mmoles), zinc powder (4.39 g,67.47 mmoles) were added, and the reaction was carried out in an ice bath, after the completion of the reaction, the zinc powder was filtered off, washed with a small amount of solvent, then the solvent was distilled off, extracted 3 times with EA, and the organic phase was dried over anhydrous MgSO 4 After drying, filtration was performed under reduced pressure, and the filtrate was concentrated to give a yellow oil.Yellow oily substance (0.65 g,4.33 mmoL) was dissolved in 20mL of glacial acetic acid, KSCN (1.68 g,17.32 mmoL) was added, then the reaction flask was moved to the ice bath, a solution of liquid bromine (0.24 mL,4.76 mmoL) dissolved in 2mL of glacial acetic acid was slowly added dropwise to the reaction solution, the reaction was carried out after the dropwise addition was completed to room temperature, the reaction was carried out at 75℃until disappearance of the substrate was detected by thin layer chromatography. The reaction mixture was adjusted to pH 9 by adding 2N NaOH solution, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous MgSO 4 After drying, suction filtration under reduced pressure, concentration of the filtrate followed by stirring with (PE: ea=2:1) solution gave 0.54g of pale yellow solid. The yield was 56.2%. The melting point is 182.6-184.3 ℃. 1 H NMR(400MHz,DMSO)δ7.56(s,1H),7.45(s,2H),7.27(d,J＝8.1Hz,1H),7.13(d,J＝7.9Hz,1H),3.44(s,2H),2.17(s,6H). 13 C NMR(101MHz,DMSO)δ166.94,152.53,131.34,131.10,127.07,121.74,117.74,63.38,44.96.ESI-MS,m/z:208.4[M+H] + .
Preparation of 2-amino-6- (diethylaminomethyl) benzothiazole (1 e): the synthesis procedure was the same as 1d to give 1e as a pale yellow solid in 49.8% yield. The melting point is 138.8-139.9 ℃. 1 H NMR(400MHz,DMSO)δ7.56(s,1H),7.39(s,2H),7.26(d,J＝8.1Hz,1H),7.14(d,J＝8.0Hz,1H),3.53(s,2H),2.46(d,J＝6.4Hz,4H),0.97(t,J＝7.0Hz,6H). 13 C NMR(101MHz,DMSO)δ166.76,152.32,133.01,131.40,126.74,121.30,117.80,57.31,46.52,12.18.ESI-MS,m/z:236.3[M+H] + .
Preparation of 2-amino-6- (4-methylpiperazinomethyl) benzothiazole (1 f): the synthesis method was the same as 1d, to give 1f as a pale yellow solid in 50.7% yield. The melting point is 217.9-219.2 ℃. 1 H NMR(400MHz,DMSO)δ7.52(s,1H),7.41(s,2H),7.25(d,J＝8.1Hz,1H),7.10(d,J＝8.1Hz,1H),3.42(s,2H),2.32(s,8H),2.13(s,3H). 13 C NMR(101MHz,DMSO)δ166.79,152.42,131.38,131.35,126.97,121.58,117.74,62.53,55.23,52.96,46.23.ESI-MS,m/z:263.2[M+H] + .
Preparation of 2-amino-6- (4-ethylpiperazinomethyl) benzothiazole (1 g): the synthesis was carried out in the same manner as in 1d to obtain 1g of pale yellow solid, the yield was 53.6%. The melting point is 194.6-196.2 ℃. 1 H NMR(400MHz,DMSO)δ7.52(s,1H),7.40(s,2H),7.25(d,J＝8.1Hz,1H),7.10(d,J＝8.2Hz,1H),3.42(s,2H),2.30(s,8H),2.25(q,J＝7.1Hz,2H),0.96(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ166.77,152.39,131.34,126.93,121.54,117.71,53.03,52.86,52.09,12.47.ESI-MS,m/z:277.3[M+H] + .
Preparation of 2-amino-6- (3-methylpiperidinylmethyl) benzothiazole (1 h): the synthesis method is the same as 1d, and light yellow solid is obtained for 1h, and the yield is 55.3%. The melting point is 170.3-172.4 ℃. 1 H NMR(400MHz,DMSO)δ7.52(s,1H),7.40(s,2H),7.25(d,J＝8.1Hz,1H),7.10(d,J＝8.1Hz,1H),3.40(s,2H),2.70(t,J＝9.3Hz,2H),1.81(t,J＝10.6Hz,1H),1.62(d,J＝12.8Hz,1H),1.56(s,1H),1.53(s,2H),1.47-1.33(m,1H),0.86-0.79(m,1H),0.78(d,J＝5.7Hz,3H). 13 C NMR(101MHz,DMSO)δ166.75,152.34,131.63,131.30,126.92,121.50,117.70,63.02,61.68,53.80,33.13,31.10,25.51,20.06.ESI-MS,m/z:262.3[M+H] + .
Preparation of 2-amino-6- (morpholinomethyl) benzothiazole (1 i): the synthesis procedure was the same as 1d to give 1i as a pale yellow solid in 58.1% yield. The melting point is 177.4-179.8 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.60(s,1H),7.49(d,J＝8.2Hz,1H),7.28(s,1H),5.49(s,2H),3.76-3.72(m,4H),3.56(s,2H),2.48(s,4H). 13 C NMR(101MHz,CDCl 3 )δ166.14,151.36,131.93,131.67,127.38,121.49,118.70,67.02,63.32,53.60.ESI-MS,m/z:250.3[M+H] + .
Preparation of 4- (2-aminobenzothiazol-6-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (1 j): the synthesis method was the same as 1d, to give 1j as a pale yellow solid in 52.1% yield. The melting point is 145.4-146.8 ℃. 1 H NMR(400MHz,DMSO)δ7.54(s,1H),7.42(s,2H),7.26(d,J＝8.2Hz,1H),7.12(d,J＝8.2Hz,1H),3.46(s,2H),3.29(s,4H),2.29(s,4H),1.38(s,9H). 13 C NMR(101MHz,DMSO)δ166.86,154.27,152.51,131.39,130.79,127.08,121.72,117.76,79.20,62.39,60.25,52.75,28.54.ESI-MS,m/z:349.3[M+H] + ,371.3[M+Na] + .
Preparation of 2-amino-6-morpholinyl benzothiazole (1 k): the synthesis was carried out in the same manner as 1d to obtain 1k as a white solid in a yield of 56.9%. The melting point is 220.4-222.7 ℃. 1 H NMR(400MHz,DMSO)δ7.25(d,J＝1.8Hz,1H),7.21(d,J＝8.6Hz,3H),6.94-6.81(m,1H),3.73(d,J＝4.0Hz,4H),3.02(d,J＝4.2Hz,4H). 13 C NMR(101MHz,DMSO)δ164.97,146.94,146.83,132.48,118.33,115.38,108.39,66.70,50.42.ESI-MS,m/z:236.2[M+H] + .
(2) Synthesis of benzenesulfonamide intermediate 2:
synthesis of intermediates 2 a-f: 4-chlorosulfonyl benzoic acid is taken as a raw material, dichloromethane is taken as a solvent, triethylamine is added, and then the mixture is acylated with amines with different substituents to obtain benzenesulfonamide intermediates 2a-f. The yield is between 39 and 84 percent.
4- [ N- (2-cyanoethyl) sulfamoyl]Preparation of benzoic acid (2 a): to 10mL of CH under ice bath 2 Cl 2 Adding 4-chlorosulfonylbenzoic acid (0.6 g,2.72 mmoL), stirring to dissolve, adding 3-aminopropionitrile (0.38 mL,5.45 mmoL), adding triethylamine (1.13 mL,8.16 mmoL) into the reaction solution, reacting at room temperature, TLC monitoring the reaction completion, spin-drying the solvent, adding distilled water to adjust pH to 1 with dilute hydrochloric acid, extracting with EA 3 times, washing with saturated saline, and washing the organic phase with anhydrous MgSO 4 After drying, the filtrate was suction-filtered and distilled under reduced pressure and stirred (PE: ea=10:1) to give 0.58g of a white solid. The yield was 83.5%. The melting point is 212.1-214.7 ℃. 1 H NMR(400MHz,DMSO)δ13.46(s,1H),8.26(t,J＝5.9Hz,1H),8.13(d,J＝8.5Hz,2H),7.92(d,J＝8.5Hz,2H),3.03(q,J＝6.3Hz,2H),2.63(t,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ166.69,144.22,134.82,130.70,127.28,119.24,39.03,19.12.ESI-MS,m/z:253.0[M-H] - .
4- [ N- (2-ethoxy-2-oxoethyl) sulfamoyl]Preparation of benzoic acid (2 b): the synthesis was identical to 2a, giving 2b as a white solid in 57.4% yield. The melting point is 211.1-213.4 ℃. 1 HNMR(400MHz,DMSO)δ13.42(s,1H),8.40(t,J＝6.2Hz,1H),8.10(d,J＝8.5Hz,2H),7.90(d,J＝8.4Hz,2H),3.96(q,J＝7.1Hz,2H),3.75(d,J＝6.2Hz,2H),1.08(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ169.26,166.70,144.89,134.59,130.43,127.19,61.11,44.28,14.30.ESI-MS,m/z:486.1[M-H] - .
(S) -4- [ N- (1-methoxy-1-oxopropan-2-yl) sulfamoyl]Preparation of benzoic acid (2 c): the synthesis was carried out in the same manner as 2a to obtain 2c as a white solid in 45.2% yield. The melting point is 196.6-198.1 ℃. 1 H NMR(400MHz,DMSO)δ13.42(s,1H),8.53(d,J＝8.4Hz,1H),8.10(d,J＝8.5Hz,2H),7.87(d,J＝8.4Hz,2H),3.98-3.90(m,1H),3.41(s,3H),1.18(d,J＝7.2Hz,3H). 13 C NMR(101MHz,DMSO)δ172.41,166.74,145.19,134.57,130.48,127.17,52.34,51.64,18.63.ESI-MS,m/z:486.4[M-H] - .
(S) -4- [ N- (1-methoxy-3-methyl-1-oxobutan-2-yl) sulfamoyl]Preparation of benzoic acid (2 d): the synthesis procedure was the same as 2a to give 2d as a white solid in 56.1% yield. The melting point is 213.9-215.1 ℃. 1 H NMR(400MHz,DMSO)δ13.39(s,1H),8.46(d,J＝9.4Hz,1H),8.09(d,J＝8.4Hz,2H),7.85(d,J＝8.4Hz,2H),3.61-3.57(m,1H),3.34(s,3H),1.99-1.85(m,1H),0.79(t,J＝7.7Hz,6H). 13 C NMR(101MHz,DMSO)δ171.52,166.75,144.94,134.50,130.36,127.26,61.94,52.03,30.88,19.22,18.60.ESI-MS,m/z:314.0[M-H] - .
4- [ N- ((2S, 3R) -1-methoxy-3-methyl-1-oxopentan-2-yl) sulfamoyl]Preparation of benzoic acid (2 e): the synthesis was carried out in the same manner as 2a to obtain 2e as a white solid in 48.6% yield. The melting point is 208.6-209.9 ℃. 1 H NMR(400MHz,DMSO)δ13.43(s,1H),8.49(d,J＝9.3Hz,1H),8.09(d,J＝8.4Hz,2H),7.85(d,J＝8.4Hz,2H),3,65-3.61(m,1H),3.31(s,3H),1.74-1.60(m,1H),1.44-1.29(m,1H),1.18-1.03(m,1H),0.76(d,J＝3.3Hz,3H),0.75-0.67(m,3H). 13 C NMR(101MHz,DMSO)δ171.49,166.74,144.87,134.53,130.38,127.27,60.56,51.97,37.10,24.86,15.59,11.00.ESI-MS,m/z:328.4[M-H] - .
(S) -4- [ N- (1-methoxy-1-oxo-3-phenylpropan-2-yl) sulfamoyl]Preparation of benzoic acid (2 f): the synthesis was carried out in the same manner as 2a to obtain 2f as a white solid in 39.7% yield. The melting point is 180.4-182.4 ℃. 1 H NMR(400MHz,DMSO)δ13.36(s,1H),8.72(d,J＝9.0Hz,1H),7.97(d,J＝8.2Hz,2H),7.65(d,J＝8.2Hz,2H),7.21-7.11(m,5H),4.08-3.93(m,1H),3.36(s,3H),2.96–2.92(m,1H),2.79-2.73(m,1H). 13 C NMR(101MHz,DMSO)δ171.58,166.73,144.83,136.68,134.34,130.32,129.62,128.70,127.14,126.92,57.89,52.27,38.00.ESI-MS,m/z:362.3[M-H] - .
(3) Preparation of intermediate ethyl 2-chlorobenzothiazole-6-carboxylate (3)
Taking a 100mL eggplant-shaped bottle, adding 30mL acetonitrile as a solvent, and adding anhydrous CuCl 2 (0.46 g,3.40 mmoL) was dissolved by stirring, tert-butyl nitrite (0.62 mL,5.16 mmoL) was added dropwise under ice bath, ethyl 2-aminobenzothiazole-6-carboxylate (0.50 g,2.50 mmoL) was added three times in total every 1h, the ice-water bath was removed, the reaction was carried out at room temperature, the progress of the reaction was monitored by thin layer chromatography, the reaction was completed for 6h, the solvent was distilled off under reduced pressure, then a 1N diluted hydrochloric acid solution was added to the reaction solution, extraction was carried out three times with ethyl acetate, the organic phase was washed with distilled water and saturated brine in this order, and the organic phase was washed with anhydrous Na 2 SO 4 Drying, concentrating the dried organic phase under reduced pressure, and purifying by column chromatography (PE: ea=25:1) to obtain white solid 3 with a yield of 80.9%. The melting point is 134.0-135.0 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J＝0.5Hz,1H),8.17(dd,J＝8.6,0.7Hz,1H),7.98(d,J＝8.6Hz,1H),4.42(q,J＝7.1Hz,2H),1.43(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ165.76,156.60,153.88,136.06,128.04,127.94,123.21,122.67,61.53,14.37.ESI-MS,m/z:242.0[M+H] + .
(4) Preparation of ethyl 2- [4- (tert-Butoxycarbonylamino) piperidine ] benzothiazole-6-carboxylate (4 a)
Ethyl 2-chlorobenzothiazole-6-carboxylate (1.50 g,6.22 mmoL) was dissolved in 5mL of DMF, 4-Boc aminopiperidine (1.87 g,9.34 mmoL) and cesium carbonate (4.05 g,12.44 mmoL) were added, and the mixture was transferred to an oil bath at 120℃to conduct a reaction, and the reaction was monitored by thin layer chromatography. After 2h, the reaction was completed, the reaction mixture was cooled to room temperature, extracted with EA (30 mL. Times.3), the organic phase was washed with distilled water and saturated brine, and the organic phase was washed with anhydrous MgSO 4 After drying, filtration under reduced pressure, concentration of the filtrate and separation by column chromatography (PE: ea=5:1) gave 1.71g of a white solid. The yield thereof was found to be 68.0%. The melting point is 175.3-176.9 ℃. 1 HNMR(400MHz,CDCl 3 )δ8.29(s,1H),7.99(d,J＝8.5Hz,1H),7.51(d,J＝8.5Hz,1H),4.51(d,J＝6.5Hz,1H),4.37(q,J＝7.1Hz,2H),4.14(d,J＝13.2Hz,2H),3.74(s,1H),3.35-3.22(m,2H),2.10(d,J＝11.0Hz,2H),1.57-1.49(m,2H),1.45(s,9H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.45,166.50,155.09,130.70,127.98,123.40,122.69,118.20,60.84,47.62,31.90,28.41,14.44.ESI-MS,m/z:406.4[M+H] + ,428.1[M+Na] + .
Preparation of ethyl 2- (4-tert-butoxycarbonylpiperazine) benzothiazole-6-carboxylate (4 b)
The synthesis procedure was identical to that of 4a, giving 4b as a white solid in 60.5% yield. The melting point is 174.5-175.9 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝1.3Hz,1H),8.00(dd,J＝8.5,1.5Hz,1H),7.53(d,J＝8.5Hz,1H),4.36(q,J＝7.1Hz,2H),3.67-3.65(m,4H),3.60-3.57(m,4H),1.48(s,9H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.69,166.44,156.25,154.51,130.51,128.04,123.68,122.79,118.48,80.59,60.90,48.28,28.41,14.44.ESI-MS,m/z:392.2[M+H] + ,414.1[M+Na] + .
(5) Preparation of ethyl 2- (4-aminopiperidine) benzothiazole-6-carboxylate (5 a)
2- [4- (tert-Butoxycarbonylamino) piperidine]Benzothiazole-6-carboxylic acid ethyl ester (1.50 g,3.70 mmoL) was dissolved in 20mL CH 2 Cl 2 In the above, trifluoroacetic acid (3.85 mL,51.85 mmoL) was added, and after completion of the substrate reaction by thin layer chromatography, saturated sodium carbonate was added to the reaction mixture in an ice-water bath to adjust the pH to 7, at this time, a large amount of white solid was precipitated, the reaction mixture was filtered under reduced pressure, and the cake was washed with distilled water to give 1.04g of a white solid, with a yield of 92.1%. The crude product of this reaction was directly fed to the next reaction without purification.
The synthesis method of 5b is the same as that of 5a, and the yield is 89.5% after the next step without purification.
Example 2: compound J 1 -J 19 Synthetic preparation and structural confirmation of (2)
4-chlorosulfonyl benzoic acid is taken as a raw material, triethylamine is added, and the mixture is acylated with 3-aminopropionitrile to obtain an intermediate 2a; then condensed with HATU, DIEA and intermediate 1 at room temperature to give the target compoundObject J 1 -J 19 . The synthetic route is as follows:
(1) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (methoxy) benzothiazol-2-yl]Benzamide (J) 1 ) Is prepared from
To DMF was added in sequence 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid (0.10 g,0.39 mmoL), DIEA (0.14 mL,0.78 mmoL), HATU (0.22 g,0.58 mmoL), and 2-amino-6-methoxybenzothiazole (0.08 g,0.43 mmoL) were added thereto and reacted at room temperature by TLC (CH 2 Cl 2 ：CH 3 Oh=15:1), 25mL of distilled water was added to the reaction solution, extracted three times with EA, washed with distilled water, saturated brine in this order, and the organic phase was dried over anhydrous MgSO 4 Drying, vacuum filtering, concentrating the filtrate under reduced pressure, and separating by column Chromatography (CH) 2 Cl 2 ：CH 3 Oh=25:1) to yield 0.12g of a pale yellow solid. The yield was 73.3%. The melting point is 212.0-212.5 ℃. 1 H NMR(400MHz,DMSO)δ12.99(s,1H),8.30(d,J＝8.4Hz,2H),8.27(s,1H),7.97(d,J＝8.3Hz,2H),7.69(d,J＝8.7Hz,1H),7.62(d,J＝2.0Hz,1H),7.08(dd,J＝8.8,2.3Hz,1H),3.83(s,3H),3.07(q,J＝6.2Hz,2H),2.66(t,J＝6.3Hz,2H). 13 C NMR(101MHz,DMSO)δ156.87,143.94,129.83,127.18,119.29,115.70,105.24,56.16,39.07,19.19.ESI-MS,m/z:417.1[M+H] + ,439.1[M+Na] + .
(2) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- (6-fluorobenzothiazol-2-yl) benzamide (J) 2 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-fluorobenzothiazole to obtain a pale yellow solid J 2 The yield was 72.4%. The melting point is 212.7-213.0 ℃. 1 H NMR(400MHz,DMSO)δ13.14(s,1H),8.31(d,J＝8.5Hz,2H),8.29(d,J＝6.3Hz,1H),7.98(d,J＝8.4Hz,2H),7.94(d,J＝2.6Hz,1H),7.81(dd,J＝8.0,4.5Hz,1H),7.34(td,J＝9.1,2.7Hz,1H),3.07(q,J＝6.3Hz,2H),2.66(t,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ160.55,158.16,150.62,144.22,136.06,133.14,129.88,127.20,122.03,119.16,115.02,114.81,108.87,108.60,108.52,39.12,19.16.ESI-MS,m/z:405.0[M+H] + ,426.8[M+Na] + .
(3) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- (6-chlorobenzothiazol-2-yl) benzamide (J) 3 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-chlorobenzothiazole to obtain pale yellow solid J 3 The yield was 62.3%. The melting point is 253.8-255.0 ℃. 1 H NMR(400MHz,DMSO)δ13.23(s,1H),8.31(d,J＝8.5Hz,2H),8.28(s,1H),8.18(d,J＝1.9Hz,1H),7.98(d,J＝8.4Hz,2H),7.79(d,J＝8.6Hz,1H),7.50(dd,J＝8.6,2.0Hz,1H),3.07(q,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ144.12,135.91,133.62,129.94,128.43,127.20,127.15,122.07,119.30,39.06,19.20.ESI-MS,m/z:421.1[M+H] + ,443.0[M+Na] + .
(4) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- (benzothiazol-2-yl) -benzamide (J) 4 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-aminobenzothiazole to obtain white solid J 4 The yield was 64.9%. The melting point is 212.5-214.8 ℃. 1 H NMR(400MHz,DMSO)δ13.13(s,1H),8.32(d,J＝8.4Hz,2H),8.29(d,J＝5.9Hz,1H),8.03(d,J＝7.8Hz,1H),7.98(d,J＝8.4Hz,2H),7.79(d,J＝8.0Hz,1H),7.48(t,J＝7.2Hz,1H),7.36(t,J＝7.5Hz,1H),3.06(q,J＝6.2Hz,2H),2.66(t,J＝6.3Hz,2H). 13 C NMR(101MHz,DMSO)δ144.03,136.28,131.72,129.91,127.19,126.84,124.38,122.39,120.69,119.28,39.08,19.19.ESI-MS,m/z:386.8[M+H] + ,408.8[M+Na] + .
(5) 2- [4- (N-2-cyanoethylsulfamoyl) benzamide]Benzothiazole-6-carboxylic acid ethyl ester (J) 5 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with ethyl 2-aminobenzothiazole-6-carboxylate to give pale yellow solid J 5 The yield is49.3%. The melting point is 260.9-261.4 ℃. 1 H NMR(400MHz,DMSO)δ13.33(s,1H),8.70(s,1H),8.32(d,J＝8.3Hz,2H),8.29(d,J＝5.9Hz,1H),8.05(dd,J＝8.5,1.6Hz,1H),7.99(d,J＝8.4Hz,2H),7.87(d,J＝8.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.09(q,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ165.96,144.19,129.99,127.71,127.21,125.61,124.43,119.28,61.29,39.07,19.19,14.73.ESI-MS,m/z:459.2[M+H] + ,481.1[M+Na] + .
(6) 2-aminobenzothiazol-6-yl-4- [ N- (2-cyanoethyl) sulfamoyl]Benzoate (J) 6 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-hydroxybenzothiazole to obtain pale yellow solid J 6 The yield was 72.6%. The melting point is 194.3-195.6 ℃. 1 HNMR(400MHz,DMSO)δ8.36(d,J＝5.9Hz,1H),8.33(d,J＝8.4Hz,2H),8.02(d,J＝8.4Hz,2H),7.66(d,J＝2.3Hz,1H),7.54(s,2H),7.38(d,J＝8.6Hz,1H),7.14(dd,J＝8.6,2.3Hz,1H),3.06(q,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ167.37,164.47,151.48,145.07,144.78,133.05,131.90,131.27,127.58,119.81,119.27,118.20,114.90,39.04,19.16.ESI-MS,m/z:403.2[M+H] + ,425.2[M+Na] + .
(7) 2- [4- (N-2-cyanoethylsulfamoyl) benzamide]Benzothiazol-6-yl acetate (J) 7 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-acetoxybenzothiazole to obtain pale yellow solid J 7 The yield was 48.7%. The melting point is 241.5-243.0 ℃. 1 H NMR(400MHz,DMSO)δ13.22(s,1H),8.38(d,J＝3.4Hz,2H),8.36(s,1H),8.04(d,J＝8.4Hz,2H),7.92(d,J＝2.1Hz,1H),7.87(d,J＝8.7Hz,1H),7.31(dd,J＝8.7,2.3Hz,1H),3.12(q,J＝6.2Hz,2H),2.72(t,J＝6.3Hz,2H),2.37(s,3H). 13 C NMR(101MHz,DMSO)δ170.02,147.18,144.06,136.07,133.06,129.93,127.20,121.38,119.31,115.55,39.06,21.34,19.20.ESI-MS,m/z:445.1[M+H] + ,467.1[M+Na] + .
(8) Tert-butyl-2- [4- (N-2-cyanoethylsulfamoyl) benzamide]Benzothiazol-6-yl carbonate (J) 8 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-tert-butoxycarbonyloxybenzothiazole to obtain a white solid J 8 The yield was 43.6%. The melting point is 253.2-254.5 ℃. 1 H NMR(400MHz,DMSO)δ13.25(s,1H),8.37(d,J＝8.0Hz,3H),8.04(d,J＝8.4Hz,2H),8.00(d,J＝2.2Hz,1H),7.86(d,J＝8.8Hz,1H),7.37(dd,J＝8.7,2.4Hz,1H),3.12(q,J＝6.2Hz,2H),2.72(t,J＝6.3Hz,2H),1.57(s,9H). 13 C NMR(101MHz,DMSO)δ144.12,129.94,128.43,127.20,127.15,122.07,119.30,39.06,19.20.ESI-MS,m/z:503.1[M+H] + ,525.2[M+Na] + .
(9) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- (6-hydroxybenzothiazol-2-yl) benzamide (J) 9 ) Is prepared from
Take J 8 (0.15 g,0.30 mmoL) was dissolved in 10mL of methylene chloride, and trifluoroacetic acid (0.31 mL,4.18 mmoL) was added thereto, followed by stirring at room temperature and detecting the progress of the reaction by thin layer chromatography. After the completion of the reaction, the pH was adjusted to 7 with saturated sodium carbonate in an ice bath, a white solid was precipitated, suction filtration was performed under reduced pressure, and the cake was washed with distilled water to obtain 0.08g of a white solid. The yield was 66.6%. The melting point is 258.1-259.2 ℃. 1 H NMR(400MHz,DMSO)δ12.98(s,1H),9.68(s,1H),8.35(d,J＝8.2Hz,3H),8.02(d,J＝8.2Hz,2H),7.65(d,J＝8.7Hz,1H),7.40(s,1H),6.99(d,J＝8.5Hz,1H),3.12(q,J＝6.1Hz,2H),2.71(t,J＝6.2Hz,2H). 13 C NMR(101MHz,DMSO)δ165.42,156.61,154.97,143.98,141.24,136.47,133.16,129.77,127.18,121.28,119.18,116.02,107.09,39.11,19.16.ESI-MS,m/z:403.2[M+H] + ,425.1[M+Na] + .
(10) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (2-hydroxyethoxy) benzothiazol-2-yl]Benzamide (J) 10 ) Is prepared from
3mL of DMF was added to a three-necked flask, J 9 (0.1 g,0.25 mmoL), 2-bromoethanol (0.09 mL,1.27 mmoL), and potassium carbonate (0.085 g,0.62 mmoL) were sequentially added to a reaction flask, followed by addition of N 2 Protecting and reacting at 60 ℃. TLC monitoring reverseThe process should be performed. After the reaction was completed for 4 hours, the reaction mixture was cooled to room temperature, and then ice distilled water was added to the reaction mixture, followed by stirring, to precipitate a solid, suction filtration was performed under reduced pressure, and the cake was washed with distilled water to obtain 0.06g of a yellow solid. The yield was 54.9%. The melting point is 234.3-236.1 ℃. 1 H NMR(400MHz,DMSO)δ9.78(s,1H),8.41(d,J＝8.1Hz,2H),8.23(t,J＝5.7Hz,1H),7.93(d,J＝8.1Hz,2H),7.60(d,J＝8.9Hz,1H),7.30(s,1H),6.98(d,J＝8.4Hz,1H),4.98(t,J＝5.4Hz,1H),4.59(s,2H),3.87(d,J＝5.3Hz,2H),3.03(q,J＝6.0Hz,2H),2.64(t,J＝6.2Hz,2H). 13 C NMR(101MHz,DMSO)δ172.27,166.81,155.08,143.16,140.68,130.48,130.19,127.41,127.06,119.19,116.02,114.60,108.77,58.81,48.84,39.10,19.10.ESI-MS,m/z:447.2[M+H] + ,469.0[M+Na] + .
(11) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (dimethylaminomethyl) benzothiazol-2-yl]Benzamide (J) 11 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-dimethylaminomethyl benzothiazole to obtain a white solid J 11 The yield was 40.2%. The melting point is 202.0-203.0 ℃. 1 H NMR(400MHz,DMSO)δ8.32(d,J＝5.4Hz,2H),8.31(s,1H),8.14(s,1H),7.99(d,J＝8.3Hz,2H),7.88(d,J＝8.2Hz,1H),7.58(d,J＝8.3Hz,1H),4.35(s,2H),3.07(q,J＝6.2Hz,2H),2.74(s,6H),2.66(q,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO)δ165.95,160.76,150.84,149.03,144.15,136.03,132.15,129.95,129.59,129.08,127.22,126.68,125.02,120.95,120.88,119.29,60.37,42.42,39.06,19.19.ESI-MS,m/z:444.0[M+H] + ,466.2[M+Na] + .
(12) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (diethylaminomethyl) benzothiazol-2-yl]Benzamide (J) 12 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6 diethylaminomethyl benzothiazole to obtain a white solid J 12 The yield was 54.3%. The melting point is 169.9-171.4 ℃. 1 H NMR(400MHz,DMSO)δ8.33(d,J＝8.2Hz,2H),8.31(s,1H),8.18(s,1H),7.99(d,J＝8.4Hz,2H),7.88(d,J＝8.3Hz,1H),7.61(d,J＝8.3Hz,1H),4.37(s,2H),3.08(d,J＝3.2Hz,4H),3.05(d,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H),1.23(t,J＝7.2Hz,6H). 13 C NMR(101MHz,DMSO)δ165.94,160.75,148.94,144.15,136.04,132.19,129.95,129.57,128.99,127.22,124.95,120.92,119.29,55.55,46.37,39.06,19.19,9.13.ESI-MS,m/z:472.0[M+H] + ,494.2[M+Na] + .
(13) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (4-methylpiperazinylmethyl) benzothiazol-2-yl]Benzamide (J) 13 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (4-methylpiperazine methyl) benzothiazole to obtain white solid J 13 The yield was 42.2%. The melting point is 229.0-230.9 ℃. 1 H NMR(400MHz,DMSO)δ8.31(d,J＝8.2Hz,3H),7.97(d,J＝8.2Hz,2H),7.91(s,1H),7.71(d,J＝8.2Hz,1H),7.40(d,J＝8.1Hz,1H),3.58(s,2H),3.06(s,2H),2.66(t,J＝6.2Hz,2H),2.45(s,8H),2.24(s,3H). 13 CNMR(101MHz,DMSO)δ166.10,160.34,147.42,143.75,136.95,134.35,131.84,129.84,127.78,127.13,122.23,120.06,119.29,62.38,55.01,52.74,45.90,39.08,19.18.ESI-MS,m/z:499.1[M+H] + ,521.1[M+Na] + .
(14) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (4-ethylpiperazinomethyl) benzothiazol-2-yl]Benzamide (J) 14 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (4-ethylpiperazinomethyl) benzothiazole to obtain a white solid J 14 The yield was 46.3%. The melting point is 188.8-190.5 ℃. 1 H NMR(400MHz,DMSO)δ8.31(d,J＝7.7Hz,3H),7.98(d,J＝8.0Hz,3H),7.76(d,J＝8.0Hz,1H),7.44(d,J＝7.9Hz,1H),3.70(s,2H),3.27-2.81(m,10H),2.66(t,J＝5.9Hz,4H),1.17(t,J＝6.7Hz,3H). 13 C NMR(101MHz,DMSO)δ165.85,159.63,144.05,136.23,131.82,129.89,128.11,127.20,122.59,120.35,119.28,61.32,51.27,50.14,39.06,19.17,9.93.ESI-MS,m/z:513.1[M+H] + ,535.0[M+Na] + .
(15) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (3-methylpiperidinylmethyl) benzothiazole-2-yl]Benzamide (J) 15 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (3-methylpiperidinylmethyl) benzothiazole to obtain a white solid J 15 The yield was 46.5%. The melting point is 210.7-211.7 ℃. 1 H NMR(400MHz,DMSO)δ12.56(s,1H),8.31(d,J＝8.4Hz,2H),8.26(s,1H),7.97(d,J＝8.4Hz,2H),7.94(s,1H),7.74(d,J＝8.2Hz,1H),7.43(d,J＝8.3Hz,1H),3.67(s,2H),3.09-3.03(m,2H),2.83(t,J＝11.9Hz,2H),2.66(t,J＝6.4Hz,2H),2.12-1.95(m,1H),1.82-1.70(m,1H),1.70-1.62(m,2H),1.62-1.57(m,1H),1.57-1.42(m,1H),0.95-0.84(m,1H),0.81(d,J＝6.3Hz,3H). 13 C NMR(101MHz,DMSO)δ165.96,160.17,147.74,143.94,136.47,131.84,129.88,128.47,127.18,123.10,120.26,119.28,62.00,60.51,53.24,39.07,32.30,30.45,24.62,19.75,19.17.ESI-MS,m/z:498.2[M+H] + ,520.2[M+Na] + .
(16) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (morpholinylmethyl) benzothiazol-2-yl]Benzamide (J) 16 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (morpholinomethyl) benzothiazole to obtain a white solid J 16 The yield was 55.4%. The melting point is 245.4-247.0 ℃. 1 H NMR(400MHz,DMSO)δ13.12(s,1H),8.31(d,J＝8.4Hz,2H),8.28(s,1H),7.97(d,J＝8.3Hz,2H),7.94(s,1H),7.73(d,J＝8.2Hz,1H),7.43(d,J＝8.2Hz,1H),3.62(s,2H),3.58(s,4H),3.06(q,J＝6.0Hz,2H),2.66(t,J＝6.3Hz,2H),2.39(s,4H). 13 C NMR(101MHz,DMSO)δ165.83,159.65,147.25,143.99,136.33,134.16,131.74,129.88,128.02,127.19,122.43,120.21,119.29,66.64,62.79,53.63,39.08,19.19.ESI-MS,m/z:486.0[M+H] + ,508.1[M+Na] + .
(17) 4- {2- [4- (N-2-cyanoethylsulfamoyl) benzoylamino]Benzothiazol-6-ylmethyl } piperazine-1-carboxylic acid tert-butyl ester (J) 17 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (4-tert-butoxycarbonyl piperazinylmethyl) benzothiazole to obtainTo white solid J 17 The yield was 46.1%. The melting point is 207.1-209.1 ℃. 1 H NMR(400MHz,DMSO)δ13.07(s,1H),8.31(d,J＝8.4Hz,2H),8.28(s,1H),7.97(d,J＝8.2Hz,2H),7.94(s,1H),7.74(d,J＝8.2Hz,1H),7.43(d,J＝8.2Hz,1H),3.61(s,2H),3.33(s,4H),3.08-3.04(m,2H),2.66(t,J＝6.2Hz,2H),2.36(s,4H),1.39(s,9H). 13 C NMR(101MHz,DMSO)δ165.82,159.59,154.27,147.27,144.01,136.27,134.23,131.76,129.89,128.05,127.19,122.49,120.26,119.28,117.41,79.26,62.25,52.80,39.07,28.54,19.18.ESI-MS,m/z:585.2[M+H] + ,607.0[M+Na] + .
(18) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (piperazinylmethyl) benzothiazol-2-yl]Benzamide (J) 18 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6- (piperazinylmethyl) benzothiazole to obtain a white solid J 18 The yield was 57.8%. The melting point is 169.5-171.5 ℃. 1 H NMR(400MHz,DMSO)δ8.31(d,J＝8.4Hz,2H),7.88(d,J＝8.4Hz,2H),7.73(s,1H),7.54(d,J＝8.2Hz,1H),7.25(d,J＝8.2Hz,1H),3.57(s,2H),3.04(t,J＝6.4Hz,2H),2.94(s,4H),2.65(t,J＝6.4Hz,2H),2.48(s,4H). 13 C NMR(101MHz,DMSO)δ168.45,166.50,149.03,142.01,141.54,132.78,131.37,129.51,126.88,126.73,121.98,119.34,119.05,62.60,51.26,44.38,39.11,19.11.ESI-MS,m/z:485.0[M+H] + ,507.2[M+Na] + .
(19) 4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (morpholinyl) benzothiazol-2-yl]Benzamide (J) 19 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-morpholinyl benzothiazole to obtain white solid J 19 The yield was 65.6%. The melting point is 273.9-275.3 ℃. 1 H NMR(400MHz,DMSO)δ12.95(s,1H),8.30(d,J＝8.2Hz,3H),7.97(d,J＝8.3Hz,2H),7.64(d,J＝8.8Hz,1H),7.53(s,1H),7.17(d,J＝8.9Hz,1H),3.76(s,4H),3.14(t,J＝12.1Hz,4H),3.06(q,J＝6.2Hz,2H),2.66(t,J＝6.3Hz,2H). 13 C NMR(101MHz,DMSO)δ148.91,143.86,136.39,133.26,129.80,127.17,120.92,119.31,116.63,107.29,66.61,49.77,39.06,19.19.ESI-MS,m/z:472.3[M+H]+,494.2[M+Na]+.
Example 3: compound J 20 -J 24 Synthetic preparation and structural confirmation of (2)
Sequentially adding 2-amino-6-n-butylbenzothiazole (1 a), DIEA, HATU and mono-substituted or polysubstituted benzoic acid into DMF, and reacting at room temperature to obtain a target compound J 20 -J 24 The synthetic route is as follows:
(1) N- (6-Butylbenzothiazol-2-yl) -2, 6-difluorobenzamide (J) 20 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Substitution of benzoic acid with 2, 6-difluorobenzoic acid gives a white solid J 20 The yield was 62.7%. The melting point is 175.4-177.5 ℃. 1 H NMR(400MHz,DMSO)δ13.15(s,1H),7.85(s,1H),7.70(d,J＝8.3Hz,1H),7.69-7.60(m,1H),7.32(d,J＝1.9Hz,1H),7.29(s,1H),7.27(s,1H),2.70(t,J＝7.6Hz,2H),1.69-1.53(m,2H),1.41-1.25(m,2H),0.91(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ161.57,161.51,159.03,158.97,158.80,158.38,145.55,139.25,133.28,133.17,133.07,131.71,127.07,120.48,119.58,112.31,112.06,35.57,33.91,22.29,13.96.ESI-MS,m/z:347.1[M+H] + ,369.1[M+Na] + .
(2) N- (6-butylbenzothiazol-2-yl) -3- (trifluoromethyl) benzamide (J) 21 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3-trifluoromethyl benzoic acid to obtain a white solid J 21 The yield was 47.8%. The melting point is 121.2-122.8 ℃. 1 H NMR(400MHz,DMSO)δ13.09(s,1H),8.52(s,1H),8.40(d,J＝7.8Hz,1H),8.02(d,J＝7.7Hz,1H),7.82(s,1H),7.80(d,J＝8.2Hz,1H),7.67(d,J＝8.2Hz,1H),7.29(d,J＝8.2Hz,1H),2.68(t,J＝7.6Hz,2H),1.65-1.53(m,2H),1.38-1.26(m,2H),0.90(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ165.25,159.76,144.88,139.60,133.25,131.68,131.37,131.19,129.60,129.37,129.34,127.19,125.29,125.26,120.77,119.61,35.61,33.89,22.30,13.97.ESI-MS,m/z:379.1[M+H] + ,401.0[M+Na] + .
(3) N- (6-butylbenzothiazol-2-yl) -3- (trifluoromethoxy) benzamide (J) 22 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3-trifluoromethoxybenzoic acid to obtain a white solid J 22 The yield was 50.5%. The melting point is 120.4-121.7 ℃. 1 H NMR(400MHz,DMSO)δ13.03(s,1H),8.17(d,J＝7.5Hz,1H),8.11(s,1H),7.82(s,1H),7.75-7.69(m,1H),7.68(s,1H),7.67(s,1H),7.30(d,J＝8.2Hz,1H),2.69(t,J＝7.6Hz,2H),1.67-1.55(m,2H),1.38-1.26(m,2H),0.91(t,J＝7.3Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ164.96,159.42,149.66,145.16,139.54,134.46,131.77,130.52,127.18,125.98,125.17,120.90,120.70,119.79,35.62,33.88,22.31,13.97.ESI-MS,m/z:395.3[M+H] + ,417.1[M+Na] + .
(4) N- (6-butylbenzothiazol-2-yl) -2- (trifluoromethyl) benzamide (J) 23 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethyl benzoic acid to obtain a white solid J 23 The yield was 47.1%. The melting point is 147.3-148.4 ℃. 1 H NMR(400MHz,DMSO)δ12.96(s,1H),7.89(d,J＝7.6Hz,1H),7.83(s,1H),7.81(s,1H),7.81(s,1H),7.79-7.75(m,1H),7.69(d,J＝8.2Hz,1H),7.30(d,J＝8.3Hz,1H),2.70(t,J＝7.6Hz,2H),1.67-1.55(m,2H),1.39-1.27(m,2H),0.91(t,J＝7.3Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ166.08,158.86,145.24,139.22,133.28,132.07,131.51,130.97,128.54,127.01,126.90,126.85,124.71,121.99,120.44,119.38,35.57,33.94,22.30,13.99.ESI-MS,m/z:379.3[M+H] + ,401.3[M+Na] + .
(5) N- (6-butylbenzothiazol-2-yl) -2- (trifluoromethoxy) benzamide (J) 24 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethoxybenzoic acid to obtain a white solid J 24 The yield was 43.2%. The melting point is 110.7-112.4 ℃. 1 H NMR(400MHz,DMSO)δ12.89(s,1H),7.83(s,1H),7.82(s,1H),7.75-7.70(m,1H),7.69(d,J＝8.3Hz,1H),7.57(d,J＝7.7Hz,1H),7.56-7.52(m,1H),7.30(dd,J＝8.3,0.9Hz,1H),2.70(t,J＝7.6Hz,2H),1.66-1.56(m,2H),1.38-1.27(m,2H),0.91(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ157.70,146.39,146.10,139.28,133.66,132.11,131.68,127.50,127.10,126.21,121.54,121.19,120.51,120.16,118.95,35.64,33.96,22.34,13.99.ESI-MS,m/z:395.3[M+H] + ,417.0[M+Na] + .
Example 4: compound J 25 -J 29 Synthetic preparation and structural confirmation of (2)
Condensing 2-amino-6-n-butylbenzothiazole serving as a raw material with various substituted benzenesulfonamide intermediates 2 to obtain a target compound J 25 -J 29 The synthetic route is as follows:
(1) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } glycine ethyl ester (J) 25 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid is replaced with 4- [ N- (ethoxyformylmethyl) sulfamoyl ]]Benzoic acid, giving a white solid J 25 The yield was 47.4%. The melting point is 222.6-224.3 ℃. 1 H NMR(400MHz,DMSO)δ13.04(s,1H),8.44(s,1H),8.28(d,J＝8.0Hz,2H),7.94(d,J＝8.2Hz,2H),7.83(s,1H),7.68(d,J＝8.2Hz,1H),7.31(d,J＝8.2Hz,1H),3.98(q,J＝7.0Hz,2H),3.78(d,J＝5.1Hz,2H),2.70(t,J＝7.4Hz,2H),1.67-1.54(m,2H),1.33(dd,J＝14.6,7.3Hz,2H),1.10(t,J＝7.0Hz,3H),0.91(t,J＝7.2Hz,3H). 13 C NMR(101MHz,DMSO)δ169.34,144.72,138.90,136.12,135.46,131.85,129.63,127.50,127.12,126.55,121.35,120.30,61.20,44.37,35.29,33.94,22.25,14.39,14.28.ESI-MS,m/z:476.3[M+H] + ,498.3[M+Na] + .
(2) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } -L-alanine methyl ester (J) 26 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid is replaced with 4- [ N- (1-methoxyformylethyl) sulfamoyl]Benzoic acid, giving a white solid J 26 The yield was 49.2%. The melting point is 205.7-206.9 ℃. 1 H NMR(400MHz,DMSO)δ13.06(s,1H),8.56(d,J＝8.4Hz,1H),8.28(d,J＝8.4Hz,2H),7.93(d,J＝8.4Hz,2H),7.84(s,1H),7.69(d,J＝7.9Hz,1H),7.31(d,J＝8.3Hz,1H),4.04-3.93(m,1H),3.43(s,3H),2.70(t,J＝7.6Hz,2H),1.67-1.57(m,2H),1.38-1.28(m,2H),1.21(d,J＝7.2Hz,3H),0.92(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO)δ172.42,144.97,138.90,129.63,127.51,127.05,121.37,52.40,51.69,35.29,33.96,22.26,18.67,14.30.ESI-MS,m/z:476.1[M+H] + ,498.3[M+Na] + .
(3) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } -L-valine methyl ester (J) 27 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid is replaced with 4- [ N- (1-methoxyformyl-2-methylpropyl) sulfamoyl]Benzoic acid, giving a white solid J 27 The yield was 57.8%. The melting point is 220.5-221.8 ℃. 1 H NMR(400MHz,DMSO)δ13.08(s,1H),8.51(d,J＝9.4Hz,1H),8.27(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.83(s,1H),7.68(d,J＝7.8Hz,1H),7.31(d,J＝8.3Hz,1H),3.64(dd,J＝9.2,7.1Hz,1H),3.35(s,3H),2.69(t,J＝7.6Hz,2H),2.00-1.87(m,1H),1.67-1.51(m,2H),1.39-1.26(m,2H),0.91(t,J＝7.3Hz,3H),0.82(dd,J＝9.6,6.8Hz,6H). 13 C NMR(101MHz,DMSO)δ171.53,144.71,138.88,131.86,129.51,127.51,127.14,121.38,120.40,61.97,52.12,35.29,33.97,30.91,22.27,19.26,18.63,14.30.ESI-MS,m/z:504.3[M+H] + ,526.2[M+Na] + .
(4) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } -L-isoleucine methyl ester (J) 28 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid is replaced with 4- [ N- (1-methoxyformyl-2-methylbutyl) sulfamoyl]Benzoic acid, giving a white solid J 28 The yield was 44.6%. The melting point is 223.3-225.4 ℃. 1 H NMR(400MHz,DMSO)δ13.08(s,1H),8.53(d,J＝9.4Hz,1H),8.27(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.83(s,1H),7.69(d,J＝7.8Hz,1H),7.31(d,J＝8.3Hz,1H),3.68(dd,J＝9.1,7.5Hz,1H),3.34(s,3H),2.70(t,J＝7.6Hz,2H),1.71-1.67(m,1H),1.65-1.55(m,2H),1.43–1.38(m,1H),1.36-1.29(m,2H),1.19-1.10(m,1H),0.91(t,J＝7.3Hz,3H),0.80-0.73(m,6H). 13 C NMR(101MHz,DMSO)δ171.49,144.65,138.89,135.95,129.53,127.51,127.14,121.39,60.62,52.07,37.13,35.29,33.97,24.89,22.27,15.62,14.30,11.05.ESI-MS,m/z:518.2[M+H] + ,540.0[M+Na] + .
(5) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } -L-phenylalanine methyl ester (J) 29 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid is replaced with 4- [ N- (1-methoxyformyl-2-phenylethyl) sulfamoyl]Benzoic acid, giving a white solid J 29 The yield was 60.5%. The melting point is 211.2-212.9 ℃. 1 H NMR(400MHz,DMSO)δ13.05(s,1H),8.74(d,J＝9.0Hz,1H),8.17(d,J＝8.5Hz,2H),7.83(s,1H),7.71(d,J＝8.6Hz,2H),7.68(d,J＝8.4Hz,1H),7.31(dd,J＝8.3,1.6Hz,1H),7.24-7.22(m,1H),7.20(s,1H),7.20-7.16(m,1H),7.15(d,J＝1.6Hz,1H),7.13(s,1H),4.10-4.02(m,1H),3.36(s,3H),2.99-2.94(m,1H),2.99-2.94(m,1H),2.70(t,J＝7.6Hz,2H),1.66-1.56(m,2H),1.38-1.28(m,2H),0.91(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO)δ171.55,144.60,138.84,136.67,135.98,131.80,129.64,129.47,128.75,127.49,127.21,126.84,121.37,57.91,52.32,38.05,35.30,33.97,22.27,14.31.ESI-MS,m/z:552.0[M+H] + ,574.1[M+Na] + .
Example 5: compound J 30 -J 49 Synthetic preparation and structural confirmation of (2)
Anhydrous CuCl 2 Adding tert-butyl nitrite and acetonitrile as solvent into a reaction bottle, adding 2-aminobenzothiazole-6-ethyl formate, reacting at room temperature to obtain an intermediate 3, carrying out alkylation reaction on the intermediate 3 and 4-Boc aminopiperidine (1-Boc piperazine) to obtain an intermediate 4, deprotecting the intermediate 4, and condensing with benzoic acid with different substituents to obtain a D-class target product J 30 -J 49 The synthetic route is as follows:
(1) 2- {4- [4- [ N- (2-cyanoethyl) sulfamoyl ]]Benzamido groups]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 30 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 5a to obtain white solid J 30 The yield was 58.7%. The melting point is 252.3-254.4 ℃. 1 H NMR(400MHz,DMSO)δ8.58(d,J＝7.5Hz,1H),8.40(s,1H),8.20(t,J＝5.6Hz,1H),8.03(d,J＝8.1Hz,2H),7.89(d,J＝8.0Hz,2H),7.86(s,1H),7.49(d,J＝8.4Hz,1H),4.30(q,J＝7.0Hz,2H),4.16(s,1H),4.11(d,J＝12.7Hz,2H),3.39(t,J＝12.0Hz,2H),3.00(q,J＝6.0Hz,2H),2.63(t,J＝6.2Hz,2H),1.98(d,J＝10.1Hz,2H),1.70-1.62(m,2H),1.32(t,J＝7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ166.03,164.99,157.10,142.69,138.59,131.26,130.71,128.80,128.46,127.96,127.29,127.01,126.05,123.35,122.71,119.28,118.28,60.95,47.90,46.79,39.01,31.06,19.12,14.76.ESI-MS,m/z:542.1[M+H] + ,564.2[M+Na] + .
(2) 2- [4- (2, 6-difluorobenzamide) piperidinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 31 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]Substitution of benzoic acid with 2, 6-difluorobenzoic acid gives a white solid J 31 The yield was 48.0%. The melting point is 245.1-247.4 ℃. 1 H NMR(400MHz,DMSO)δ8.80(d,J＝7.5Hz,1H),8.39(s,1H),7.87(d,J＝8.4Hz,1H),7.57-7.49(m,1H),7.48(d,J＝8.3Hz,1H),7.17(t,J＝7.9Hz,2H),4.30(q,J＝7.0Hz,2H),4.11(d,J＝7.2Hz,1H),4.04(d,J＝13.0Hz,2H),3.42(t,J＝11.4Hz,2H),1.99(d,J＝10.2Hz,2H),1.60-1.52(m,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ170.81,166.02,159.43,157.06,131.22,127.94,123.33,122.70,118.28,116.26,116.03,115.80,112.48,112.24,60.94,47.43,46.44,30.96,14.75.ESI-MS,m/z:446.1[M+H] + ,468.1[M+Na] + .
(3) 2- [4- (2, 3-dichlorobenzamido) piperidinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 32 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 3-dichlorobenzoic acid to obtain a white solid J 32 The yield was 45.2%. The melting point is 235.5-237.7 ℃. 1 H NMR(400MHz,DMSO)δ8.60(d,J＝7.7Hz,1H),8.39(s,1H),7.87(d,J＝8.4Hz,1H),7.70(d,J＝6.9Hz,1H),7.48(d,J＝8.5Hz,1H),7.43(d,J＝7.5Hz,1H),7.39(d,J＝6.2Hz,1H),4.30(q,J＝6.9Hz,2H),4.11(s,1H),4.05(d,J＝12.8Hz,2H),3.42(t,J＝11.2Hz,2H),2.00(d,J＝10.4Hz,2H),1.61-1.54(m,2H),1.32(t,J＝7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ170.80,166.02,165.48,157.08,139.85,132.45,131.43,131.22,129.00,128.55,127.95,127.70,123.34,122.69,118.27,60.94,47.50,46.35,30.91,14.76.ESI-MS,m/z:478.2[M+H] + ,500.0[M+Na] + .
(4) 2- [4- (2, 4-dichlorobenzamido) piperidinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 33 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 4-dichlorobenzoic acid to obtain a white solid J 33 The yield was 54.4%. The melting point is 248.0-249.6 ℃. 1 H NMR(400MHz,DMSO)δ8.55(d,J＝7.6Hz,1H),8.39(s,1H),7.87(d,J＝8.4Hz,1H),7.68(s,1H),7.48(d,J＝4.2Hz,2H),7.46(d,J＝7.9Hz,1H),4.30(q,J＝7.0Hz,2H),4.11(s,1H),4.05(d,J＝12.9Hz,2H),3.41(t,J＝11.3Hz,2H),1.99(d,J＝10.2Hz,2H),1.58(td,J＝14.2,3.8Hz,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ170.80,166.02,165.29,157.08,136.35,134.88,131.63,131.22,130.68,129.55,127.95,127.79,123.34,122.69,118.27,60.94,47.53,46.36,30.94,14.76.ESI-MS,m/z:478.0[M+H] + ,500.0[M+Na] + .
(5) 2- [4- (3, 4-dichlorobenzamido) piperidinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 34 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3, 4-dichlorobenzoic acid to obtain a white solid J 34 The yield was 51.2%. The melting point is 244.1-245.5 ℃. 1 H NMR(400MHz,DMSO)δ8.52(d,J＝7.5Hz,1H),8.39(s,1H),8.09(d,J＝1.3Hz,1H),7.90-7.79(m,2H),7.74(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),4.30(q,J＝7.0Hz,2H),4.15(s,1H),4.10(d,J＝13.3Hz,2H),3.39(d,J＝12.0Hz,2H),1.97(d,J＝10.8Hz,2H),1.64(dd,J＝20.3,11.2Hz,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ170.83,166.02,163.80,157.09,135.24,134.47,131.68,131.26,131.13,129.69,128.17,127.95,123.33,122.71,118.28,60.94,47.88,46.84,31.02,14.75.ESI-MS,m/z:478.1[M+H] + ,500.2[M+Na] + .
(6) 2- [4- (2, 6-dichlorobenzamido) piperidinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 35 ) Is prepared from
The synthesis method is the same as J 1 The difference is that2-amino-6-methoxybenzothiazole was substituted with 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 6-dichlorobenzoic acid to obtain a white solid J 35 The yield was 47.9%. The melting point is 257.1-259.3 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝1.3Hz,1H),7.98(dd,J＝8.5,1.5Hz,1H),7.51(d,J＝8.5Hz,1H),7.31(d,J＝1.8Hz,1H),7.29(s,1H),7.26-7.21(m,1H),5.86(d,J＝8.0Hz,1H),4.38(q,J＝7.1Hz,2H),4.32(d,J＝8.6Hz,1H),4.19(d,J＝13.5Hz,2H),3.44-3.31(m,2H),2.25(dd,J＝12.8,2.8Hz,2H),1.67(qd,J＝12.1,4.3Hz,2H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.40,166.52,163.93,156.52,135.68,132.15,130.73,128.05,127.99,123.39,122.70,118.24,60.89,47.53,46.91,31.10,14.42.ESI-MS,m/z:478.2[M+H] + ,500.1[M+Na] + .
(7) 2- {4- [3- (trifluoromethyl) benzamide group]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 36 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3-trifluoromethyl benzoic acid to obtain a white solid J 36 The yield was 50.1%. The melting point is 207.9-209.9 ℃. 1 H NMR(400MHz,DMSO)δ8.61(d,J＝7.6Hz,1H),8.40(s,1H),8.19(s,1H),8.17(d,J＝7.9Hz,1H),7.91(s,1H),7.88-7.82(m,1H),7.71(t,J＝7.8Hz,1H),7.49(d,J＝8.5Hz,1H),4.30(q,J＝7.1Hz,2H),4.19(m,,1H),4.11(d,J＝12.6Hz,2H),3.38(d,J＝7.8Hz,2H),1.99(d,J＝10.5Hz,2H),1.67(qd,J＝12.4,3.9Hz,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ170.83,166.02,164.59,157.09,135.78,131.99,131.26,130.07,128.26,127.95,125.85,124.31,124.28,123.33,122.72,118.28,60.93,47.96,46.82,31.07,14.74.ESI-MS,m/z:478.0[M+H] + ,500.1[M+Na] + .
(8) 2- {4- [3- (trifluoromethoxy) benzamide group]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 37 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]Benzoic acid substitution with 3Trifluoromethoxybenzoic acid to give white solid J 37 The yield was 55.1%. The melting point is 203.6-205.4 ℃. 1 H NMR(400MHz,DMSO)δ8.51(d,J＝7.6Hz,1H),8.40(s,1H),7.90(d,J＝7.7Hz,1H),7.87(d,J＝8.5Hz,1H),7.81(s,1H),7.61(t,J＝7.9Hz,1H),7.54(d,J＝8.1Hz,1H),7.49(d,J＝8.4Hz,1H),4.30(q,J＝7.0Hz,2H),4.26-4.14(m,1H),4.11(d,J＝13.0Hz,2H),3.41(s,2H),1.97(d,J＝10.2Hz,2H),1.66(qd,J＝12.5,3.7Hz,2H),1.32(t,J＝7.1Hz,3H). 13 CNMR(101MHz,DMSO)δ170.83,166.02,164.44,157.10,148.76,137.14,131.27,130.94,127.95,126.94,124.22,123.33,122.72,120.31,118.28,60.93,47.94,46.80,31.06,14.73.ESI-MS,m/z:494.1[M+H] + ,516.1[M+Na] + .
(9) 2- {4- [2- (trifluoromethyl) benzamide group]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 38 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethyl benzoic acid to obtain a white solid J 38 The yield was 43.2%. The melting point is 239.6-240.8 ℃. 1 H NMR(400MHz,DMSO)δ8.55(d,J＝7.6Hz,1H),8.39(s,1H),7.87(d,J＝8.5Hz,1H),7.78(d,J＝7.8Hz,1H),7.72(t,J＝7.4Hz,1H),7.64(t,J＝7.6Hz,1H),7.52(d,J＝7.5Hz,1H),7.48(d,J＝8.5Hz,1H),4.30(q,J＝7.0Hz,2H),4.11(s,1H),4.06(d,J＝13.8Hz,2H),3.41(t,J＝11.4Hz,2H),1.98(d,J＝10.3Hz,2H),1.56(td,J＝14.4,3.9Hz,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ170.80,166.94,166.02,157.08,137.05,132.92,131.21,130.09,128.97,127.95,126.66,126.61,125.67,123.33,122.68,118.26,60.94,47.57,46.29,30.87,14.74.ESI-MS,m/z:478.2[M+H] + ,500.1[M+Na] + .
(10) 2- {4- [2- (trifluoromethoxy) benzamide group]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 39 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5a and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethoxybenzoic acid to obtain a white solid J 39 Yield was 47.6%. The melting point is 219.2-220.0 ℃. 1 H NMR(400MHz,DMSO)δ8.49(d,J＝7.7Hz,1H),8.39(s,1H),7.87(d,J＝8.3Hz,1H),7.59(d,J＝7.8Hz,1H),7.56(s,1H),7.49(d,J＝2.8Hz,1H),7.47(s,1H),7.43(d,J＝8.8Hz,1H),4.30(q,J＝7.0Hz,2H),4.13(s,1H),4.07(d,J＝13.6Hz,2H),3.40(t,J＝11.5Hz,2H),1.96(d,J＝10.5Hz,2H),1.58(td,J＝14.3,3.6Hz,2H),1.32(t,J＝7.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.41,166.50,163.62,156.53,145.85,132.53,131.70,130.74,128.00,127.65,123.47,122.72,121.57,121.41,118.99,118.27,60.86,47.56,46.94,31.35,14.44.ESI-MS,m/z:494.2[M+H] + ,516.2[M+Na] + .
(11) 2- {4- [4- [ N- (2-cyanoethyl) sulfamoyl ]]Benzoyl group]Piperazine-6-carboxylic acid ethyl ester (J) 40 ) Is prepared from
The synthesis method is the same as J 1 The difference is that 2-amino-6-methoxybenzothiazole is replaced by 5b to obtain white solid J 40 The yield was 60.5%. The melting point is 241.3-243.1 ℃. 1 H NMR(400MHz,DMSO)δ8.43(d,J＝1.1Hz,1H),8.22(t,J＝5.9Hz,1H),7.90(d,J＝8.1Hz,2H),7.87(d,J＝1.4Hz,1H),7.68(d,J＝8.2Hz,2H),7.51(d,J＝8.5Hz,1H),4.30(q,J＝7.1Hz,2H),3.81(s,2H),3.77(s,2H),3.66(s,2H),3.47(s,2H),3.05(q,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ171.09,168.42,166.00,156.70,141.47,140.00,131.12,128.42,127.99,127.30,123.51,122.99,119.31,118.57,60.99,39.06,19.14,14.75.ESI-MS,m/z:528.2[M+H] + ,550.2[M+Na] + .
(12) 2- [4- (2, 6-difluorobenzoyl) piperazinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 41 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]Substitution of benzoic acid with 2, 6-difluorobenzoic acid gives a white solid J 41 The yield was 56.5%. The melting point is 188.8-190.6 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝1.4Hz,1H),8.02(dd,J＝8.5,1.6Hz,1H),7.55(d,J＝8.5Hz,1H),7.47-7.35(m,1H),7.01(t,J＝7.7Hz,2H),4.37(q,J＝7.1Hz,2H),4.06-3.94(m,2H),3.85-3.76(m,2H),3.76-3.59(m,2H),3.58-3.46(m,2H),1.40(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ171.04,165.99,159.84,159.73,157.38,157.30,156.65,132.80,132.70,132.60,131.16,127.96,123.51,123.03,118.60,113.78,113.54,113.31,112.89,112.66,60.99,48.69,48.14,45.99,41.24,14.74.ESI-MS,m/z:432.2[M+H] + ,454.1[M+Na] + .
(13) 2- [4- (2, 3-dichlorobenzoyl) piperazinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 42 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 3-dichlorobenzoic acid to obtain a white solid J 42 The yield was 48.7%. The melting point is 188.9-190.0 ℃. 1 H NMR(400MHz,DMSO)δ8.43(s,1H),7.88(d,J＝8.4Hz,1H),7.74(d,J＝7.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.48(d,J＝7.8Hz,1H),7.44(d,J＝7.4Hz,1H),4.30(q,J＝7.1Hz,2H),3.93-3.80(m,2H),3.80-3.69(m,2H),3.69-3.58(m,2H),3.34(s,2H),1.32(t,J＝7.1Hz,3H). 13 CNMR(101MHz,DMSO)δ171.08,165.99,165.43,156.66,138.08,132.63,131.53,131.14,129.62,127.97,127.09,123.52,123.02,118.59,60.99,48.47,48.05,45.93,41.03,14.75.ESI-MS,m/z:464.0[M+H] + ,486.1[M+Na] + .
(14) 2- [4- (2, 4-dichlorobenzoyl) piperazinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 43 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 4-dichlorobenzoic acid to obtain a white solid J 43 The yield was 51.8%. The melting point is 190.5-192.4 ℃. 1 H NMR(400MHz,DMSO)δ8.43(s,1H),7.88(d,J＝8.4Hz,1H),7.77(s,1H),7.56(d,J＝8.0Hz,1H),7.51(d,J＝5.0Hz,1H),7.49(d,J＝4.8Hz,1H),4.30(q,J＝7.0Hz,2H),3.93-3.78(m,2H),3.76(d,J＝4.0Hz,2H),3.63(s,2H),3.33(s,2H),1.32(t,J＝7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ171.07,165.98,165.45,156.66,134.96,134.80,131.13,130.91,129.98,129.64,128.48,127.97,123.51,123.02,118.58,60.99,48.45,48.09,45.95,41.06,14.74.ESI-MS,m/z:464.2[M+H] + ,486.1[M+Na] + .
(15) 2- [4- (3, 4-dichlorobenzoyl) piperazinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 44 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3, 4-dichlorobenzoic acid to obtain a white solid J 44 The yield was 41.2%. The melting point is 206.9-207.9 ℃. 1 H NMR(400MHz,DMSO)δ8.43(s,1H),7.88(d,J＝8.5Hz,1H),7.76(s,1H),7.74(s,1H),7.51(d,J＝8.5Hz,1H),7.46(dd,J＝8.2,1.2Hz,1H),4.30(q,J＝7.1Hz,2H),3.76(s,2H),3.76-3.70(m,2H),3.67(s,2H),3.50(s,2H),1.32(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.41,168.24,166.36,155.98,134.79,134.73,133.34,130.88,130.61,129.43,128.12,126.47,124.06,122.89,118.76,60.98,48.33,14.45.ESI-MS,m/z:464.1[M+H] + ,486.1[M+Na] + .
(16) 2- [4- (2, 6-dichlorobenzoyl) piperazinyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 45 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2, 6-dichlorobenzoic acid to obtain a white solid J 45 The yield was 46.7%. The melting point is 210.6-211.9 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.32(d,J＝1.1Hz,1H),8.01(dd,J＝8.5,1.4Hz,1H),7.54(d,J＝8.5Hz,1H),7.37(d,J＝1.6Hz,1H),7.35(s,1H),7.32-7.28(m,1H),4.37(q,J＝7.1Hz,2H),4.08-3.97(m,2H),3.84-3.78(m,2H),3.78-3.67(m,2H),3.48-3.36(m,2H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.38,166.37,163.97,156.04,134.37,131.78,130.83,130.63,128.28,128.09,123.99,122.86,118.71,60.95,48.47,48.27,45.58,40.92,14.44.ESI-MS,m/z:464.1[M+H] + ,486.1[M+Na] + .
(17) 2- {4- [3- (trifluoromethyl) benzamide group]Piperazine-6-carboxylic acid ethyl ester (J) 46 ) Is prepared from
The synthesis method is the same as J 1 The difference is that2-amino-6-methoxybenzothiazole was substituted with 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3-trifluoromethyl benzoic acid to obtain a white solid J 46 The yield was 58.3%. The melting point is 228.9-229.9 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.33(s,1H),8.01(d,J＝8.5Hz,1H),7.74(s,1H),7.72(s,1H),7.63(d,J＝7.5Hz,1H),7.61-7.56(m,1H),7.54(d,J＝8.5Hz,1H),4.37(q,J＝7.1Hz,2H),4.01-3.53(m,8H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.43,169.09,166.36,156.03,135.83,131.54,131.21,130.62,130.45,129.40,128.10,127.06,127.02,124.27,124.23,124.03,122.87,118.75,60.96,48.33,14.42.ESI-MS,m/z:464.1[M+H] + ,486.2[M+Na] + .
(18) 2- {4- [3- (trifluoromethoxy) benzamide group]Piperazine-6-carboxylic acid ethyl ester (J) 47 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 3-trifluoromethoxybenzoic acid to obtain a white solid J 47 The yield was 49.2%. The melting point is 201.9-203.4 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝1.0Hz,1H),8.02(dd,J＝8.5,1.3Hz,1H),7.55(d,J＝8.5Hz,1H),7.49(t,J＝7.8Hz,1H),7.38(d,J＝7.6Hz,1H),7.33(s,1H),7.31(s,1H),4.37(q,J＝7.1Hz,2H),4.02-3.50(m,8H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.44,168.90,166.36,156.02,149.31,136.91,130.61,130.47,128.10,125.49,124.02,122.87,122.67,119.89,118.74,60.95,48.34,14.43.ESI-MS,m/z:480.1[M+H] + ,502.2[M+Na] + .
(19) 2- {4- [2- (trifluoromethyl) benzamide group]Piperazine-6-carboxylic acid ethyl ester (J) 48 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethyl benzoic acid to obtain a white solid J 48 The yield was 45.4%. The melting point is 171.8-172.9 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.32(d,J＝1.4Hz,1H),8.01(dd,J＝8.5,1.6Hz,1H),7.74(d,J＝7.8Hz,1H),7.63(t,J＝7.3Hz,1H),7.57(d,J＝7.6Hz,1H),7.53(d,J＝8.5Hz,1H),7.36(d,J＝7.4Hz,1H),4.37(q,J＝7.1Hz,2H),4.10-4.04(m,1H),3.97-3.84(m,1H),3.85-3.69(m,2H),3.68-3.57(m,2H),3.35(t,J＝5.1Hz,2H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.43,167.65,166.37,156.07,134.16,132.43,130.64,129.62,128.08,126.95,126.90,123.98,122.86,118.71,60.94,48.20,47.92,46.33,41.12,14.43.ESI-MS,m/z:464.2[M+H] + ,486.2[M+Na] + .
(20) 2- {4- [2- (trifluoromethoxy) benzamide group]Piperazine-6-carboxylic acid ethyl ester (J) 49 ) Is prepared from
The synthesis method is the same as J 1 Except that 2-amino-6-methoxybenzothiazole was replaced with 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid is replaced by 2-trifluoromethoxybenzoic acid to obtain a white solid J 49 The yield was 49.6%. The melting point is 137.1-139.0 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.32(s,1H),8.02(d,J＝8.4Hz,1H),7.54(d,J＝8.5Hz,1H),7.49(t,J＝7.7Hz,1H),7.43(d,J＝6.0Hz,1H),7.41-7.35(m,1H),7.33(d,J＝8.2Hz,1H),4.37(q,J＝7.1Hz,2H),4.08(s,1H),3.84(d,J＝11.4Hz,2H),3.72(s,1H),3.69(s,2H),3.43(d,J＝23.5Hz,2H),1.39(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.42,166.37,165.74,156.03,144.85,131.27,130.59,129.00,128.10,127.52,123.99,122.86,121.69,120.74,119.12,118.68,60.95,48.34,46.23,41.29,14.43.ESI-MS,m/z:480.3[M+H] + ,502.2[M+Na] +
Compound J synthesized in examples 2 to 5 above 1 ～J 49 The following table is collated.
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Examples of drug effects: PCSK9 inhibitory Activity
1. Cell culture
The human liver cancer cell strain HepG2 cells are cultivated in MEM culture medium containing 10% fetal bovine serum; PCSK9 p-LUC HepG2 was cultured in MEM medium containing 500. Mu.g/mLG 418 and 10% fetal bovine serum; all cells were cultured at 37℃with 5% CO 2 Culturing in an incubator.
2. PCSK9 inhibition activity test method
Taking PCSK9 p-LUC HepG2 cells in logarithmic growth phase, treating the cells in 96-well culture plate with 100 μl of single cell suspension per well, and controlling cell number at about 5×10 5 /mL。
After the cells are cultured for 6-8h and the cells are completely attached, the original culture medium is removed, and the cells are rinsed once by a buffer solution. Each well was filled with 5. Mu.g/ml of compound solution, two wells per compound.
After 18-24h the medium was removed, rinsed 1 time with buffer solution, 25. Mu.l of cell lysate was added to the well plate and the cells were lysed at 37℃for 30-45min. After complete cell lysis, 50 μl of firefly luciferase detection reagent was rapidly added to each well, and the assay white plate was immediately placed in an microplate reader for detection.
The following is a calculation formula for the influence of the inhibitory activity of the test compound on PCSK 9: PCSK9 activity inhibition (%) = (luciferase activity after addition of the blank sample-luciferase activity after addition of the compound)/luciferase activity after addition of the blank sample x 100%. When the inhibition rate of the compound to be tested is more than or equal to 50%, the result is positive.
The pharmacological activity test experiment is completed by the national new drug screening center.
3. Test results
The inhibition activity of the above synthesized 49 target compounds on PCSK9 was tested in this study, and the test results are shown in the following Table, compound J 13 、J 14 、J 15 、J 16 、J 17 、J 19 、J 20 、J 21 、J 22 、J 23 、J 32 、J 33 、J 34 、J 35 、J 36 、J 43 、J 44 And J 49 Has inhibiting effect on PCSK 9.
The above-described embodiments serve to describe the substance of the present invention in detail, but those skilled in the art should understand that the scope of the present invention should not be limited to this specific embodiment.

Claims (5)

1. Benzothiazole compounds are compounds shown in a general formula I or pharmaceutically acceptable salts thereof:
wherein in formula I, n=1, R 1 Is 3-methyl-1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-t-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl.
2. A process for the preparation of a compound of formula I in claim 1, characterized by the following synthetic procedures and routes: 4-chlorosulfonyl benzoic acid is taken as a raw material, triethylamine is added, and the mixture is acylated with 3-aminopropionitrile to obtain an intermediate 2a; then condensing with HATU, DIEA and intermediate 1 at normal temperature to obtain the final product;
wherein n=1, r 1 Is 3-methyl-1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-t-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl.
3. Use of benzothiazole compounds according to claim 1 for the preparation of a PCSK9 inhibitor medicament.
4. Use of a benzothiazole compound of claim 1 for the manufacture of a medicament for the treatment of a disease treated or ameliorated by the blockade of PCSK 9.
5. The use according to claim 4, wherein the disease comprises hypercholesterolemia.
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