CN115109011A - Benzothiazole compound, preparation method and application - Google Patents

Benzothiazole compound, preparation method and application Download PDF

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CN115109011A
CN115109011A CN202210954718.9A CN202210954718A CN115109011A CN 115109011 A CN115109011 A CN 115109011A CN 202210954718 A CN202210954718 A CN 202210954718A CN 115109011 A CN115109011 A CN 115109011A
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dmso
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piperazinyl
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CN115109011B (en
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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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Institute of Medicinal Biotechnology of CAMS
Hebei Normal University
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D277/82—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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

Abstract

The invention discloses a benzothiazole compound, a preparation method and application thereof. The invention provides a series of benzothiazole compounds, and activity studies show that the benzothiazole compounds have good inhibition effect on PCSK9, can be used for developing and preparing PCSK9 inhibitor medicaments, and can be used for preparing medicaments for treating diseases which are treated or alleviated 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 disease (CVD) which is mainly characterized by Atherosclerosis (AS) is the most life-threatening disease in modern society, approximately 1770 million people die globally, the death rate caused by CVD in China exceeds 40%, and huge economic burden is brought to the country every year.
Numerous studies have shown that Low density lipoprotein cholesterol (LDL-C) in blood is closely related to the development of AS cardiovascular disease. Low Density Lipoprotein (LDL) clearance mediated by ldlrr is a major factor in determining LDL-C levels in circulation, and lowering LDL-C levels can significantly reduce disability rate and mortality rate in cardiovascular diseases.
Proprotein convertase subtilisin type 9 (PCSK 9) encodes a liver secretory protein whose mutations are closely related to LDL-C levels. Studies have shown that PCSK9 interacts directly with cell surface LDLR, which together internalizes into the cell via the clathrin fossa, PCSK9 and LDLR form a tight complex and enter lysosomes for degradation, thereby reducing the level of hepatic cell surface LDLR and decreasing hepatic clearance of LDL-C, a process important for maintaining relatively constant levels of LDL in plasma. Therefore, blocking PCSK9 function has become a new strategy for treating hypercholesterolemia.
The invention is particularly proposed based on the results of the synthesis development research of the PCSK9 inhibitor.
Disclosure of Invention
The invention aims to provide a benzothiazole compound, a preparation method and application.
The above purpose of the invention is realized by the following technical scheme:
a benzothiazole compound, which is a compound shown as a general formula I, II or III, or a pharmaceutically acceptable salt thereof:
Figure BDA0003790752780000011
wherein in the general formula I, n is 0 or 1, R 1 Is 3-methyl-1-piperidyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl;
Figure BDA0003790752780000012
wherein in the general formula II, R 2 Is 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl;
Figure BDA0003790752780000021
wherein in the general formula III, the moiety A represents
Figure BDA0003790752780000022
R 4 Is 2, 3-dichloro, 2, 4-dichloro, 3, 4-dichloro, 2, 6-dichloro, 3-trifluoromethyl or 2-trifluoromethoxy.
A preparation method, a synthesis method and a synthesis route of the compound shown in the general formula I are as follows: 4-chlorosulfonylbenzoic acid is taken as a raw material, triethylamine is added, and the mixture and 3-aminopropionitrile are acylated to obtain an intermediate 2 a; then condensing with HATU, DIEA and the intermediate 1 at normal temperature to obtain the compound;
Figure BDA0003790752780000023
wherein n is 0 or 1, R 1 Is 3-methyl-1-piperidyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl.
A preparation method, a synthesis method and a synthesis route of the compound shown in the general formula II are as follows: sequentially adding 2-amino-6-n-butylbenzothiazole (1a), DIEA, HATU and mono-substituted or poly-substituted benzoic acid into DMF, and reacting at normal temperature to obtain the compound I;
Figure BDA0003790752780000024
wherein in the general formula II, R 2 Is 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl.
A preparation method, a synthesis method and a synthesis route of the compound shown in the general formula III are as follows: anhydrous CuCl is added 2 Adding tert-butyl nitrite into a reaction bottle, taking acetonitrile as a solvent, then adding 2-aminobenzothiazole-6-ethyl formate, reacting at normal temperature to obtain an intermediate 3, carrying out alkylation reaction on the intermediate 3 and 4-Boc aminopiperidine to obtain an intermediate 4, deprotecting the intermediate 4, and finally condensing with benzoic acid with different substituents to obtain the intermediate;
Figure BDA0003790752780000025
wherein, in the general formula III, the dotted line is
Figure BDA0003790752780000031
When the 4-Boc aminopiperidine is substituted 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 a PCSK9 inhibitor medicine.
The benzothiazole compound is used for preparing a medicament for treating diseases which are treated or alleviated by blocking PCSK 9.
Further, the disease includes hypercholesterolemia.
Has the beneficial effects that:
the invention provides a series of benzothiazole compounds, and activity researches show that the benzothiazole compounds have a good inhibition effect on PCSK9, can be used for developing and preparing PCSK9 inhibitor medicines, and can be used for preparing medicines for treating diseases which are treated or alleviated by blocking PCSK9, such as hypercholesterolemia.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
Example 1: synthesis of intermediates
(1) Synthesis of 2-aminobenzothiazole intermediate 1:
synthesis of 2-amino-6-n-butylbenzothiazole: sequentially adding 4-n-butylaniline and potassium thiocyanate into glacial acetic acid, slowly dropwise adding a mixed solution of liquid bromine and the glacial acetic acid under the ice-water bath condition, and reacting at 75 ℃ after dropwise adding is finished to obtain an intermediate 1a with the yield of 88.2%.
Figure BDA0003790752780000032
Preparation of 2-amino-6-n-butylbenzothiazole (1 a): dissolving potassium thiocyanate (4.92g, 50.66mmoL) in 25mL of glacial acetic acid, adding 4-n-butylaniline (2mL, 12.67mmoL) into a reaction bottle after 10min, stirring at room temperature for 10min, slowly dropwise adding a solution of liquid bromine (0.71mL, 13.93mmoL) dissolved in 2mL of glacial acetic acid into the reaction solution under an ice bath, removing the ice bath after the dropwise addition is finished, raising the temperature to room temperature, transferring to a 75 ℃ oil bath, heating for reaction, monitoring the reaction progress by TLC, and completing the reaction after 5 h. Cooling the reaction liquid to room temperature, adding NaOH solution, adjusting the pH value to 9, extracting with EA, and using anhydrous sulfuric acid to extract an organic phaseAfter drying the magnesium, the drying agent was filtered off, and the filtrate was concentrated and then subjected to column chromatography (PE: EA ═ 3:1) to obtain 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 the synthesis of (2-aminobenzothiazol-6-yl) tert-butyl carbonate: 2-amino-6-hydroxybenzothiazole is used as a raw material, NaOH is used as alkali to react with di-tert-butyl dicarbonate in an ice bath to generate an intermediate 2-aminobenzothiazole-6-tert-butyl dicarbonate 1b, and the yield is 79.4%.
Figure BDA0003790752780000041
Preparation of (2-aminobenzothiazol-6-yl) tert-butyl carbonate (1 b): 2-amino-6-hydroxybenzothiazole (0.2g, 1.20mmoL) and di-tert-butyl dicarbonate (0.33mL, 1.44mmoL) were added to 10mL of THF in this order, 5mL of 2N NaOH solution was slowly added dropwise to the reaction solution, the reaction was carried out at room temperature, the progress of the reaction was monitored by thin layer chromatography, and the reaction was complete after 2 hours. Distilling the reaction solution under reduced pressure to remove most of the solvent, adding 25mL of distilled water to the reaction solution, extracting with EA for 3 times, washing the organic layer with saturated brine, and removing anhydrous MgSO 4 Drying, filtering, concentrating the filtrate to obtain a crude product, and eluting the crude product by silica gel column chromatography (PE: EA is 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] + .
Synthesis of (2-aminobenzothiazol-6-yl) acetate: 2-amino-6-hydroxybenzothiazole, triethylamine and acetic anhydride are sequentially added into a reaction bottle and react under the condition of ice-water bath to obtain an intermediate 2-aminobenzothiazole-6-acetic ester 1c, wherein the yield is 48.0%.
Figure BDA0003790752780000042
Preparation of (2-aminobenzothiazol-6-yl) acetate (1 c): 2-amino-6-hydroxybenzothiazole (0.5g, 3.01mmoL), acetic anhydride (3.15mL, 3.31mmoL), triethylamine (0.63mL, 4.51mmoL) were added to dichloromethane (15mL) in this order under ice bath, reaction was carried out at room temperature, TLC detection was carried out, after completion of the reaction, extraction was carried out 3 times with DCM, washing was carried out with distilled water and saturated brine in this order, 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] + .
Synthesis of intermediate 1 d-k: using 4-nitrobromobenzene or 4-nitrobenzyl bromide as an initial raw material, firstly alkylating with secondary amine, then reducing the nitro group on the 4 th position to obtain amino, and finally reacting with potassium thiocyanate and liquid bromine for cyclization to obtain an intermediate 1 d-k.
Figure BDA0003790752780000051
Preparation of 2-amino-6- (dimethylaminomethyl) benzothiazole (1 d): dimethylamine hydrochloride (0.57g, 6.99mmoL) was weighed out and dissolved in 20mL of acetonitrile, and p-nitrobenzyl bromide (1.0g, 4.63mmoL) was added in three portions, and the reaction was carried out at room temperature by adding the solution once every 30 min. After the reaction was complete, the solvent was evaporated, extracted three times with DCM and the organic phase with anhydrous MgSO 4 Drying, filtering, vacuum concentrating the filtrate to obtain yellow oily intermediate, and adding the yellow oily intermediate (A)0.81g, 4.50mmoL) in methanol: ethanol: adding ammonium chloride (1.43g, 26.99mmoL) and zinc powder (4.39g, 67.47mmoL) into a solvent (25mL) of water (6: 3:1), carrying out a reaction in ice bath, filtering out the zinc powder after the reaction is finished, washing the zinc powder with a small amount of solvent, evaporating the solvent, extracting with EA for 3 times, and using anhydrous MgSO (MgSO) for an organic phase 4 After drying, filtration under reduced pressure and concentration of the filtrate gave a yellow oil. The yellow oil (0.65g, 4.33mmoL) was dissolved in 20mL of glacial acetic acid, KSCN (1.68g, 17.32mmoL) was added, the reaction flask was moved to an ice bath, a solution of liquid bromine (0.24mL, 4.76mmoL) dissolved in 2mL of glacial acetic acid was slowly added dropwise to the reaction solution, the reaction was carried out after the solution was warmed to room temperature, and the reaction was carried out at 75 ℃ until disappearance of the substrate was detected by thin layer chromatography. Adding 2N NaOH solution into the reaction solution to adjust pH to 9, extracting with ethyl acetate for three times, and extracting the organic phase with anhydrous MgSO 4 After drying, suction filtration was performed under reduced pressure, and the filtrate was concentrated and then purified by agitation with a (PE: EA ═ 2:1) solution to obtain 0.54g of a 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 was as in 1d to give 1e as a pale yellow solid with a yield of 49.8%. 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-methylpiperazinylmethyl) benzothiazole (1 f): the synthesis was performed as in 1d to give 1f as a pale yellow solid with a yield of 50.7%. 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-ethylpiperazinylmethyl) benzothiazole (1 g): the synthesis was as in 1d to give 1g of a pale yellow solid with 53.6% yield. 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 procedure was the same as 1d, and a pale yellow solid was obtained in 1h with a yield of 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, yielding 1i as a pale yellow solid with 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 was performed as in 1d to give 1j as a pale yellow solid with a yield of 52.1%. 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-morpholinobenzothiazole (1 k): the synthesis was as in 1d to give 1k as a white solid with 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-chlorosulfonylbenzoic acid is taken as a raw material, dichloromethane is taken as a solvent, triethylamine is added, and the triethylamine and amines with different substituent groups are acylated to obtain benzenesulfonamide intermediates 2 a-f. The yield is between 39 and 84 percent.
Figure BDA0003790752780000071
4- [ N- (2-cyanoethyl) sulfamoyl]Preparation of benzoic acid (2 a): in ice bath, 10mL of CH 2 Cl 2 Adding 4-chlorosulfonylbenzoic acid (0.6g, 2.72mmoL), stirring for dissolving, adding 3-aminopropionitrile (0.38mL, 5.45mmoL), adding triethylamine (1.13mL, 8.16mmoL), reacting at room temperature, monitoring by TLC, removing solvent, adding distilled water, adjusting pH to 1 with diluted hydrochloric acid, extracting with EA for 3 times, washing with saturated saline solution, and collecting organic phase with anhydrous MgSO 4 After drying, the filtrate was filtered, distilled under reduced pressure, and washed with stirring (PE: EA ═ 10:1) to obtain 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): synthesis ofProcedure as in 2a gave 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-oxoprop-2-yl) sulfamoyl]Preparation of benzoic acid (2 c): the synthesis was as in 2a to give 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 was as in 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 as in 2a to give 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 radical]Preparation of benzoic acid (2 f): the synthesis was as in 2a to give 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)
Adding 30mL acetonitrile into 100mL eggplant-shaped bottle as solvent, and adding anhydrous CuCl 2 (0.46g, 3.40mmoL) is stirred and dissolved, tert-butyl nitrite (0.62mL, 5.16mmoL) is added dropwise in an ice bath, 2-aminobenzothiazole-6-ethyl formate (0.50g, 2.50mmoL) is added in three times in one time every 1h, the ice bath is removed, the reaction is carried out at room temperature, the reaction process is monitored by thin-layer chromatography, the reaction is completed in 6h, the solvent is removed by distillation under reduced pressure, 1N dilute hydrochloric acid solution is added into the reaction solution, extraction is carried out for three times by ethyl acetate, the organic phase is washed by distilled water and saturated brine in sequence, and the organic phase is washed by anhydrous Na 2 SO 4 Drying, concentrating the dried organic phase under reduced pressure, and purifying by column chromatography (PE: EA ═ 25:1) to give 3 as a white solid in 80.9% yield. 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 (4a)
2-chlorobenzothiazole-6-carboxylic acid ethyl ester (1.50g, 6.22mmoL) was dissolved in 5mL of DMF, and 4-Boc aminopiperidine (1.87g, 9.34mmoL) and cesium carbonate (4.05g, 12.44mmoL) were added thereto, and the mixture was transferred to an oil bath pan and reacted at 120 ℃ with monitoring of the reaction by thin layer chromatography. After 2h the reaction was complete, the reaction was cooled to room temperature and extracted with EA(30 mL. times.3), the organic phase was washed with distilled water and saturated brine in that order, and the organic phase was washed with anhydrous MgSO 4 After drying, filtration was performed under reduced pressure, and the filtrate was concentrated and then subjected to column chromatography (PE: EA ═ 5:1) to obtain 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 (4b)
The synthesis was performed as in 4a to give 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 (5a)
2- [4- (tert-butoxycarbonylamino) piperidine]Benzothiazole-6-carboxylic acid ethyl ester (1.50g, 3.70mmoL) is dissolved in 20mL CH 2 Cl 2 Trifluoroacetic acid (3.85mL, 51.85mmoL) is added to react at room temperature, after the completion of the reaction of the substrate is detected by thin-layer chromatography, saturated sodium carbonate is added to the reaction solution in an ice-water bath to adjust the pH to 7, a large amount of white solid is precipitated at this time, the reaction solution is filtered under reduced pressure, and the filter cake is washed with distilled water to obtain 1.04g of white solid with the yield of 92.1%. The crude product of this reaction is directly put into the next reaction without purification.
The synthesis of 5b was performed in the same manner as 5a, and was carried out in the next step without purification, with a yield of 89.5%.
Example 2: compound J 1 -J 19 Synthetic preparation and structural confirmation of
4-chlorosulfonylbenzoic acid is taken as a raw material, triethylamine is added, and the mixture and 3-aminopropionitrile are acylated to obtain an intermediate 2 a; then condensing with HATU, DIEA and intermediate 1 at room temperature to obtain target compound J 1 -J 19 . The synthetic route is as follows:
Figure BDA0003790752780000091
(1)4- [ N- (2-cyanoethyl) sulfamoyl]-N- [6- (methoxy) benzothiazol-2-yl]Benzamide (J) 1 ) Preparation of
Adding 4- [ N- (2-cyanoethyl) sulfamoyl to DMF]Benzoic acid (0.10g,0.39mmoL), DIEA (0.14mL,0.78mmoL), HATU (0.22g, 0.58mmoL), reacted for 2h in ice bath, to which was added 2-amino-6-methoxybenzothiazole (0.08g, 0.43mmoL), reacted at room temperature, and TLC (CH) 2 Cl 2 ：CH 3 OH 15:1) was completely reacted, 25mL of distilled water was added to the reaction solution, extracted three times with EA, washed with distilled water and saturated brine in this order, and the organic phase was washed with 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 give 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 ) Preparation of (2)
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxyReplacement of the phenylbenzothiazole with 2-amino-6-fluorobenzothiazole gave J as a pale yellow solid 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 ) Preparation of (2)
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-chlorobenzothiazole, giving a 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-aminobenzothiazole, giving a 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) benzamido]Benzothiazole-6-carboxylic acid ethyl ester (J) 5 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with ethyl 2-aminobenzothiazole-6-carboxylate to give a pale yellow solid J 5 The yield was 49.3%. 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]Benzoic acid ester (J) 6 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-hydroxybenzothiazole, giving a 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) benzamido]Benzothiazol-6-yl acetate (J) 7 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-acetoxybenzothiazole, giving a 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) benzamido]Benzothiazol-6-yl carbonate (J) 8 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-tert-butoxycarbonyloxybenzothiazole to give 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 ) Preparation of
Get J 8 (0.15g, 0.30mmoL) was dissolved in 10mL of methylene chloride, and trifluoroacetic acid (0.31mL, 4.18mmoL) was added thereto, stirred at room temperature, and the progress of the reaction was checked by thin layer chromatography. After the reaction was completed, the pH was adjusted to 7 with saturated sodium carbonate in an ice bath, and a white solid was precipitated, which was then filtered under reduced pressure, and the filter 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 group]-N- [6- (2-hydroxyethoxy) benzothiazol-2-yl]Benzamide (J) 10 ) Preparation of
To a three-necked flask was added 3mL of DMF, and J was added 9 (0.1g, 0.25mmoL), 2-bromoethanol (0.09mL, 1.27mmoL), and potassium carbonate (0.085g, 0.62mmoL) were added sequentially to the reaction flask with N 2 Protected and reacted at 60 ℃. TLC monitored the progress of the reaction. After 4h of reaction, the reaction solution was cooled to room temperature, ice distilled water was added to the reaction solution and stirred, and a solid precipitated, and the filtrate was filtered under reduced pressure, and the filter 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced with 2-amino-6-dimethylaminomethylbenzothiazole, giving 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 ) Preparation of (2)
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6 diethylaminomethylbenzothiazole, giving 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (4-methylpiperazinomethyl) benzothiazole to give a 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-ethylpiperazinylmethyl) benzothiazol-2-yl]Benzamide (J) 14 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (4-ethylpiperazinylmethyl) benzothiazole to give 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) benzothiazol-2-yl]Benzamide (J) 15 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (3-methylpiperidinylmethyl) benzothiazole, giving 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- (morpholinomethyl) benzothiazol-2-yl]Benzamide (J) 16 ) Preparation of (2)
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (morpholinomethyl) benzothiazole, giving 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (4-tert-butoxycarbonylpiperazinylmethyl) benzothiazole to give a 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6- (piperazinylmethyl) benzothiazole, giving 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 2-amino-6-morpholinylbenzothiazole, giving a 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
Sequentially adding 2-amino-6-n-butylbenzothiazole (1a), DIEA, HATU and mono-substituted or poly-substituted benzoic acid into DMF, and reacting at room temperature to obtain a target compound J 20 -J 24 The synthetic route is as follows:
Figure BDA0003790752780000151
(1) n- (6-butylbenzothiazol-2-yl) -2, 6-difluorobenzamide (J) 20 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 6-difluorobenzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 Region ofOther than replacing 2-amino-6-methoxybenzothiazole with 2-amino-6-butylbenzothiazole, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3-trifluoromethylbenzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid was replaced with 3-trifluoromethoxybenzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2-trifluoromethylbenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid was replaced with 2-trifluoromethoxybenzoic acid to give 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-amino-6-n-butylbenzothiazole is taken as a raw material and condensed with various substituted benzene sulfonamide intermediates 2 to obtain a target compound J 25 -J 29 The synthetic route is as follows:
Figure BDA0003790752780000161
(1) { [4- (6-n-butylbenzothiazol-2-yl) carbamoyl]Phenylsulfonyl } glycine ethyl ester (J) 25 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 4- [ N- (ethoxyformylmethyl) sulfamoyl]Benzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 4- [ N- (1-Methoxycarbonylethyl) sulfamoyl]Benzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino is substitutedReplacement of-6-methoxybenzothiazole with 2-amino-6-butylbenzothiazole, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 4- [ N- (1-methoxycarbonyl-2-methylpropyl) sulfamoyl]Benzoic acid to give 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 ) Preparation of (2)
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 4- [ N- (1-methoxycarbonyl-2-methylbutyl) sulfamoyl]Benzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 2-amino-6-butylbenzothiazole and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 4- [ N- (1-methoxycarbonyl-2-phenylethyl) sulfamoyl]Benzoic acid to give 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
Anhydrous CuCl is added 2 Adding tert-butyl nitrite into a reaction bottle, taking acetonitrile as a solvent, adding 2-aminobenzothiazole-6-ethyl formate, reacting at room temperature to obtain an intermediate 3, performing alkylation reaction on the intermediate 3 and 4-Boc aminopiperidine (1-Boc piperazine) to obtain an intermediate 4, deprotecting the intermediate 4, and finally condensing with benzoic acid with different substituents to obtain a D-class target product J 30 -J 49 The synthetic route is as follows:
Figure BDA0003790752780000191
(1)2- {4- [4- [ N- (2-cyanoethyl) sulfamoyl]Benzamido group]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 30 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 5a, giving a 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-difluorobenzamido) piperidyl]Benzothiazole-6-carboxylic acid ethyl ester (J) 31 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 6-difluorobenzoic acid to give a white solid J 31 The yield was 48.0%. The melting point is 245.1-247.4 deg.C. 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 3-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 4-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3, 4-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 6-Dichlorobenzoic acid to give J as a white solid 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) benzamido]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 36 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3-trifluoromethylbenzoic acid to give 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) benzamido]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 37 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid was replaced with 3-trifluoromethoxybenzoic acid to give a 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) benzamido]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 38 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2-trifluoromethylbenzoic acid to give J as a white solid 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) benzamido]Piperidinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 39 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5a, 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid was replaced with 2-trifluoromethoxybenzoic acid to give a white solid J 39 The 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 radical]Piperazinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 40 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole was replaced by 5b, giving a 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxyReplacement of the phenylbenzothiazole by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 6-difluorobenzoic acid to give 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 3-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 4-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3, 4-Dichlorobenzoic acid to give J as a white solid 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 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2, 6-Dichlorobenzoic acid to give J as a white solid 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) benzamido]Piperazinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 46 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3-trifluoromethylbenzoic acid to give 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) benzamido]Piperazinyl benzothiazole-6-carboxylic acid ethyl ester (J) 47 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b, 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 3-trifluoromethoxybenzoic acid to give J as a white solid 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) benzamido]Piperazinyl benzothiazole-6-carboxylic acid ethyl ester (J) 48 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]Replacement of benzoic acid with 2-trifluoromethylbenzoic acid to give J as a white solid 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) benzamido]Piperazinyl } benzothiazole-6-carboxylic acid ethyl ester (J) 49 ) Preparation of
The synthesis method is the same as J 1 With the difference that 2-amino-6-methoxybenzothiazole is replaced by 5b and 4- [ N- (2-cyanoethyl) sulfamoyl]The benzoic acid was replaced with 2-trifluoromethoxybenzoic acid to give 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] +
Compounds J synthesized in examples 2 to 5 above 1 ～J 49 The arrangement is shown in the following table.
Figure BDA0003790752780000251
Figure BDA0003790752780000261
Figure BDA0003790752780000271
Figure BDA0003790752780000281
Figure BDA0003790752780000291
Figure BDA0003790752780000301
The drug effect example: PCSK9 inhibitory Activity
1. Cell culture
Culturing human liver cancer cell strain HepG2 in MEM culture medium containing 10% fetal calf 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 inhibitory activity test method
PCSK9 p-LUC HepG2 cells were collected in the logarithmic growth phase, and the cells were treated with 100. mu.L of single cell suspension per well in a 96-well plate, and the cell number was controlled at about 5X 10 5 /mL。
Culturing the cells for 6-8h, removing the original culture medium after the cells are completely attached to the wall, and rinsing the cells once by using a buffer solution. A5. mu.g/ml solution of the compound was added to each well, with two duplicate wells for each compound.
After 18-24h the medium was removed, the buffer was rinsed 1 time, 25. mu.l of cell lysate was added to the well plate and the cells were lysed at 37 ℃ for 30-45 min. After the cells are completely lysed, 50 mul of firefly luciferase detection reagent is rapidly added into each hole, and the analysis white plate is immediately placed into an enzyme labeling instrument for detection.
The following calculation formula is the influence of the test compound on the inhibition activity of PCSK 9: PCSK9 activity inhibition (%) - (luciferase activity after addition of blank control sample-luciferase activity after addition of compound)/luciferase activity after addition of blank control sample × 100%. When the inhibition rate of the compound to be tested is more than or equal to 50 percent, the result is positive.
The pharmacological activity test experiment is completed by the national new drug screening center.
3. Test results
The study tested the inhibitory activity of the 49 target compounds synthesized above on PCSK9, with the results shown in the table below, 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 inhibitory effect on PCSK 9.
Figure BDA0003790752780000311
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims (7)

1. A benzothiazole compound, which is a compound shown as a general formula I, II or III, or a pharmaceutically acceptable salt thereof:
Figure FDA0003790752770000011
wherein, in the general formula I,n is 0 or 1, R 1 Is 3-methyl-1-piperidyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl;
Figure FDA0003790752770000012
wherein in the general formula II, R 2 Is 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl;
Figure FDA0003790752770000013
wherein, in the formula III, the A ring moiety represents
Figure FDA0003790752770000014
R 4 Is 2, 3-dichloro, 2, 4-dichloro, 3, 4-dichloro, 2, 6-dichloro, 3-trifluoromethyl or 2-trifluoromethoxy.
2. A process for the preparation of compounds of formula i according to claim 1, characterized in that the synthesis and the synthetic route are as follows: 4-chlorosulfonylbenzoic acid is taken as a raw material, triethylamine is added, and the mixture and 3-aminopropionitrile are acylated to obtain an intermediate 2 a; then condensing with HATU, DIEA and the intermediate 1 at normal temperature to obtain the compound;
Figure FDA0003790752770000016
wherein n is 0 or 1, R 1 Is 3-methyl-1-piperidyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl, 1-morpholinyl or 1-piperazinyl.
3. A process for the preparation of a compound of formula ii according to claim 1, characterized in that the synthesis and the synthetic route are as follows: sequentially adding 2-amino-6-n-butylbenzothiazole (1a), DIEA, HATU and mono-substituted or poly-substituted benzoic acid into DMF, and reacting at normal temperature to obtain the compound I;
Figure FDA0003790752770000015
wherein in the general formula II, R 2 Is 2, 6-difluoro, 3-trifluoromethoxy, 3-trifluoromethyl or 2-trifluoromethyl.
4. A process for the preparation of a compound of formula iii according to claim 1, characterized in that the synthesis and the route of synthesis are as follows: anhydrous CuCl is added 2 Adding tert-butyl nitrite into a reaction bottle, taking acetonitrile as a solvent, then adding 2-aminobenzothiazole-6-ethyl formate, reacting at normal temperature to obtain an intermediate 3, carrying out alkylation reaction on the intermediate 3 and 4-Boc aminopiperidine to obtain an intermediate 4, deprotecting the intermediate 4, and finally condensing with benzoic acid with different substituents to obtain the intermediate;
Figure FDA0003790752770000021
wherein, in the general formula III, the dotted line is
Figure FDA0003790752770000022
When the 4-Boc aminopiperidine is used, 1-Boc piperazine is used instead of the 4-Boc aminopiperidine;
R 4 is 2, 3-dichloro, 2, 4-dichloro, 3, 4-dichloro, 2, 6-dichloro, 3-trifluoromethyl or 2-trifluoromethoxy.
5. Use of the benzothiazole compounds of claim 1 for the manufacture of a PCSK9 inhibitor medicament.
6. Use of the benzothiazole compounds of claim 1 for the preparation of a medicament for the treatment of a disease that is treated or alleviated by the blockade of PCSK 9.
7. The use according to claim 6, said disease comprising hypercholesterolemia.
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