CN110483496B - Derivative with uracil-benzothiazole structure, preparation method thereof and application of anti-HCV (hepatitis C virus) medicament - Google Patents

Derivative with uracil-benzothiazole structure, preparation method thereof and application of anti-HCV (hepatitis C virus) medicament Download PDF

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CN110483496B
CN110483496B CN201910647056.9A CN201910647056A CN110483496B CN 110483496 B CN110483496 B CN 110483496B CN 201910647056 A CN201910647056 A CN 201910647056A CN 110483496 B CN110483496 B CN 110483496B
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uracil
benzothiazole
thiazol
benzo
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CN110483496A (en
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席建军
庄让笑
张建康
何若愚
赵艳梅
邵益丹
潘旭旺
刘寿荣
蔡兆斌
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Hangzhou Xixi Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Abstract

The invention designs and synthesizes uracil-benzothiazole NS5B RdRp inhibitor with a brand-new structure, which has the structure of a general formula (1):

Description

Derivative with uracil-benzothiazole structure, preparation method thereof and application of anti-HCV (hepatitis C virus) medicament
Technical Field
The invention relates to the field of medicines, in particular to a novel derivative with a uracil-benzothiazole structure, a preparation method and application thereof, and application of the compound in preparation of anti-hepatitis C medicines.
Background
Hepatitis C (Hepatitis C) is an infectious liver disease that seriously threatens human health and is caused by Hepatitis C Virus (HCV), which is mainly replicated in hepatocytes, damages the hepatocytes, causes inflammation, degeneration and necrosis of the hepatocytes, is the most important cause of liver cirrhosis and liver cancer, and is extremely harmful to the health and life of patients. HCV is prevalent worldwide, and according to the statistics of the World Health Organization (WHO), the global HCV infection rate is 2.8%, about 1.85 million people are infected with HCV, and nearly 40 million patients die each year due to HCV infection (model Practical medicine.2018,30,284 286). At present, no vaccine is available for HCV, timely antiviral therapy is the key for improving prognosis, and direct-acting antiviral Drugs (DAAs) can clear viruses by directly acting on target targets of HCV, so that the development of DAAs therapeutic drugs with novel, high-efficiency and small toxic and side effects is urgent.
NS5B is a nonstructural protein that plays an important role in HCV replication, and the protein gene encodes a 591 amino acid NS5B protein that encodes an RNA-dependent RNA polymerase (RdRp) necessary for HCV replication, the catalytic center of NS5B polymerase consists of the N-terminal 530 amino acids, and the last 21 highly hydrophobic amino acids of the C-terminal bind to the membrane of the host cell, thereby anchoring NS5B to the cell membrane and interacting with its catalytic center to modulate RdRp activity of NS 5B. RdRp plays a crucial role in the replication process of HCV, and an entire negative strand RNA is synthesized by using the RNA gene of the virus as a template, and a positive strand HCV RNA is synthesized by using the negative strand as a template, while cells not infected by HCV in vivo do not express NS5B, and RNA-dependent RNA polymerase (RdRp) plays a crucial role in the replication process. Therefore, NS5B RdRp has become an important target and research hotspot for anti-HCV drug development.
Disclosure of Invention
Aiming at the defects of the prior art, the technical problems to be solved by the invention are as follows: uracil-benzothiazole NS5B RdRp inhibitors with a brand-new structure are designed and synthesized, and activity evaluation is carried out on the compounds. The results show that the compounds have better HCV inhibitory activity, and are expected to provide a new drug selection for clinical treatment of HCV as a novel NS5B RdRp inhibitor.
The object of the present invention is to provide a novel uracil-benzothiazole NS5B RdRp inhibitor compound having the following general structure:
Figure BDA0002133934080000021
wherein:
l is selected from
Figure BDA0002133934080000022
Wherein R iseSelected from H, C1-C3An alkyl group;
r is independently selected from C5-C7Aryl, heterocyclic, heteroaromatic and halogen-substituted aryl of (a);
halogen is selected from fluorine and chlorine;
the 'aryl' in the invention is a benzene ring preferably substituted by benzene ring and halogen.
As used herein, "heteroaryl" refers to an unsaturated carbocyclic ring of 5 to 6 ring atoms in which one or more carbons are replaced with a heteroatom such as nitrogen, oxygen, etc. Heteroaryl groups according to the invention are, for example, pyridyl and pyrazinyl.
The "heterocyclyl" according to the present invention is a carbocyclic group having at least one ring in which at least one carbon atom is replaced by a heteroatom, preferably a heteroatom selected from N, O, S, and which is saturated or partially unsaturated, said heterocyclyl preferably being piperidinyl, piperazinyl, pyridinyl, morpholinyl.
The "alkyl" groups described herein (by themselves or as part of a chemical group) are straight or branched chain hydrocarbons, preferably having from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.
Further, L is selected from
Figure BDA0002133934080000023
Wherein R iseSelected from H, C1-C2An alkyl group;
r is selected from C5-C6Aryl of (a), a phenyl ring, a fluoro-substituted phenyl ring, pyridyl, piperazinyl, morpholinyl,
C1-C2the alkyl group is selected from the group consisting of methyl and ethyl,
the halogen is selected from the group consisting of fluorine,
further, L is selected from
Figure BDA0002133934080000024
Wherein R iseIs selected from the group consisting of H or methyl,
r is selected from C6Aryl of (a), a phenyl ring, a fluoro-substituted phenyl ring, pyridyl, piperazinyl, morpholinyl,
the aryl is selected from benzene ring and substituted benzene ring;
the heterocyclic radical is selected from piperidyl, piperazinyl, methylpiperazine and morpholinyl.
More specifically, the uracil-benzothiazole structure derivative having the structure of the general formula (i) of the present invention is preferably:
compound 1: n- (4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) methanesulfonamide
Compound 2: 4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N, N-dimethylbenzenesulfonamide
Compound 3: 4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N- (4-fluorophenyl) benzamide
Compound 4: n- (4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide
Compound 5: 1- (2- (4- (4-methylpiperazine-1-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione
Compound 6: 1- (2- (4- (morpholine-4-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione
The invention also provides a preparation method of the uracil-benzothiazole structure derivative with the structure of the general formula (I), the compound of the general formula (I) is prepared by the reaction of three main components of the compound, namely a head (II), a center (III) and a tail (IV) of the compound, and the synthetic route of part of the compound of the general formula (I) is as follows:
Figure BDA0002133934080000031
as shown in the reaction formula, the intermediate (V) is obtained by reacting the center (III) and the head (II) of the formula under the condition of DMF, then the intermediate (VI) is synthesized by cyclization under the alkaline condition, and the intermediate (VI) and the tail (IV) of the formula are reacted under the existence of alkali and a catalyst to finally obtain the target compound (I).
Wherein: l is selected from
Figure BDA0002133934080000032
Wherein R iseSelected from H or methyl;
r is independently selected from C5-C7Aryl, heterocyclic, heteroaryl, and halogen-substituted aryl.
Another object of the present invention is to provide a pharmaceutical composition comprising the uracil-benzothiazole structure derivative of the present invention having the structure of general formula (I) as an active ingredient, and one or more pharmaceutically acceptable carriers.
The carrier includes conventional diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc., and flavoring agent, sweetener, etc. may be added if necessary. The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field.
The pharmaceutical composition comprises various pharmaceutical dosage forms, such as oral administration, injection, inhalation, implantation and the like, and preferably injection administration and oral administration; the dosage forms of the composition provided by the invention are injection, freeze-dried powder injection, tablets, capsules or granules and other dosage forms.
The pharmaceutical compositions of the present invention and the various formulations of the compositions can be prepared using conventional pharmaceutical carriers.
The invention also provides application of uracil-benzothiazole structure derivatives with the structure of the general formula (I), and a preferable compound in any form and a pharmaceutical composition thereof in preparing a medicament for treating hepatitis C.
Experiments prove that the uracil-benzothiazole NS5B RdRp inhibitor synthesized by the invention has better inhibitory activity on the replication of HCV. The compound of the invention has the advantages of easily obtained raw materials for synthesis, reasonable route design, mild reaction conditions, high yield of each step, simple and convenient operation and suitability for industrial production.
Detailed Description
In order to better understand the essence of the invention, the invention is further illustrated in the following examples, however, the examples of the invention are intended to illustrate the invention and not to limit the invention, and simple modifications made to the invention according to the essence of the invention are within the scope of the invention as claimed.
EXAMPLE 12 Synthesis of bromo-6-nitro-benzo [ d ] thiazole (Compound 2)
Figure BDA0002133934080000041
2-amino-6-nitrobenzothiazole (10.0g, 51.0mmol) and CuBr (0.88g,6.1mmol) were suspended in 48% aqueous HBr (100mL) and water (90mL), and NaNO was added slowly2(30.5g,442mmol), continuing to react for 1 hour at room temperature, extracting with DCM and EtOAC respectively after the reaction is finished to obtain a crude product, then recrystallizing with isopropanol, filtering and drying to obtain the compound. The yield is 88.4%;1H-NMR(400MHz,CDCl3):δ＝8.78(d,J＝2.0Hz,1H),8.38(dd,J＝1.6Hz,7.2 Hz,1H),8.11(d,J＝7.2Hz,1H)。
EXAMPLE 22 Synthesis of bromo-6-amino-benzo [ d ] thiazole (Compound 3)
Figure BDA0002133934080000042
Compound 2(45mmol,11.6g), Fe (225mmol,12.6g), NH4Placing Cl (135mmol,7.22g) in a 500mL round-bottom flask, adding anhydrous ethanol (150mL) and water (50mL), heating and refluxing for 2-3h at 100 ℃ under the protection of nitrogen, filtering with diatomite while the reaction is still hot, and filtering the filtrate with K2CO3After adjusting the pH to the base, the mixture was extracted with DCM (50 mL. times.2), the solvent was distilled off under reduced pressure, and isopropyl alcohol was addedRecrystallization of the alcohol gives compound 3. The yield is 78.2%;1H-NMR(400MHz,d6-DMSO):δ＝7.61(d,J＝7.6Hz, 1H,Ar),7.05(d,J＝2.0Hz,1H,Ar),6.76(dd,J＝1.6Hz,6.8Hz,1H,Ar),5.53(s,2H,NH)。
example 3 Synthesis of (E) -N- ((2-bromobenzo [ d ] thiazol-6-yl) carbamoyl) -3-ethoxyacrylamide (Compound 6)
Figure BDA0002133934080000051
Silver isocyanate (12.0g,80mmol) at 100 ℃ in P2O5Vacuum drying, adding 80mL of anhydrous toluene, protecting with nitrogen, keeping out of the sun, and heating and refluxing for 0.5 h; dissolving 3-ethoxyacryloyl chloride (4.82g,40mmol) in 15mL of anhydrous toluene, slowly dripping the solution into the reaction solution, continuously heating and refluxing for 0.5h, and reacting at room temperature for 3 h;
dissolving the compound 3(1.64g,7.14mmol) in an anhydrous DMF solution (60mL), slowly adding the supernatant of the reaction solution into the reaction solution, reacting at room temperature overnight, concentrating and evaporating the solvent after the reaction is finished, and performing column chromatography (EtOAC: PE 5: 3) to obtain a compound 6 with the yield of 71.9%;1H-NMR(400MHz,CDCl3):δ＝11.1(s,1H,Ar),10.6(s,1H,Ar), 8.43(d,J＝2.0Hz,1H,CH),7.93(d,J＝7.2Hz,1H,CH),7.71(dd,J＝2.0Hz,7.2Hz,1H,Ar),7.55(q, J＝2.0Hz,7.2Hz,1H,NH),5.61(d,J＝9.6Hz,1H,NH),4.02(q,J＝5.6Hz,11.2Hz,2H,CH2), 1.28(t,J＝5.6Hz,11.2Hz,3H,CH3)。
EXAMPLE 41 Synthesis of- (2-bromobenzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione (Compound 7)
Figure BDA0002133934080000052
Compound 6(2.0g,3.6mmol) was placed in a 500mL round bottom flask and 14M NH was added4OH (200mL) and 1, 4-dioxane (50mL) were heated under reflux for 48h, the solvent was evaporated under reduced pressure, the solid was washed with methanol and filtered to give compound 7. The yield is 80.2%;1H-NMR(400MHz,d6-DMSO):δ＝11.5(s,1H,Ar),8.24(d,J＝2.0Hz,1H,Ar), 8.10(d,J＝8.8Hz,1H,CH),7.80(d,J＝8.0Hz,1H,CH),7.55(q,J＝2.0Hz,8.4Hz,1H,Ar)；5.73(d, J＝7.6Hz,1H,NH)。
example 5 Synthesis of N- (4-bromophenyl) nicotinamide (Compound 8)
Figure BDA0002133934080000061
Nicotinic acid (12mmol, 1.48g) was dissolved in 50mL of dichloromethane, HOBt (12mmol,1.62g) and EDCI (18mmol, 3.46g) were added and reacted at room temperature for 30 min. 4-bromoaniline (10mmol, 1.72g) and N, N-diisopropylethylamine (12mmol, 2.1mL) were added to the reaction mixture and reacted at room temperature for 2 h. Diluting with 50mL of saturated sodium bicarbonate, separating the organic layer, washing with saturated brine (50 mL. times.1), drying over anhydrous sodium sulfate, recovering the solvent under reduced pressure, and separating by column chromatography (EtOAC: CH)2Cl21:2) compound 8 is obtained. The yield is 93.9%;1H-NMR(400MHz,CDCl3):δ＝9.08(d,J＝2.0Hz,1H,Pyridine-H), 8.78(dd,J＝1.6Hz,4.8Hz,1H,Pyridine-H),8.20(td,J＝2.0Hz,8.0Hz,1H,Pyridine-H),7.95(s,1H, Pyridine-H),7.57-7.56(m,2H,Ar),7.51-7.49(m,2H,Ar),7.47-7.44(m,1H,NH)。
EXAMPLE 6 Synthesis of N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) nicotinamide (Compound 9)
Figure BDA0002133934080000062
Compound 8(886.8mg,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, evaporating under reduced pressure to remove solvent, and separating by column chromatography (EtOAC: CH)2Cl21:2) to obtain the compound 9. Yield: 58.5 percent;1H-NMR(400MHz,CDCl3):δ＝9.10(d,J＝2.0Hz,1H,Pyridine-H),8.78(dd,J ＝1.6Hz,4.8Hz,1H,Pyridine-H),8.22(td,J＝2.0Hz,7.6Hz,1H,Pyridine-H),7.90(s,1H, Pyridine-H),7.84(d,J＝8.4Hz,2H,Ar),7.67(m,2H,Ar),7.47-7.44(m,1H,NH),1.35(s,12H, 4CH3)。
EXAMPLE 74 Synthesis of bromo-N- (4-fluorophenyl) benzamide (Compound 10)
Figure BDA0002133934080000063
To bromobenzoic acid (12mmol, 2.4g) was dissolved in 50mL of dichloromethane, HOBt (12mmol,1.62g) and EDCI (18mmol, 3.46g) were added and reacted at room temperature for 30 min. 4-fluoroaniline (10mmol, 1.11g) and N, N-diisopropylethylamine (12mmol, 2.1mL) were then added to the reaction mixture and reacted at room temperature for 2 h. After diluting with 50mL of saturated sodium bicarbonate, the organic layer was separated, washed with saturated brine (50 mL. times.1), dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure, and separated by column chromatography (EtOAC: PE 1:5) to obtain Compound 10. Yield: 91.5 percent;1H-NMR(400MHz,CDCl3):δ＝7.79(s,1H,NH),7.73(d, J＝8.4Hz,2H,Ar-H),7.63(d,J＝8.4Hz,2H,Ar-H),7.60-7.56(m,2H,Ar-H),7.07(t,J＝8.4,17.2 Hz,2H,Ar-H,NH)。
EXAMPLE 8 Synthesis of N- (4-fluorophenyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (Compound 11)
Figure BDA0002133934080000071
Compound 10(941.2mg,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4After drying, the solvent was evaporated under reduced pressure and column chromatography (EtOAC: PE 1:5) was carried out to give compound 11. Yield: 60.7 percent;1H-NMR(400MHz,CDCl3):δ＝7.92(d,J＝8.0Hz,2H,Ar-H),7.85-7.82(m,3H, Ar-H),7.63-7.59(m,3H,Ar-H),7.07(t,J＝8.8,17.6Hz,2H,Ar-H,NH),1.37(s,12H,4CH3)。
EXAMPLE 9 Synthesis of (4-bromophenyl) (4-methylpiperazin-1-yl) methanone (Compound 12)
Figure BDA0002133934080000072
To bromobenzoic acid (12mmol, 2.4g) was dissolved in 50mL of dichloromethane, HOBt (12mmol,1.62g) and EDCI (18mmol, 3.46g) were added and reacted at room temperature for 30 min. 4-methylpiperazine (10mmol, 1.00g) and N, N-diisopropylethylamine (12mmol, 2.1mL) were added to the reaction mixture at once and reacted at room temperature for 2 h. Diluting with 50mL of saturated sodium bicarbonate, separating the organic layer, washing with saturated brine (50 mL. times.1), drying over anhydrous sodium sulfate, recovering the solvent under reduced pressure, and separating by column Chromatography (CH)2Cl2: MeOH 50:1) affords compound 12. Yield: 89.6 percent;1H-NMR(400MHz,CDCl3):δ＝7.56-7.53(m,2H, Ar-H),7.30-7.28(m,2H,Ar-H),3.78(s,2H,CH2),3.43(s,2H,CH2),2.48-2.47(m,2H, CH2),2.35-2.32(m,5H,CH2,CH3)。
example 10 Synthesis of (4-methylpiperazin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone (Compound 13)
Figure BDA0002133934080000081
Compound 12(1.06g,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, distilling off solvent under reduced pressure, and separating by column Chromatography (CH)2Cl2: MeOH 50:1) to yield the compoundAnd (3) a substance 13. Yield: 59.6 percent;1H-NMR(400MHz,CDCl3):δ＝7.84(d,J＝7.6Hz,2H,Ar-H),7.38(d,J＝8.0 Hz,2H,Ar-H),3.80(s,2H,CH2),3.40(s,2H,CH2),2.49(s,2H,CH2),2.32(s,2H,CH2),1.35(s,12H, 4CH3)。
EXAMPLE 11 Synthesis of (4-bromophenyl) (morpholine) methanone (Compound 14)
Figure BDA0002133934080000082
To bromobenzoic acid (12mmol, 2.4g) was dissolved in 50mL of dichloromethane, HOBt (12mmol,0.87g) and EDCI (18mmol, 3.46g) were added and reacted at room temperature for 30 min. Morpholine (10mmol, 1.11g) and N, N-diisopropylethylamine (12mmol, 2.1mL) were then added to the reaction mixture and allowed to react at room temperature for 2 h. After diluting with 50mL of saturated sodium bicarbonate, the organic layer was separated, washed with saturated brine (50 mL. times.1), dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure, and separated by column chromatography (EtOAC: PE 1:1) to obtain Compound 14.1H-NMR(400MHz,CDCl3):δ＝7.57-7.55(m,2H,Ar-H),7.30-7.28(m,2H, Ar-H),3.83-3.45(m,8H,CH2)。
EXAMPLE 12 Synthesis of morpholine (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone (Compound 15)
Figure BDA0002133934080000091
Compound 14(1.02g,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4After drying, the solvent was evaporated under reduced pressure and column chromatography (EtOAC: PE 1:1) was carried out to give compound 15.1H-NMR(400MHz,CDCl3):δ＝7.85(d,J＝8.0Hz,2H,Ar-H),7.39(d,J＝8.0Hz,2H, Ar-H),3.77-3.40(m,8H,CH2),1.35(s,12H,4CH3)。
EXAMPLE 13 Synthesis of N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (Compound 16)
Figure BDA0002133934080000092
N, N-dimethyl-4-bromobenzenesulfonamide (845.1mg,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4After drying, the solvent was evaporated under reduced pressure and column chromatography (EtOAC: PE 1:3) was carried out to give compound 16. Yield: 53.8 percent;1H-NMR(400MHz,CDCl3):δ＝7.96(d,J＝8.4Hz,2H,Ar-H), 7.76(d,J＝8.0Hz,2H,Ar-H),2.69(s,6H,2CH3),1.36(s,12H,4CH3)。
EXAMPLE 14 Synthesis of N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanesulfonamide (Compound 17)
Figure BDA0002133934080000093
N- (4-bromophenyl) methanesulfonamide (800.4mg,3.2mmol), (BPIN)2(2.03g,8.0mmol),Pd(dppf)Cl2(263.2mg, 322.4. mu. mol) and Na2CO3(678.4mg,6.4mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, evaporating under reduced pressure to remove solvent, and separating by column chromatography (EtOAC: CH)2Cl21:3) to give compound 16. Yield: 63.2 percent;1H-NMR(400MHz,CDCl3):δ＝10.0(s,1H,NH),7.63(d,J＝8.4Hz, 2H,Ar-H),7.21(d,J＝8.4Hz,2H,Ar-H),3.02(s,3H,CH3),1.28(s,12H,4CH3)。
EXAMPLE 15 Synthesis of N- (4- (6- (2, 4-dione-3, 4-dihydropyridin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) methanesulfonamide (Compound 18)
Figure BDA0002133934080000101
Compound 7(400.2mg,1.6mmol), compound 17(535.0mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, vacuum evaporating to remove solvent, and separating by column chromatography to obtain compound 18.1H-NMR(400 MHz,d6-DMSO):δ＝11.5(s,1H,NH),10.3(s,1H,NH),8.25(s,1H,Ar-H),8.10(d,J＝6.0Hz,3H, Ar-H,CH),7.82(d,J＝7.6Hz,1H,Ar-H),7.58(d,J＝8.4Hz,1H,Ar-H),7.39(d,J＝8.4Hz,2H, Ar-H),5.72(d,J＝7.6Hz,1H,CH),3.13(s,3H,CH3)；13C NMR(100MHz,d6-DMSO):δ＝169.0, 164.2,153.6,151.0,146.1,142.2,136.4,135.0,129.2,127.9,126.5,123.2,121.5,119.4,102.2. ESI-MS:m/z＝415.1[M+H]+。
EXAMPLE synthesis of 164- (6- (2, 4-dione-3, 4-dihydropyridin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N, N-dimethylmethanesulfonamide (Compound 19)
Figure BDA0002133934080000102
Compound 7(400.2mg,1.6mmol), compound 16(560.2mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, vacuum evaporating to remove solvent, and separating by column chromatography to obtain compound 19.1H-NMR(400 MHz,CDCl3):δ＝8.28(d,2H,J＝8.4Hz,Ar-H),8.21(d,1H,J＝8.0Hz,CH),7.99(s,1H,NH), 7.93(d,2H,J＝8.4Hz,Ar-H),7.51-7.49(m,1H,Ar-H),7.43(d,J＝8.0Hz,1H,Ar-H),5.89(d,J＝ 7.6Hz,2H,Ar-H,CH),2.78(s,6H,2CH3)；13C NMR(100MHz,d6-DMSO):δ＝164.9,162.4, 150.4,150.1,146.1,142.8,140.9,139.8,139.3,138.0,131.4,129.8,121.4,121.4,121.1,115.0, 98.3,35.8.ESI-MS:m/z＝429.1[M+H]+。
Example 17 Synthesis of N- (4- (6- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide (Compound 20)
Figure BDA0002133934080000111
Compound 7(400.2mg,1.6mmol), compound 9(583.5mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, evaporating the solvent under reduced pressure, and performing column chromatography to obtain the compound 20.1H-NMR(400 MHz,CDCl3):δ＝9.70(s,1H,NH),8.96(d,1H,J＝8.0Hz,pyridine-H),8.68(dq,1H,J＝8.0Hz, pyridine-H),8.12-8.10(m,2H,pyridine-H,Ar-H),7.99-7.98(m,2H,Ar-H),7.70-7.69(m,2H,Ar-H), 7.65(d,J＝6.0Hz,1H,Ar-H),7.60(d,J＝6.0Hz,1H,CH),7.48(t,J＝5.6Hz,11.6Hz,1H, pyridine-H),7.32(dq,1H,J＝8.0Hz,Ar-H),5.89(d,1H,J＝8.0Hz,CH)；13C NMR(100MHz, d6-DMSO):δ＝169.9,164.9,162.4,150.4,150.4,150.1,149.1,144.4,142.8,139.8,138.0,135.8, 134.4,129.8,127.5,124.3,122.3,121.4,121.1,115.0,98.3.ESI-MS:m/z＝442.3[M+H]+。
EXAMPLE 184 Synthesis of (6- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N- (4-fluorophenyl) benzamide (Compound 21)
Figure BDA0002133934080000112
Compound 7(400.2mg,1.6mmol), compound 11(614.1mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, evaporating the solvent under reduced pressure, and performing column chromatography to obtain the compound 21.1H-NMR(400 MHz,CDCl3):δ＝9.63(s,1H,NH),8.96(d,1H,J＝8.0Hz,Ar-H),7.94(d,2H,J＝6.0Hz,Ar-H), 7.80(d,2H,J＝6.0Hz,Ar-H),7.65(d,1H,J＝6.0Hz,Ar-H),7.60(d,J＝6.0Hz,1H,CH), 7.44-7.41(m,2H,Ar-H),7.33(dq,1H,J＝8.0Hz,Ar-H),7.13(t,2H,J＝6.0Hz,12.4Hz,Ar-H), 5.89(d,1H,J＝8.4Hz,CH)；13C NMR(100MHz,d6-DMSO):δ＝167.6,164.92,162.4,160.0, 150.4,150.1,142.8,139.8,138.0,137.2,136.7,134.3,128.5,128.1,123.3,121.4,121.1,116.1, 115.0,98.3.ESI-MS:m/z＝459.1[M+H]+。
Example Synthesis of 191- (2- (4- (4-methylpiperazine-1-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione (Compound 22)
Figure BDA0002133934080000121
Compound 7(400.2mg,1.6mmol), compound 13(594.4mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, vacuum evaporating to remove solvent, and separating by column chromatography to obtain compound 22.1H-NMR(400 MHz,CDCl3):δ＝8.13(d,1H,J＝8.0Hz,Ar-H),7.98-7.97(m,2H,Ar-H),7.88-7.87(m,2H,Ar-H), 7.69(d,1H,J＝6.0Hz,Ar-H),7.61(d,1H,J＝8.8Hz,CH),7.36-7.35(m,1H,Ar-H),5.89(d,1H,J ＝8.8Hz,CH),3.62(t,2H,J＝4.0Hz,8.4Hz,CH2),3.52-3.50(m,2H,CH2),2.69-2.59(m,2H, CH2),2.39-2.37(m,2H,CH2),2.27(s,3H,CH3)；13C NMR(100MHz,d6-DMSO):δ＝169.4, 164.9,162.4,150.4,150.1,142.8,139.8,138.0,137.5,135.0,127.7,127.1,121.4,121.1,114.9, 98.5,52.7,46.0,44.6.ESI-MS:m/z＝448.4[M+H]+。
Example 201 Synthesis of- (2- (4- (morpholine-4-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione (Compound 23)
Figure BDA0002133934080000131
Compound 7(400.2mg,1.6mmol), compound 15(570.9mg,1.8mmol), Pd (dppf) Cl2(131.6mg, 161.2. mu. mol) and Na2CO3(339.2mg,3.2mmol) in DMF/H2O (10/1,20mL) solution was heated to reflux under nitrogen overnight. After the reaction was complete, water (20mL) was added, DCM (50mL) was added for dilution, and DCM was used for extraction (50 mL. times.3). The organic layers were combined and Na was added2SO4Drying, evaporating the solvent under reduced pressure, and performing column chromatography to obtain the compound 23.1H-NMR(400 MHz,CDCl3):δ＝8.13(s,1H,Ar-H),7.99-7.97(m,2H,Ar-H),7.87(d,2H,J＝6.0Hz,Ar-H), 7.70-7.68(m,1H,Ar-H),7.61(d,1H,J＝8.8Hz,CH),7.36-7.35(m,1H,Ar-H),5.89(d,1H,J＝8.4 Hz,CH),3.74-3.67(m,6H,CH2),3.60(t,2H,J＝3.6Hz,7.6Hz,CH2)；13C NMR(100MHz, d6-DMSO):δ＝169.4,164.9,162.4,150.4,150.1,142.8,139.8,138.0,137.6,135.0,127.7,127.1, 121.6,121.1,114.9,98.5,66.1,44.6.ESI-MS:m/z＝435.3[M+H]+。
Example 21 in vitro Activity of uracil-benzothiazoles NS5B RdRp polymerase inhibitors against 1b genotype hepatitis C Virus replicons (HCV-1b)
HCV-1b stably transfected replicon (wild-type HCV-1b) cells were used to test compounds for inhibitory activity against HCV genotype 1b replicon. ABT-333 (Dassabuvir, AbbVie) was used as a positive control compound. And simultaneously, HCV-1b cells are used for determining the influence of the compound on the cell activity, and the test concentration of the compound in the compound cytotoxicity test is the same as the test concentration of the compound in the anti-HCV activity test.
The compound 18-23 prepared by the invention is dissolved by 100% DMSO to prepare a solution of 30 mu M. The compounds were diluted 9-fold in 96-well plates. Each concentration was repeated 3 times. Adding 8X 10 of the mixture into each hole3Suspension of HCV replicating cells (Huh7cell lines) in Petri dishes at 37 ℃ with 5% CO2Incubate for 72 hours. Cell Titer-Fluor assay for HCV-1b Cell activity, luciferase assay (Bright-Glo) assay for anti-HCV genotype 1b replicon activity, data analysis and calculation of anti-HCV replicon activity of the compound, and Graphpad Prism software to calculate the half-Effective Concentration (EC) of the compound50) And Cytotoxicity (CC)50) The values, results are shown in Table 1.
TABLE 1 inhibitory Activity of Compounds prepared according to the present invention on HCV genotype 1b replicon
Figure BDA0002133934080000132
Figure BDA0002133934080000141
As can be seen from the data in the table, the target compound synthesized by the invention has better HCV inhibitory activity, and the HCV inhibitory activity of the compound is less than 3 mu M, so that the compound related to the invention has better HCV inhibitory activity. In conclusion, the compounds have better anti-HCV application prospect, and thus have commercial value for further development.

Claims (9)

1. A uracil-benzothiazole derivative having the structure of general formula (I):
Figure FDA0002902481550000011
wherein:
l is selected from
Figure FDA0002902481550000012
Wherein R iseSelected from H, C1-C3An alkyl group;
r is selected from C6-C7Aryl, heterocyclic, heteroaryl, fluoro-substituted phenyl ring of (a); the heterocyclic group is selected from piperidyl, piperazinyl and morpholinyl; the heteroaryl group is selected from unsaturated carbocyclic rings referring to 5 to 6 ring atoms in which one or more carbons are replaced with a heteroatom; the heteroatom is selected from N or O.
2. Uracil-benzothiazole structural derivatives having general formula (i) according to claim 1, characterized in that they are each chosen from the following groups:
l is selected from
Figure FDA0002902481550000013
Wherein R iseSelected from H, methyl, ethyl;
r is selected from C6Aryl, fluoro-substituted phenyl, pyridyl, piperazinyl, morpholinyl.
3. Uracil-benzothiazole structural derivatives having general formula (i), according to claims 1 or 2, characterized in that they are respectively chosen from the following groups:
l is selected from
Figure FDA0002902481550000014
Wherein R iseSelected from H and methyl.
4. The uracil-benzothiazole structure derivative of general formula (i) according to claim 2, wherein R is phenyl.
5. Uracil-benzothiazole structural derivatives, characterized in that said derivatives are selected from the group consisting of compounds 1 to 6:
compound 1: n- (4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) methanesulfonamide
Compound 2: 4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N, N-dimethylmethanesulfonamide compound 3: n- (4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide
Compound 4: 4- (6- (2, 4-dione-3, 4-dihydropyrimidin-1 (2H) -yl) benzo [ d ] thiazol-2-yl) -N- (4-fluorophenyl) benzamide compound 5: 1- (2- (4- (4-methylpiperazine-1-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione
Compound 6: 1- (2- (4- (morpholine-4-carbonyl) phenyl) benzo [ d ] thiazol-6-yl) pyrimidine-2, 4(1H,3H) -dione.
6. The method for preparing uracil-benzothiazole structure derivatives according to claims 1 to 5, characterized in that the following synthesis is used:
Figure FDA0002902481550000021
wherein:
l is selected from the group of L selected from the derivatives of claims 1 to 4 or the corresponding site of the derivatives of claim 5;
r is selected from the group of R in claims 1 to 4 or the group of the corresponding part of the derivative in claim 5;
in the above synthetic route, the intermediate (V) is obtained by reacting the center (III) and the head (II) of the formula under the condition of DMF, then the intermediate (VI) is synthesized by cyclization under the alkaline condition, and the intermediate (VI) and the tail (IV) of the formula are reacted under the existence of alkali and catalyst, and finally the target compound (I) is obtained.
7. A pharmaceutical composition, characterized in that it comprises at least one uracil-benzothiazole structure derivative according to any of claims 1 to 5 as active ingredient, in combination with one or more pharmaceutically acceptable carriers.
8. Use of the uracil-benzothiazole structure derivative according to any one of claims 1 to 5 and the pharmaceutical composition according to claim 7 for the preparation of anti-hepatitis c drugs.
9. The pharmaceutical composition of claim 7, characterized in that: the dosage form of the pharmaceutical composition is injection, freeze-dried powder injection, tablet, capsule or granule.
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