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CN103864753B - Anti-third livering compound containing five yuan of fragrant heterocycle structures and preparation method and purposes - Google Patents

Anti-third livering compound containing five yuan of fragrant heterocycle structures and preparation method and purposes Download PDF

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CN103864753B
CN103864753B CN201410068177.5A CN201410068177A CN103864753B CN 103864753 B CN103864753 B CN 103864753B CN 201410068177 A CN201410068177 A CN 201410068177A CN 103864753 B CN103864753 B CN 103864753B
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hydrogen
ring
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CN103864753A (en
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黄青清
史培忠
祝奇文
唐炜
吕伟
左建平
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a kind of anti-third livering compound, preparation method and the purposes that contain five yuan of fragrant heterocycle structures, its compound has structure shown in formula I, it is active that this compound has good anti-hepatitis C virus, can be used for preparing anti-hepatitis C virus medicine, prepared medicine adopts oral, intravenous injection, muscle injection mode application.

Description

Anti-hepatitis C compound containing five-membered aromatic heterocyclic structure, preparation method and application
Technical Field
The invention relates to compounds containing five-membered aromatic heterocyclic structures, which have inhibitory activity on the replication of Hepatitis C Virus (HCV), and a method for preparing the compounds and application thereof. More particularly, relates to a compound I with the following structure, a preparation method and application of the compound in the field of hepatitis C virus infection resistance.
Background
Hepatitis c virus infects nearly 1 hundred million and 7 million people worldwide, with a high morbidity (2% -3%) and mortality. HCV is generally a broad-spectrum antiviral therapy with the nucleoside analog ribavirin (ribavirin) in combination with human interferon-alpha (α -IFN). However, because patients have poor tolerance and cannot act equally against various types of HCV viruses, and because of poor therapeutic effects and large side effects, it is necessary to develop an anti-HCV drug that acts directly on proteins synthesized by HCV in human cells, i.e., a direct acting antiviral drug, "direct acting antiviral" (DAAs). Most of these drugs act by inhibiting important enzymes and target proteins, which are NS3 (proteolytic enzyme), NS5A and NS5B (RNA-dependent RNA polymerase) and so on. The anti-HCV drugs, telaprevir, boceprevir, simeprevir and sofobrevir, recently approved for marketing are inhibitors that act directly on NS3 protease and NS5 BRNA-dependent RNA polymerase. However, none of them is effective in eradicating HCV infection when administered alone, as HCV soon develops resistance to DAA drugs. In addition, the new drugs are still used for clinical treatment of HCV by combining with ribavirin and/or interferon preparations, and have the defect of poor drug tolerance to a certain extent.
In order to solve the problems of poor tolerance and drug resistance in the current HCV treatment process, a therapy using a combination of multiple DAA drugs having different mechanisms of action against multiple targets is considered, and thus, the development of a novel anti-HCV drug is necessary.
Disclosure of Invention
The invention aims to find a novel compound containing five-membered aromatic heterocycle and pharmaceutically acceptable salt thereof, and the compound has the inhibition effect on HCV replication.
It is another object of the present invention to provide a method for preparing a compound containing a five-membered aromatic heterocycle and a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a composition for treating HCV infection comprising a therapeutically effective amount of one or more of the anti-HCV compounds and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. Such pharmaceutically acceptable salts include, but are not limited to, the addition salts of the compound with hydrochloric, sulfuric, phosphoric, methanesulfonic, succinic, maleic, fumaric, tartaric, citric acid, and the like.
Still another object of the present invention is to provide a use of the anti-HCV compound and pharmaceutically acceptable salts thereof for preparing anti-HCV drugs.
The compound containing the five-membered aromatic heterocycle and the pharmaceutical salt thereof have the specific structure shown in the general formula I:
wherein,
x is-N-or-C-;
y is-N-or-C-;
m is a benzene ring structure spliced with a five-membered aromatic heterocycle in the following manner
Or
Or substituted alkene structures
R1Is hydrogen, C1–C6Alkyl radical, C1–C7Cycloalkyl or a phenyl ring, wherein the phenyl ring is optionally substituted with 1, 2 or 3 substituents; wherein the substituents on the benzene ring are each independently selected from halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, aryl, heteroaryl, CONRaRb、(CH2)0-3NRaRb、O(CH2)1-3NRaRb、O(CH2)0-3CONRaRb、O(CH2)0-3Aryl, O (CH)2)0-3Heteroaryl or OCHRcRd；
RaAnd RbEach independently selected from hydrogen, C1-4Alkyl or C (O) C1-4An alkyl group;
or Ra、RbTogether with the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, wherein the ring is optionally substituted with halogen, hydroxy, C1-4Alkyl or C1-4Alkoxy substitution;
Rcand RdEach independently selected from hydrogen or C1-4An alkoxy group;
or Rc、RdAnd a heteroaliphatic ring linked through a heteroatom selected from N, O and S to form 4-7 ring atoms, wherein the ring is optionally substituted with halogen, hydroxy, C1-4Alkyl or C1-4Alkoxy substitution;
and wherein said C1-4Alkyl radical, C1-4Alkoxy and aryl optionally substituted with halogen or hydroxy;
R2is selected from hydrogen and C1–C6Alkyl radical, C1–C7Cycloalkyl, benzene, pyridine or the following groups
Or
Wherein each phenyl ring is optionally substituted with 1, 2 or 3 substituents, wherein each pyridine ring is optionally substituted with 1, 2 or 3 substituents; wherein the benzene and pyridine rings are optionally substituted with R1Substituted with the substituents defined in (1);
R4is hydrogen, C1–C6An alkylsulfonyl, phenyl ring or pyridine ring, wherein each phenyl ring is optionally substituted with 1, 2 or 3 substituents, wherein each pyridine ring is optionally substituted with 1, 2 or 3 substituents; wherein the benzene and pyridine rings are optionally substituted with R1Substituted with the substituents defined in (1);
R3is hydrogen or a benzene ring, wherein the benzene ring and the pyridine ring are optionally substituted with R1Substituted with the substituents defined in (1);
R5is hydrogen or C1–C6An alkyl group;
R6and R7Is hydrogen or C1–C6Alkyl radical, R6And R7Can also be connected together to form a ring structure with the L chain;
R8is hydrogen or C1–C6Alkyl chain, C1–C6A cycloalkyl, phenyl or pyridyl ring, wherein each phenyl ring is optionally substituted with 1, 2 or 3 substituents, wherein each pyridyl ring is optionally substituted with 1, 2 or 3 substituents; wherein the benzene and pyridine rings are optionally substituted with R1Substituted with the substituents defined in (1);
l is C1–C4Alkyl chain, phenyl, benzyl, piperazine ring or with R7The following structures are jointly formed
The compounds provided by the present invention have one of the following structures
Wherein R is1、R2、R3、R5、R6、R7And R8Have the same meanings as defined for formula I.
The compounds of formula I may be prepared according to the schemes described below:
a process for the preparation of a compound according to any one of claims 1 and 2 by reaction of a compound of formula VI and a compound of formula VII in the presence of a coupling agent and a base in a suitable organic solvent:
wherein, X, Y, M, L, R1，R2，R3，R6，R7，R8Having the meaning defined in claim 1, coupling agents such as 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate, bases such as diisopropylethylamine, organic solvents such as dimethylsulfoxide.
The compounds of formulae VI and VII are known in the art or may be prepared by conventional methods known to those skilled in the art, for example as described in the specification and examples, or by obvious alternatives.
The compound has good anti-HCV activity, and can be clinically applied in oral administration, intravenous injection, intramuscular injection and other modes.
Detailed Description
The compounds and the preparation processes of the present invention are described in more detail in the following examples, which are not to be construed as limiting the invention.
The following formula is a synthetic route to compound VI:
example 1
1.1 Synthesis of Compound 3
Dissolving 1g of tert-butyloxycarbonylpiperazine in 50mL of methyl tert-butyl ether, adding 8.5mL of triethylamine, slowly adding methyl tert-butyl ether dissolved with 8.8g of propanesulfonyl chloride into the reaction solution in an ice bath, wherein a large amount of white solid is generated, removing the ice bath to ensure that the reaction solution is heated to room temperature for 2 hours after the addition, stopping the reaction, removing the organic solvent by rotation, adding dichloromethane to dissolve residues, washing with water, washing with saturated sodium chloride solution, drying the organic layer with anhydrous sodium sulfate, drying the solvent by rotation to obtain yellow solid, pulping with petroleum ether to obtain 13.5g of light yellow solid, and directly feeding the light yellow solid to the next step.
1.2 Synthesis of Compound 4
At room temperature, 13.5g of 1-tert-butoxycarbonyl-4-propanesulfonyl piperazine was dissolved in 80mL of methanol, 15mL of concentrated hydrochloric acid was added, the mixture was heated to 60 ℃ to react for 3 hours, after the reaction, the organic solvent was removed by spinning, the residue was diluted with water, the pH was adjusted to 7 to 8 with 1N aqueous sodium hydroxide solution, extraction was performed with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and spin-drying was performed to obtain 8.2g of a pale yellow solid, with a yield in two steps of 83.6%.
1HNMR(400MHz,CDCl3)3.24(d,J=3.4Hz,4H),2.93(d,J=3.2Hz,4H),2.91–2.84(m,2H),1.86(dd,J=14.0,6.9Hz,2H),1.07(t,J=6.8Hz,3H)。
1.3 Synthesis of Compound 5
Dissolving 6.18g of p-nitrobenzyl bromide in 40mLN, N-dimethylformamide, adding 7.2g of potassium carbonate, slowly dropwise adding a solution of N, N-dimethylformamide containing 5g of 1-propanesulfonyl piperazine into the reaction solution under ice bath, keeping the ice bath for about 10min after the addition is finished, removing the ice bath, reacting at normal temperature overnight, pouring the system into 200mL of ice water after the reaction is finished, generating a large amount of white solid, performing suction filtration, washing with water, drying to obtain yellow solid, pulping with petroleum ether to obtain 7.7g of light yellow solid powder, wherein the yield is 90.6%.
1HNMR(400MHz,CDCl3)8.19(d,J=7.7Hz,2H),7.51(d,J=7.7Hz,2H),3.63(s,2H),3.32(s,4H),2.88(d,J=6.2Hz,2H),2.54(s,4H),1.86(d,J=6.8Hz,2H),1.07(t,J=6.8Hz,3H)。
1.4 Synthesis of Compound 6
3.5g of 1-p-nitrobenzyl-4-propanesulfonyl piperazine is dissolved in 50mL of methanol, 0.4g of 5% palladium carbon is added, the reaction is carried out for 3h under a hydrogen atmosphere, after the reaction is finished, suction filtration is carried out, and filtrate is dried by spinning to obtain 2.73g of light yellow oily liquid with the yield of 78.5%.
1HNMR(400MHz,CDCl3)7.07(d,J=8.4Hz,2H),6.64(d,J=8.4Hz,2H),3.64(s,2H),3.42(s,2H),3.30–3.20(m,4H),2.95–2.77(m,2H),2.58–2.41(m,4H),1.85(m,2H),1.05(t,J=7.4Hz,3H)。
The following formula is a synthetic route for the compounds of the present invention:
example 2
2.1 preparation of Compound 8
6.1g 4-amino-3-nitrobenzoic acid methyl ester was dissolved in 100mL methanol to displace N2Under stirring at N20.6g of 10% palladium on carbon was added under an atmosphere to replace H2The reaction solution is filtered by diatomite for 4 hours at room temperature, and the solvent is dried by spinning to obtain 5g of dark purple viscous oily liquid. The yield was 96.7%.
2.2 preparation of Compound 9
Dissolving 3, 4-diaminobenzoic acid methyl ester 1g and 2-pyridine formaldehyde 0.65g in a mixed solvent of acetonitrile 30mL and water 1mL, adding potassium hydrogen persulfate 2.23g under vigorous stirring, reacting at room temperature for 2h, removing acetonitrile after the reaction, diluting the residue with water, extracting with ethyl acetate, washing the organic phase with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain red oily matter. Column chromatography using petroleum ether and ethyl acetate as mobile phase to obtain light yellow solid 1.1g with 73.0% yield.
1HNMR(400MHz,CDCl3)10.74(s,1H),8.66(t,J=5.6Hz,1H),8.57(s,1Hmajor),8.45(d,J=7.9Hz,1H),8.25(s,1Hminor),8.09–7.99(m,1H),7.90(t,J=7.8Hz,1H),7.86(d,J=8.5Hz,1Hminor),7.53(d,J=8.4Hz,1Hmajor),7.46–7.37(m,1H),3.96(s,3H)。
2.3 preparation of Compound 10
At room temperature, 1g of 2- (pyridine-2) -1H-benzimidazole-5-carboxylic acid methyl ester is dissolved in 50mL of methanol, then 5mL of 2N sodium hydroxide aqueous solution is added into the system, the system is heated to 40-50 ℃ for reaction overnight, organic solvent is removed by spinning, the residue is diluted by water, the pH value is adjusted to be 2-3 by 1N hydrochloric acid solution, white solid is separated out, the white solid is filtered by suction, filter cake is washed by water, and the yellow brown solid is obtained by drying, wherein the yield is 90.4%.
1HNMR(400MHz,DMSO)13.43(s,1H),12.75(s,1H),8.77(d,J=4.6Hz,1H),8.37(d,J=7.9Hz,1H),8.23(d,J=22.5Hz,1H),8.04(td,J=7.8,1.5Hz,1H),7.86(s,1H),7.69(d,J=50.2Hz,1H),7.58(dd,J=6.9,5.2Hz,1H)。
2.4 preparation of the Compound HCV301
0.1g of 2- (pyridine-2) -1H-benzimidazole-5-carboxylic acid is dissolved in 5mL of dimethyl sulfoxide, then 0.3mL of N, N-diisopropylethylamine and 0.2g of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are added, finally 125mg of the compound 6 are added, the reaction is carried out for 4 hours at room temperature, 100mL of water is added into the system after the reaction is finished, a large amount of white solid is separated out, suction filtration is carried out, a filter cake is washed by water, drying is carried out, and the white solid is separated by column purification by taking dichloromethane and methanol 50:1 as mobile phases, wherein 0.09g of the white solid is obtained, and the yield is 41.6%.
1HNMR(400MHz,DMSO)13.43(d,J=30.5Hz,1H),10.27(d,J=32.2Hz,1H),8.78(s,1H),8.44–8.34(m,2H),8.15(s,1H),8.04(t,J=7.4Hz,1H),7.83(ddd,J=34.3,17.5,8.5Hz,3H),7.63(d,J=8.4Hz,1H),7.57(s,1H),7.29(d,J=8.2Hz,2H),3.50(s,2H),3.17(s,4H),3.06–2.96(m,2H),2.44(s,4H),1.69(dd,J=15.1,7.5Hz,2H),0.99(t,J=7.4Hz,3H)。
The following formula is a synthetic route for the compounds of the present invention:
example 3
3.1 preparation of Compound 11
At room temperature, 8.5g of 3-amino-4- (cyclohexylamino) ethyl benzoate and 15.76g of N, N' -carbonyldiimidazole are dissolved in 75mLN, N-dimethylformamide, heated to 80 ℃ for reaction overnight, after the reaction is finished, 400mL of water is added for separating out a solid, a brown filter cake is obtained by suction filtration, and after drying, dichloromethane is used for pulping to obtain 8.6g of a light pink solid, and the yield is 87.2%.
3.2 preparation of Compound 12
At room temperature, 8.1g of 1-cyclohexyl-2-oxo-2, 3-dihydro-1H-benzimidazole-5-carboxylic acid ethyl ester is dissolved in 50mL of phosphorus oxychloride, the mixture is heated to 100 ℃ to react for 24 hours, after the reaction is finished, the excessive phosphorus oxychloride is removed by distillation, the residue is dissolved by water, the pH value is adjusted to 7-8 by using a saturated sodium bicarbonate aqueous solution under ice bath, a large amount of solid is separated out, and the mixture is subjected to suction filtration, water washing and drying to obtain 5.1g of crude reddish brown solid with the yield of 59%.
1HNMR(500MHz,CDCl3):8.38(s,1H),7.97–7.99(m,1H),7.55(d,J=8.6Hz,1H),4.38–4.42(m,3H),2.22–2.24(m,2H),2.20–2.21(m,4H),1.97–2.02(m,1H),1.48–1.51(m,2H),1.38–1.43(m,4H)。
3.3 preparation of Compound 13
At room temperature, 0.32g of 2-chloro-1-cyclohexyl-1H-benzimidazole-5-carboxylic acid ethyl ester and 0.3g of the compound 4 are dissolved in 10mL of dimethyl sulfoxide, 0.73mL of LN, N-diisopropylethylamine are added, the mixture is heated to 110 ℃ to react for 24 hours, after the reaction is finished, 100mL of water is added, solid is separated out, solid is obtained by suction filtration and drying, 245mg of solid is obtained by column chromatography separation, and the yield is 50.8%.
1HNMR(400MHz,CDCl3)8.33(s,1H),7.89(d,J=8.5Hz,1H),7.46(d,J=8.5Hz,1H),4.38(q,J=7.1Hz,2H),4.21–4.06(m,1H),3.60–3.46(m,4H),3.42–3.31(m,4H),3.02–2.90(m,2H),2.31–2.14(m,2H),2.07–1.96(m,2H),1.95–1.78(m,5H),1.52–1.32(m,6H),1.09(t,J=7.4Hz,3H)。
3.4 preparation of Compound 14
At room temperature, 0.245g of 1-cyclohexyl-2- (4- (propylsulfonyl) piperazinyl-1) -1H-benzimidazole-5-carboxylic acid ethyl ester is dissolved in 15mL of methanol, 2mL of 2N sodium hydroxide aqueous solution is added, the mixture is heated to 50 ℃ for reaction for 5H, after the reaction is finished, the methanol is removed by spinning, the residue is diluted with water, the pH value is adjusted to 2-3 by 1N hydrochloric acid aqueous solution, a large amount of solid is precipitated, and the solid is filtered, washed and dried to obtain 0.18g of white solid with the yield of 78%.
3.5 preparation of the Compound HCV302
0.12g of 1-cyclohexyl-2- (4- (propylsulfonyl) piperazinyl-1) -1H-benzimidazole-5-carboxylic acid is dissolved in 5mL of dimethyl sulfoxide, then 0.2mL of N, N-diisopropylethylamine and 0.137g of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are added, and finally 82mg of the compound 6 are added, the reaction is carried out at room temperature for 4 hours, 100mL of water is added into the system after the reaction is finished, a large amount of white solid is separated out, suction filtration is carried out, a filter cake is washed with water, drying is carried out, and the white solid is separated by column purification by taking dichloromethane and methanol 50:1 as mobile phases, wherein 85mg of the white solid is obtained, and the yield is 43.1%.
1HNMR(400MHz,CDCl3)8.06(d,J=1.4Hz,1H),7.91(s,1H),7.78(dd,J=8.5,1.6Hz,1H),7.61(d,J=8.4Hz,2H),7.54(d,J=8.5Hz,1H),7.31(d,J=8.4Hz,2H),4.20–4.08(m,1H),3.57–3.47(m,6H),3.41–3.34(m,4H),3.33–3.25(m,4H),3.01–2.92(m,2H),2.92–2.84(m,2H),2.59–2.48(m,4H),2.30–2.15(m,2H),2.01(d,J=13.2Hz,2H),1.92–1.82(m,6H),1.75(s,1H),1.45(dd,J=24.0,11.9Hz,3H),1.07(dt,J=12.4,7.4Hz,6H)。
The following formula is a synthetic route for the compounds of the present invention:
example 4
4.1 preparation of Compound 17
Ice bath, N2Under protection, 2.34ml of N-dimethylformamide dimethyl acetal is dropwise added into 1g of ethyl isocyanoacetate in ethanol solution, ice bath is removed after the addition is finished, the reaction is carried out for 24 hours at room temperature, solvent is removed by rotation, petroleum ether and ethyl acetate are used as 10:1 mobile phase, and the mixture is subjected to column separation to obtain 0.74g of light yellow liquid with the yield of 51%.
1HNMR(400MHz,CDCl3)7.19(s,1H),4.20(q,J=7.1Hz,2H),3.58–2.87(m,6H),1.29(t,J=7.1Hz,3H)。
4.2 Synthesis of Compound 18
0.737g of (Z) -1- (dimethylamino) -2-ethylisocyanoacrylate was dissolved in 1.5mL of cyclohexylamine, and the mixture was heated to 70 ℃ to effect a reaction for 2 hours, after the reaction was completed, the desired compound was obtained in a yield of 58 mg by column chromatography.1HNMR(400MHz,CDCl3)7.67(d,J=1.0Hz,1H),7.55(s,1H),4.36(q,J=7.1Hz,2H),3.94(tt,J=11.8,3.8Hz,1H),2.13(d,J=11.0Hz,2H),1.92(d,J=13.6Hz,2H),1.76(d,J=13.1Hz,1H),1.64(qd,J=12.4,3.3Hz,2H),1.46(dt,J=12.6,3.2Hz,1H),1.42–1.34(m,4H),1.33–1.19(m,1H)。
4.3 Synthesis of Compound 19
Cooling to 0 ℃ in ice bath, and N2Under the air flow, a tetrahydrofuran solution dissolved with 6.9g of 1-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester is slowly dripped into a tetrahydrofuran suspension containing 2.36g of lithium aluminum hydride, after the addition, the reaction is carried out for 2 hours at room temperature, after the reaction, water and 15% sodium hydroxide aqueous solution are sequentially added for extraction and extinction reaction, the mixture is diluted by ethyl acetate, stirred for 0.5 hour, filtered by a pad of diatomite in a suction manner, the filtrate is dried in a spinning manner, and a light yellow solid is obtained by column chromatography separation, wherein the yield is 78.5 percent.
1HNMR(400MHz,CDCl3)7.49(s,1H),6.91(s,1H),4.58(s,2H),3.85(tt,J=11.7,3.7Hz,1H),2.08(d,J=11.8Hz,2H),1.89(d,J=13.4Hz,2H),1.74(d,J=12.9Hz,1H),1.60(qd,J=12.4,3.2Hz,2H),1.47–1.32(m,2H),1.24(tt,J=12.7,3.3Hz,1H)。
4.4 Synthesis of Compound 20
435mg of 1-cyclohexyl-4-hydroxymethyl imidazole is dissolved in 10mL of dichloromethane, 15mg of 4-dimethylaminopyridine and 0.85mL of triethylamine are added, 545mg of tert-butyldimethylsilyl chloride is slowly dropped into the system, the reaction is carried out at room temperature for 12 hours, after the reaction is finished, dichloromethane is used for dilution, water washing and saturated sodium chloride aqueous solution washing are carried out, an organic layer is dried by anhydrous sodium sulfate, and 577mg of product is obtained through column chromatography separation, wherein the yield is 86%.
1HNMR(400MHz,CDCl3)7.34(s,1H),6.77(s,1H),4.59(s,2H),3.75(tt,J=11.7,3.7Hz,1H),1.99(d,J=11.5Hz,2H),1.79(d,J=13.5Hz,2H),1.64(d,J=13.0Hz,1H),1.51(qd,J=12.4,3.2Hz,2H),1.37–1.22(m,2H),1.21–1.06(m,1H),0.83(s,9H),-0.00(s,6H)。
4.5 Synthesis of Compound 21
6.2g of 4- (((tert-butyldimethylsilyl) oxo) methyl) -1-cyclohexyl-1H-imidazole were dissolved in 80mL of tetrahydrofuran at-78 ℃ C, N2Under protection, slowly dropwise adding 11.5mL of butyl lithium, reacting for 30min after the addition is finished, then slowly dropwise adding a tetrahydrofuran solution dissolved with 3.21g of I2, gradually raising the temperature to room temperature for reacting overnight after the addition is finished, adding 200mL of water for quenching after the reaction is finished, removing the organic solvent by rotation, extracting with ethyl acetate, washing with water, washing with saturated salt water, drying the organic layer with anhydrous sodium sulfate, drying by rotation, and separating by column chromatography to obtain 4.8g of a product with the yield of 54.2%.1HNMR(400MHz,CDCl3)6.86(s,1H),4.58(s,2H),3.81(tt,J=11.7,3.7Hz,1H),1.93(d,J=12.3Hz,2H),1.82(d,J=13.1Hz,2H),1.68(d,J=13.3Hz,1H),1.50–1.30(m,4H),1.21–1.08(m,1H),0.83(s,9H),0.01(d,J=9.9Hz,6H)。
4.6 Synthesis of Compound 22
4.8g of 4- (((tert-butyldimethylsilyl) oxo) methyl) -1-cyclohexyl-2-iodo-1H-imidazole was dissolved in 90mL of ethylene glycol di (ethyl acetate)2.8g of phenylboronic acid, 1.6g of bis (triphenylphosphine) palladium dichloride and 29mL of 2N potassium carbonate aqueous solution are added into dimethyl ether, the mixture is heated to 95 ℃ for reaction overnight, the reaction is finished, the temperature is returned to room temperature, the mixture is filtered by suction through diatomite, an organic solvent is removed by spinning, dichloromethane is used for extraction, an organic layer is washed by 2N sodium hydroxide aqueous solution, water is washed, saturated salt water is washed, anhydrous sodium sulfate is dried, the solvent is removed by spinning, and a product obtained by column chromatography is 2.9g, and the yield is 68.5%.1HNMR(400MHz,CDCl3)7.39(d,J=7.2Hz,2H),7.35–7.26(m,3H),6.87(s,1H),4.64(s,2H),3.94(ddd,J=11.9,8.3,3.7Hz,1H),1.89(d,J=11.8Hz,2H),1.74(d,J=12.7Hz,2H),1.60(s,1H),1.52(d,J=2.7Hz,2H),1.16(dd,J=20.6,10.8Hz,3H),0.83(s,9H),0.00(s,6H)。
4.7 Synthesis of Compound 23
2.9g of 4- (((tert-butyldimethylsilyl) oxo) methyl) -1-cyclohexyl-2-phenyl-1H-imidazole is dissolved in 100mL of methanol, 1.3mL of concentrated hydrochloric acid is added, the mixture is stirred at room temperature for reaction for 4H, methanol is removed by spinning, water is added to dilute the residue, the pH value is adjusted to be neutral by saturated aqueous sodium bicarbonate solution, the mixture is extracted by ethyl acetate, and the organic layer is dried by spinning to obtain 1.6g of a product with the yield of 80%.
1HNMR(400MHz,CDCl3)7.54–7.41(m,5H),7.04(s,1H),4.64(s,2H),4.06(tt,J=11.9,3.8Hz,1H),2.01(d,J=11.8Hz,2H),1.86(d,J=13.4Hz,2H),1.71(d,J=16.1Hz,3H),1.30(d,J=13.1Hz,2H),1.24–1.18(m,1H)。
4.8 Synthesis of Compound 24
Dissolving 4-hydroxymethyl-1-cyclohexyl-2-phenyl-1H-imidazole in 100mL acetonitrile, adding 2.7g fresh manganese dioxide, heating and refluxing, reacting for 4H, filtering with hot pad diatomite, removing solvent by spinning, and separating by column chromatography to obtain 1.03g product with 65% yield.
1HNMR(400MHz,CDCl3)9.92(s,1H),7.83(s,1H),7.59–7.47(m,5H),4.12(tt,J=11.8,3.5Hz,1H),2.06(d,J=12.0Hz,2H),1.89(d,J=13.1Hz,2H),1.77–1.62(m,3H),1.32(dd,J=24.9,12.0Hz,3H)。
4.9 Synthesis of Compound 26
Dissolving 1g of triphenylphosphine in 15mL of ethyl acetate, adding 0.55mL of 2-ethyl bromopropionate, stirring and reacting at room temperature for 24 hours to gradually generate a large amount of white solid, performing suction filtration, and washing with ethyl acetate to obtain 1.35g of white solid with the yield of 80.5%.
1HNMR(400MHz,CDCl3)8.06–7.63(m,15H),7.04(dd,J=15.7,7.5Hz,1H),4.08–3.97(m,2H),1.70(dd,J=18.5,7.0Hz,3H),1.02(t,J=7.1Hz,3H)。
4.10 Synthesis of Compound 27
Dissolving 3g of the compound 26 in 30mL of dichloromethane, adding 26mL of 2N potassium hydroxide aqueous solution, reacting for 20min at room temperature under vigorous stirring, after the reaction is finished, carrying out layering, drying an organic layer by anhydrous magnesium sulfate, carrying out suction filtration, and spin-drying an organic solvent to obtain 1.87g of a white solid with the yield of 76.3%.
1HNMR(400MHz,CDCl3)7.74–7.20(m,15H),4.06(q,J=7.0Hz,2Hminor),3.72(q,J=7.1Hz,2Hmajor),1.63(d,J=6.4Hz,3Hmajor),1.60(d,J=7.0Hz,3Hminor),1.25(t,J=7.0Hz,3Hminor),0.46(t,J=7.1Hz,3Hmajor)。
4.11 Synthesis of Compound 28
0.73g of wittig reagent compound 27 obtained above and 1-cyclohexyl-2-phenyl-4-1H-imidazolecarboxaldehyde were dissolved in 20mL of toluene, N2Heating to 100 ℃ under the atmosphere, reacting overnight, removing toluene after the reaction is finished, and performing column chromatography to obtain 0.35g of a product with the yield of 77.7%.
1HNMR(400MHz,CDCl3)7.68(s,1H),7.60–7.51(m,2H),7.51–7.40(m,3H),7.28(d,J=9.4Hz,1H),4.29–4.18(m,2H),4.11(m,1H),2.27(s,3H),2.04(d,J=12.1Hz,2H),1.88(d,J=11.8Hz,2H),1.67(m,3H),1.42–1.17(m,6H)。
4.12 Synthesis of Compound 29
Dissolving 0.35g of compound 28 in 20mL of methanol, adding 2mL of 2N sodium hydroxide aqueous solution, reacting at room temperature overnight, removing methanol by spinning, adding water for dilution, adjusting the pH value to be 4-5 by using dilute hydrochloric acid, separating out a large amount of white solid, performing suction filtration, washing by using water to obtain the white solid, and drying to obtain 0.24g of a product with the yield of 75%.
4.13 Synthesis of Compound HCV308
Dissolving 0.1g of compound 29 in 5mL of MSO, adding 96mg of 1-p-aminobenzyl-4-propanesulfonyl piperazine, 0.16mg of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 0.22mL of LN and N-diisopropylethylamine, reacting overnight at room temperature, adding 50mL of water after the reaction is finished, precipitating a large amount of white solid, performing suction filtration, washing a filter cake with water, drying, and performing column chromatography to obtain 89mg of white solid with the yield of 47%.
1HNMR(400MHz,CDCl3)7.80(s,1H),7.52(dd,J=30.1,7.0Hz,6H),7.37(s,1H),7.27(d,J=4.3Hz,3H),4.12(dd,J=13.3,7.1Hz,1H),3.50(s,2H),3.28(s,4H),2.93–2.81(m,2H),2.51(s,4H),2.38(s,3H),2.06(d,J=11.8Hz,2H),1.85(dt,J=14.9,8.7Hz,4H),1.69(dd,J=25.6,12.7Hz,3H),1.40–1.26(m,3H),1.05(t,J=7.3Hz,3H)。
The following formula is a synthetic route for the compounds of the present invention:
example 5
5.1 preparation of Compound 31
2g of indole-6-carboxylic acid are dissolved in 20ml of N, N-dimethylformamide and 2.1g of potassium carbonate, N2Reacting for 1h under the atmosphere, then adding 1mL of methyl iodide into the system, continuing to react for 2h, after the reaction is finished, adding a sodium thiosulfate aqueous solution to perform extraction and quenching reaction, then adding 100mL of water, separating out a large amount of white solid, performing suction filtration, washing with water, drying to obtain an off-white solid, and performing column chromatography to obtain 1.73g of the white solid with the yield of 78.3%.
1HNMR(400MHz,CDCl3)8.82(s,1H),8.17(s,1H),7.82(d,J=8.3Hz,1H),7.65(d,J=8.3Hz,1H),7.32(s,1H),6.57(s,1H),3.92(s,3H)。
5.2 preparation of Compound 32
0.14g of indole-6-carboxylic acid methyl ester was dissolved in 5ml of N, N-dimethylformamide, 80mg of potassium hydroxide was added thereto, and 0.2g of I was slowly added thereto with stirring2After the addition of the N, N-dimethylformamide solution, reacting at room temperature for 1h, adding a sodium thiosulfate aqueous solution to perform extraction and sterilization reaction, adding water, separating out a white solid, performing suction filtration, washing with water, and drying to obtain 0.2g of the white solid with the yield of 83.3%.
5.3 preparation of Compound 33
0.2g of 3-iodo-1H-indole-6-carboxylic acid methyl ester is dissolved in 20mL of dichloromethane, 0.16g of Boc anhydride, 0.28mL of triethylamine and 10mg of 4-dimethylaminopyridine are added, the reaction is carried out at room temperature for 2H, after the reaction is finished, dichloromethane is added for dilution, the reaction solution is washed twice by 5% sodium metabisulfite aqueous solution, washed by water, washed by saturated salt solution, dried by anhydrous sodium sulfate and dried by spinning to obtain 238mg of product, and the yield is 89%.
1HNMR(400MHz,CDCl3)8.84(s,1H),8.00(d,J=8.3Hz,1H),7.86(s,1H),7.43(d,J=8.3Hz,1H),3.95(s,3H),1.69(s,9H)。
5.4 preparation of Compound 34
0.5g of 1-tert-butoxycarbonyl-3-iodo-1H-indole-6-carboxylic acid methyl ester was dissolved in 30mL of ethylene glycol diglycidyl ether, 0.26g of m-trifluoromethoxybenzeneboronic acid, 0.17g of potassium carbonate, 144mg of tetrakis (triphenylphosphine) palladium and 15mL of water were added thereto, and the mixture was concentrated under reduced pressure in N2And (3) refluxing and reacting for 3h under the atmosphere, cooling to room temperature after the reaction is finished, performing suction filtration by using kieselguhr, extracting the filtrate by using ethyl acetate and water, and performing column chromatography to obtain a product of 0.17g, wherein the yield is 31.5%.
1HNMR(400MHz,CDCl3)8.91(d,J=30.6Hz,1H),7.97(dd,J=30.9,8.1Hz,1H),7.88(s,1H),7.84–7.72(m,1H),7.62–7.54(m,1H),7.54–7.39(m,2H),7.29–7.20(m,1H),3.95(d,J=8.8Hz,3H),1.72(d,J=10.2Hz,9H)。
5.5 preparation of Compound 35
0.17g of 1-tert-butoxycarbonyl-3- (3- (trifluoromethoxy) phenyl) -1H-indole-6-carboxylic acid methyl ester was dissolved in 20mL of methanol, 4mL of 2N aqueous sodium hydroxide solution was added, the mixture was heated to 50 ℃ to react overnight, methanol was removed by rotation, water was added to dilute the mixture, pH was adjusted to acidity with dilute hydrochloric acid solution, a large amount of white solid was precipitated, and the precipitate was filtered, washed with water, and dried to obtain 0.1g of white solid with a yield of 80%.
1HNMR(400MHz,DMSO)12.64(s,1H),11.91(s,1H),7.93(d,J=8.4Hz,1H),7.75(dd,J=18.5,7.9Hz,2H),7.64(s,1H),7.58(t,J=7.9Hz,1H),7.25(d,J=7.8Hz,1H)。
5.6 preparation of Compound HCV319
0.1g of 3- (3- (trifluoromethoxy) phenyl) -1H-indole-6-carboxylic acid is dissolved in 15mL of dichloromethane, 93mg of 1-p-aminobenzyl-4-propanesulfonyl piperazine, 118mg of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 0.1mLN, N-diisopropylethylamine are added for reaction at room temperature for 3 hours, after the reaction is finished, dichloromethane is added for dilution, washing is carried out, saturated salt is washed, anhydrous sodium sulfate is dried and spin-dried, and the product is separated by column chromatography to obtain 99mg of product with the yield of 53%.
1HNMR(400MHz,DMSO)11.93(d,J=2.5Hz,1H),10.26(s,1H),8.13(d,J=1.0Hz,1H),8.08(d,J=2.7Hz,1H),7.97(d,J=8.5Hz,1H),7.84–7.75(m,4H),7.67(s,1H),7.59(t,J=8.0Hz,1H),7.27(dd,J=14.2,8.4Hz,3H),3.50(s,2H),3.17(s,4H),3.08–2.95(m,2H),2.44(s,4H),1.69(dd,J=15.2,7.5Hz,2H),0.99(t,J=7.4Hz,3H)。
Example 6
HCV replication inhibition activity assay:
huh7.5.1 cell preparation: huh7.5.1 cells were seeded in 96-well plates (1X 10)4Perwell), 37 ℃ 5% CO2And culturing for 24 h.
Viral infection: the virus supernatant (moi ≈ 0.1) of J399EM was infected with Huh7.5.1 cells, while control wells of uninfected cells were set, and washed with PBS 8 hours after infection.
And (3) drug treatment: different samples were added to the J399EM virus infected Huh7.5.1 cells, no sample control wells were set, and incubation was continued for 72 hours.
Fluorescent detection of HCV proteins: after 72 hours of sample treatment, the HCV virus inhibition rate was calculated by reading the relative fluorescence intensity (RFU) on a fluorescence microplate reader at 488nm for excitation wavelength and 516nm for emission wavelength.
MTT method for detecting cytotoxicity: add 100. mu. LMTT solution (5 mg/mL) per well, add MTT solution 4 hours later, read OD 6 hours later on microplate reader570nm。
Biological activity data at 5 μm level for some compounds:
example 7
In the system of host cell huh7.5.1 infected by HCV virus, the above samples with the HCV inhibition rate of more than 80% are subjected to concentration gradient detection to detect the anti-HCV activity. The assay concentration was 40. mu.M initially, 4-fold diluted, 6 concentrations, i.e., 40. mu.M, 10. mu.M, 2.5. mu.M, 0.63. mu.M, 0.16. mu.M, 0.04. mu.M. And calculating the cytotoxicity CC50And HCV inhibitory Activity IC50。
The above table shows that the compounds of the present invention have good inhibitory activity against HCV.

Claims (3)

1. An anti-hepatitis C virus compound containing a five-membered aromatic heterocyclic structure and pharmaceutically acceptable salts thereof, which are characterized by having the following general formula:
wherein,
x is-N-;
y is-N-;
m is a benzene ring structure spliced with a five-membered aromatic heterocycle in the following manner
R1Is hydrogen, C1–C6Alkyl radical, C1–C7Cycloalkyl or a phenyl ring, wherein the phenyl ring is optionally substituted with 1 or 2 substituents; wherein the substituents on the phenyl ring are each independently selected from C1-6Alkyl radical, C1-6Alkoxy, CONRaRbOr OCHRcRd；
RaAnd RbEach independently selected from hydrogen, C1-4Alkyl or C (O) C1-4An alkyl group;
or Ra、RbTogether with the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms;
Rcand RdEach independently selected from hydrogen or C1-4An alkoxy group;
R2is selected from hydrogen and C1–C6Alkyl radical, C1–C7Cycloalkyl, benzene, pyridine or the following groups
Wherein each phenyl ring is optionally substituted with 1 or 2 substituents; wherein the phenyl ring is optionally substituted with R1Substituted with the substituents defined in (1);
R4is hydrogen, C1–C6An alkylsulfonyl, phenyl or pyridyl ring, wherein each phenyl ring is optionally substituted with 1 or 2 substituents; wherein the phenyl ring is optionally substituted with R1Substituted with the substituents defined in (1);
R6and R7Is hydrogen or C1–C6Alkyl radical, R6And R7Can also be linked together to form a ring structure with the L chain;
R8is hydrogen or C1–C6Alkyl chain, C1–C6A cycloalkyl group;
l is C1–C4Alkyl chain of (A), phenyl, benzyl or with R7The following structures are jointly formed
The anti-hepatitis C compound containing a five-membered aromatic heterocyclic structure is selected from the following compounds
And pharmaceutically acceptable salts thereof.
2. The use of a compound as claimed in claim 1, wherein the compound is used in the manufacture of a medicament for the treatment of hepatitis C, the medicament being for oral, intravenous or intramuscular administration.
3. A process for preparing a compound according to claim 1, which comprises reacting a compound of formula VI with a compound of formula VII in the presence of a coupling agent, a base, and an organic solvent to obtain the compound of claim 1;
wherein, X, Y, M, L, R1、R2、R6、R7And R8Has the same meaning as defined in the general formula I, and the coupling agent is 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate or 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride; the base is diisopropylethylamine or triethylamine; the organic solvent is dichloromethane or dimethyl sulfoxide.
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