CN104610272A - Annular flavonoids or isoflavonoid and application thereof - Google Patents

Abstract

The invention discloses a cyclic flavone or isoflavone compound represented by formula (I) or its nitrogen oxide, hydrate, solvate, metabolite or pharmaceutically acceptable salt or prodrug, When A ₁ is -C(O)-, A ₂ is -O-; when A ₁ is -O-, A ₂ is -C(O)-; Q is -O-, -S-, -C (R ₄ R ₅ )-, -C(R ₄ R ₅ )O-, -OC(R ₄ R ₅ )-, -C(R ₄ R ₅ )N(R ₆ )-, -N(R ₆ ) C(R ₄ R ₅ )-, -N(R ₆ )-, -C(R ₄ R ₅ )C(R ₄ R ₅ )-, -C(R ₄ R ₅ )-S- or -SC(R ₄ R ₅ )-; W is -(NHC(O)) _1～2 -, -(C ₁ -C ₃ )alkylene-(NHC(O)) _1～2 -, Alternatively R ₁ can be attached to W to form an imidazole ring. The cyclic flavone or isoflavone compound of the present invention has excellent anti-hepatitis C virus effect.

Description

Cyclic flavonoids or isoflavones and uses thereof

technical field

The invention belongs to the technical field of compound synthesis, and in particular relates to a cyclic flavone or isoflavone compound and its application. the

Background technique

Hepatitis C virus (HCV) is the main pathogen of post-transfusion and sporadic hepatitis. The virion is spherical, with a diameter of less than 80nm (36-40nm in liver cells, 36-62nm in blood), and a single-stranded positive chain. RNA viruses, surrounded by a lipid-containing envelope outside the nucleocapsid, with spikes on the envelope. HCV-RNA is composed of about 9500-10000bp, and there is an open reading frame (openreading frame, ORF) immediately downstream of the 5' non-coding region, and the sequence of the genome is 5'-C-E1-E2-p7-NS2-NS3- NS4-NS5-3, encoding a single polyprotein precursor of 3014 amino acids, is cleaved by host signal peptidases and viral proteases into structural proteins (C, E1, E2, P7) and nonstructural proteins (NS2, NS3, NS4 and NS5). The non-structural gene NS5 region is located at 6258-9374nt of the genome, and is cleaved into NS5A and NS5B by NS3 serine protease. The cleavage site is located between cys-2420/ser2421. The cleavage site and its flanking sequences of different HCV isolates are relatively conserved. The NS5A region is located at 6258-7601nt, encoding 1973-2420aa. The relative molecular weight of the protein is 56KD (ie P56) and 58KD (ie P58). P58 is the hyperphosphorylated form of P56. In the presence of NS3, NS4A and NS4B, P56 can Transformed into P58. the

Interferon (IFN) is currently recognized as an effective antiviral drug for hepatitis C, but HCV-infected patients have different responses to interferon therapy, with an average response rate of less than 50% and a high recurrence rate after drug withdrawal. FDA approved two NS3/4A serine protease inhibitors Telaprevir and Boceprevir in 2011, providing a new effective method for the treatment of hepatitis C. However, with the emergence of drug resistance and toxic side effects, the treatment of HCV virus still requires new drugs, such as inhibitors acting on the new target NS5a. HCV NS5a inhibitors can be used in combination with NS3/4a and NS5b inhibitors to treat patients infected with drug-resistant HCV viruses. the

Contents of the invention

The object of the present invention is to provide a kind of cyclic flavone or isoflavone compound shown in formula (I),

or its nitrogen oxide, hydrate, solvate, metabolite or pharmaceutically acceptable salt or prodrug, wherein,

When A ₁ is -C(O)-, A ₂ is -O-; when A ₁ is -O-, A ₂ is -C(O)-;

Q is -O-, -S-, -C(R ₄ R ₅ )-, -C(R ₄ R ₅ )O-, -OC(R ₄ R ₅ )-, -C(R ₄ R ₅ )N (R ₆ )-, -N(R ₆ )C(R ₄ R ₅ )-, -N(R ₆ )-, -C(R ₄ R ₅ )C(R ₄ R ₅ )-, -C(R ₄ R ₅ )-S- or -SC(R ₄ R ₅ )-;

W is -(NHC(O)) _1~2- , -(C ₁ -C ₃ )alkylene-(NHC(O)) _1~2- ,

Or R ₁ can be connected with W to form an imidazole ring, that is, R ₁ and W form a fused ring structure together with the phenyl group on the cyclic flavone or isoflavone itself—a benzimidazole ring structure, and the two nitrogen atoms on the imidazole ring A carbon atom between them connects the following formula group again:

R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently H, D, OH, halogen, CN, amino, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto , C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, surrounded by 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _1-2 amino substituted C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl , C ₆ -C ₁₀ aryloxy, glycosyloxy, or C ₁ -C ₈ alkyl substituted by 1 to 5 oxygens;

R ₆ is H, D, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkylformyl, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₃ -C ₈ Cycloalkyl, C ₂ -C ₈ heterocycloalkyl or C ₆ -C ₁₀ aryl;

Wherein, R ₁ ' is independently H, D, OH, halogen, CN, amino, or selected from the following substituent groups unsubstituted or substituted by 1 to 5 R ₀ : (C ₁ -C ₈ alkyl ) _1-2 amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto, C ₁ -C ₈ alkylsulfonyl Acyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, with 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _1-2 amino substituted C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy Alkyl, glycosyloxy, or C ₁ -C ₈ alkyl substituted by 1 to 5 oxygens;

Or R ₁ ' on two adjacent carbon atoms and the two carbon atoms it connects together form a C ₃ -C ₇ carbon ring, or two R ₁ ' on the same carbon atom forms a carbon atom that can be connected to it. A 3-7-membered ring inserted by 0-2 heteroatoms selected from N, O and S, or R ₁ ' on 2 carbon atoms interspersed by 1 carbon atom forms C together with the 2 carbon atoms it is connected to ₃ -C ₇ carbon ring;

R ₂ ' is selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ heterocycloalkane group or C ₆ -C ₁₀ aryl group;

R ₃ ' is H, D, or selected from unsubstituted or C ₁ -C ₈ alkyl substituted by 1 to 5 R ₀ ;

R ₄ ' is selected from the following substituent groups unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylformyl or C ₁ -C ₈ alkoxy Formyl;

Or R ₃ ′, R ₄ ′ and the nitrogen atom connected to it form a 3-7 membered monocyclic ring, a 4-12-membered bicyclic ring or a 5- to 12-membered spirocycle;

Wherein, R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl ) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, sugar oxy, or 1 ~5 oxygen substituted C ₁ -C ₈ alkyl groups.

In the present invention, preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₁ ′ are independently H, D, OH, halogen, CN, amino, or independently selected from unsubstituted or the following substituent groups substituted by 1 to 3 R ₀ : (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ alkoxyformyl, (C ₁ -C ₆ alkyl) _1-2 carbamoyl, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, C _{1 -C 6 alkoxy ,} C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, C ₆ -C ₈ aryl, C ₆ -C ₈ aryloxy, glycosyloxy, or C ₁ -C ₆ alkyl substituted by 1 to 3 oxygens. More preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁ ′ are independently H, D, OH, halogen, CN, amino, or independently selected from unsubstituted or replaced by 1 The following substituent groups substituted by R ₀ : (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxyformyl, (C ₁ -C ₄ alkyl) _1-2 carbamoyl , C ₁ -C ₄ Alkylmercapto, C ₁ -C ₄ Alkylsulfonyl, C ₁ -C ₄ Alkylsulfinyl, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, By 1 C ₁ -C ₄ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkane substituted by ~ 2 hydroxyl groups or 1 ~ 2 (C ₁ -C ₂ alkyl) _1-2 amino groups phenyl, phenoxy, glycosyloxy or C ₁ -C ₄ alkyl substituted by 1 oxygen.

In the present invention, preferably, R ₆ is H, D, or selected from the following substituent groups unsubstituted or substituted by 1 to 3 R ₀ : C ₁ -C ₆ alkylformyl, C ₁ -C ₆ alkoxyformyl, (C ₁ -C ₆ alkyl) ₁ , carbamoyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ Alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ heterocycloalkyl or C ₆ -C ₈ aryl. More preferably, R ₆ is H, D, or is selected from the following substituent groups unsubstituted or substituted by 1 R ₀ : C ₁ -C ₄ alkylformyl, C ₁ -C ₄ alkoxy Formyl, (C ₁ -C ₄ alkyl) _1-2 carbamoyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkyl or phenyl.

In the present invention, preferably, R ₂ ' is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C _{6 hetero} Cycloalkyl or C ₆ -C ₈ aryl. More preferably, R ₂ ' is C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkyl or phenyl which is unsubstituted or substituted by 1 R ₀ .

In the present invention, preferably, R ₃ ' is H, D, or C ₁ -C ₆ alkyl that is unsubstituted or substituted by 1-3 R ₀ . More preferably, R ₃ ' is H, D, or C ₁ -C ₄ alkyl unsubstituted or substituted by 1 R ₀ .

In the present invention, preferably, R ₄ ' is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylformyl or C ₁ -C ₆ unsubstituted or substituted by 1 to 3 R ₀ Alkoxyformyl. More preferably, R ₄ ' is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylformyl or C ₁ -C ₄ alkoxyformyl which is unsubstituted or substituted by 1 R ₀ .

In the present invention, preferably, R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ alkoxyformyl, ( C ₁ -C ₆ alkyl) _1-2 carbamoyl, C ₁ -C ₆ alkyl mercapto, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, C ₆ -C ₈ aryl, C ₆ -C ₈ aryloxy, sugar Oxygen, or C ₁ -C ₆ alkyl substituted by 1 to 3 oxygens. More preferably, R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxyformyl, (C ₁ -C ₄ alkyl) _1-2 carbamoyl, C ₁ -C ₄ alkylmercapto, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, phenyl, phenoxy, sugar oxy, or C ₁ -C substituted by 1 oxygen ₄ alkyl.

Preferably, in formula (I) One of the following substituents:

R ₁₁ ' is C ₁ -C ₈ alkyl or C ₁ -C ₈ heteroalkyl substituted by O, S, N heteroatoms, preferably C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, More preferably C ₁ -C ₄ alkyl or C ₁ -C ₄ heteroalkyl

In the present invention, the glycosyloxy group can be any monosaccharide glycosyl or disaccharide glycosyl, such as glucosyloxy, ribosyloxy, arabinosyloxy, xylosyloxy or fructose Oxygen and so on. the

In the structural formula shown in formula (I) Expressed as a single or double bond.

The present invention specifically includes the following compounds:

Another object of the present invention is to provide the use of cyclic flavone or isoflavone compounds represented by formula (I) in the preparation of medicines for treating HCV-infected diseases. the

Another object of the present invention is to provide the application of cyclic flavonoids or isoflavones represented by formula (I) in HCV-infected diseases. the

Another object of the present invention is to administer an effective amount of cyclic flavone or isoflavone compounds represented by formula (I) to patients infected with HCV. the

Another object of the present invention is to provide cyclic flavonoids or isoflavones represented by formula (I) in combination with HCVNS3/4a protease inhibitors, HCVNS5b polymerase inhibitors or other anti-hepatitis C drugs for treating patients infected with HCV. the

The synthetic process of the cyclic flavone or isoflavone compound shown in formula (I) of the present invention is as follows:

Step a: heating and reacting cyclic flavone or isoflavone raw materials with double pinacol borate under the catalyst Pd(dppf)Cl _in 1,4-dioxane solvent to obtain an intermediate compound.

Step b: then intermediate compound and (wherein L is halogen or OTf) in 1,4-dioxane/H ₂ O solvent with Pd(dppf)Cl ₂ to catalyze the reaction to obtain the target compound represented by formula (I).

Detailed ways

Example 1 Compound 1

Synthesis of Intermediate 1-1

Mix 4-bromo-2-methoxyphenylacetic acid (147mg, 0.6mmol) and resorcinol (60mg, 0.54mmol) in boron trifluoride diethyl ether (1mL), heat to 90°C overnight, point Plate detection reaction complete. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=2/1) to obtain 80 mg of product 1-1 as a yellow solid. the

¹ HNMR (400MHz, DMSO-d ₆ ) δ12.36(s, 1H), 10.67(brs, 1H), 7.91(d, J=9.2Hz, 1H), 7.17-7.09(m, 3H), 6.40(dd , J=8.4Hz, 2.0Hz, 1H), 6.26(d, J=2.4Hz, 1H), 4.24(s, 2H), 3.74(s, 3H).

Synthesis of intermediate 1-2

1-1 (1g, 2.97mmol) and sodium acetate (2.44g, 29.66mmol) were mixed uniformly in acetic anhydride (10mL), refluxed overnight, and the reaction was complete by spotting. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed several times with saturated sodium bicarbonate, then washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1～8/1) to obtain 800 mg of Product 1-2 as yellow solid. the

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.06 (d, J=8.8Hz, 1H), 7.52 (d, J=2.0 Hz, 1H) 7.30-7.26 (m, 2H), 7.23 (dd, J= 7.6Hz, 2.0Hz, 1H), 7.12(d, J=8.4Hz, 1H), 3.74(s, 3H), 2.34(s, 3H), 2.18(s, 3H)

Synthesis of Intermediates 1-3

1-2 (100mg, 0.25mmol) was dissolved in carbon tetrachloride (2mL), and dibenzoyl peroxide (12mg, 0.16mmol) and N-bromosuccinimide (138mg, 0.78 mmol), the reaction was refluxed overnight, and the plate showed that the reaction was complete. The reaction solution was quenched with water and extracted with dichloromethane. The dichloromethane layer was washed with water, washed with brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by preparative thin-layer chromatography (petroleum ether/dichloromethane/ethyl acetate=15/15/1) to obtain 60 mg of white solid product 1 -3. the

¹ HNMR (400MHz, CDC1 ₃ ) δ8.24 (d, J=8.8Hz, 1H), 7.36 (d, J=2.4Hz, 1H), 7.23 (dd, J=8.0Hz, 1.6Hz, 1H), 7.18 -7.13(m, 3H), 4.20(d, J=11.2Hz, 1H), 4.11(d, J=11.2Hz, 1H), 3.78(s, 3H), 2.39(s, 3H).

Synthesis of Intermediates 1-4

1-3 (50mg, 0.1mmol) was dissolved in dichloromethane (1mL), and boron tribromide (39mg, 0.16mmol) was added dropwise at 0°C, stirred at room temperature overnight, and the reaction was complete by spotting. The reaction solution was quenched with methanol, concentrated and purified by preparative thin-layer chromatography (dichloromethane/methanol=15/1) to obtain 40 mg of white solid product 1-4. the

¹ HNMR (400MHz, CDCl ₃ ) δ10.91(brs, 1H), 10.01(brs, 1H), 7.87(d, J=8.4Hz, 1H), 7.10-7.03(m, 3H), 6.94(dd, J =8.8Hz, 2.0Hz, 1H), 6.87(d, J=2.0Hz, 1H), 4.42(d, J=11.2Hz, 1H), 4.19(d, J=11.6Hz, 1H).

Synthesis of Intermediates 1-5

1-4 (40mg, 0.094mmol) was dissolved in DMF (dimethylformamide) (1mL), potassium carbonate (20mg, 0.14mmol) was added in batches, stirred at room temperature overnight, and the reaction was detected by spotting. The reaction solution was poured into water, acidified to pH 2 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and concentrated to obtain 30 mg of off-white solid product 1-5. the

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.93 (brs, 1H), 8.62 (d, J=8.8Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.27 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.21(d, J=2.0Hz, 1H), 6.97(dd, J=8.4Hz, 2.0Hz, 1H), 6.88(d, J=2.4Hz, 1H), 5.21(s , 2H); ESI-LCMSm/z345.0(M+H).

Synthesis of intermediates 1-6

1-5 (320mg, 0.93mmol) was suspended in dichloromethane (10mL), pyridine (147mg, 1.85mmol) and trifluoromethanesulfonic anhydride (Tf ₂ O) (314mg, 1.11mmol) were added sequentially at 0°C, Stir at room temperature for two hours, spot plate detection reaction is complete. The reaction solution was quenched with water and extracted with dichloromethane. The dichloromethane layer was washed with 1N hydrochloric acid, sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and concentrated to obtain 430 mg of product 1-6 as a yellow solid.

Synthesis of compound 1 (hydrochloride)

step a

Intermediate 1-6 (2g), bis-pinacol borate (4eq), KOAc (5eq), Pd(dppDCl ₂ ([1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium chloride) (0.1eq) was heated to 80°C overnight in 1,4-dioxane (40mL), quenched with water, extracted with ethyl acetate, column chromatography (PE/EA (petroleum ether/ethyl acetate) 100:1～10:1) to obtain 1.75g borate ester.

step b

The borate ester (100mg) obtained in step a, the compound (WO2011079327) (2eq) represented by formula (i), Na ₂ CO ₃ (6eq) and Pd(dppDCl ₂ (0.2eq) in 1,4-dioxane Ring/H ₂ O (2/1, 3mL) was stirred at 80°C overnight, and spot plate showed that the reaction was complete. The mixture was extracted with water and dichloromethane, the dichloromethane layer was washed with brine, dried, concentrated, and column chromatography (2 Chloromethane/methanol, 200:1～100:1) to obtain 80 mg light yellow product. Crude preparation plate (EA/MeOH=50/1) was separated to obtain 30 mg light yellow solid. Then dissolved in methyl tert-butyl ether/1 , 4-dioxane (1/1, 1.5mL), add HCl/1,4-dioxane (4.5N) dropwise, stir at room temperature overnight, let stand for 1 hour, absorb the supernatant, solid It was sucked dry, then stirred in ethyl acetate at room temperature for two hours, filtered, and dried to obtain compound 1 (hydrochloride) (170 mg, yield 23%).

¹ HNMR (400MHz, DMSO-d ₆ ) δ15.16(brs, 2H), 15.78-14.48(m, 2H), 8.76(d, J=8.0Hz, 1H), 8.36(d, J=6.0Hz, 1H ), 8.24(d, J=8.4Hz, 1H), 8.15(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.62(dd, J=8.0Hz, 1.6Hz, 1H), 7.58( s, 1H), 7.31(dd, J=8.4Hz, 3.6Hz, 2H), 5.33(s, 2H), 5.22-5.16(m, 2H), 4.12(t, J=7.6Hz, 2H), 4.04- 3.96(m,2H),3.88-3.72(m,2H),3.54(s,6H),2.42-2.36(m,2H),2.24-216(m,4H),2.12-1.96(m,4H), 0.85-0.76(m,12H); ESI-LCMS m/z835.5(M+H).

Example 2 Compound 2

Synthesis of Intermediate 2-1

5-Bromo-2-hydroxypropiophenone (4.9g, 21.4mmol) and 4-bromo-2-methoxybenzaldehyde (4.6g, 21.4mmol) were dissolved in absolute ethanol (50mL), then KOH (7.2 g, 12.8mmol), stirred at room temperature for 18 hours and reacted completely, the reaction solution was poured into water (150mL), adjusted to pH5-7 with hydrochloric acid, filtered, the filter cake was washed with water, washed with petroleum ether, dried, and the crude product was washed with ethyl acetate: petroleum ether (1:1) recrystallization gave yellow solid intermediate 2-1 (6.4g, yield 70%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ10.27(s, 1H), 7.49(dd, J=8.4Hz, J=2.8Hz, 1H), 7.41(d, J=2.8Hz, 1H), 7.37( d, J=8.0Hz, 1H), 7.26(d, J=2.0Hz, 1H), 7.23(dd, J=8.0Hz, J=2.0Hz, 1H), 7.19(s, 1H), 6.89(d, J=8.0Hz, 1H), 3.78(s, 3H), 2.01(s, 3H).

Synthesis of Intermediate 2-2

Intermediate 2-1 (3g, 7mmol) was dissolved in DMSO (dimethylsulfite) (30mL), iodine (1.787g, 7mmol) was added at room temperature, the temperature was raised to 140°C and stirred for 1 hour, and the reaction solution was washed with thiosulfuric acid Sodium solution (20%) was quenched, filtered, the solid was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1) to obtain a white solid 2- 2 (1.6 g, yield 54%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.16(d, J=3.0Hz, 1H), 7.95(dd, J=9.2Hz, J=2.8Hz, 1H), 7.62(d, J=8.8Hz, 1H), 7.47(d, J=8.4Hz, 1H), 7.46(d, J=1.6Hz, 1H), 7.34(dd, J=8.0Hz, J=1.6Hz, 1H), 3.85(s, 3H) , 1.78(s, 3H).

Synthesis of Intermediate 2-3

Intermediate 2-2 was used as raw material, and the method was the same as the synthesis of intermediate 1-3 in Example 1 to obtain intermediate 2-3 (150 mg, yield 63%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.20(d, J=2.4Hz, 1H), 8.01(dd, J=8.8Hz, J=2.8Hz, 1H), 7.67(d, J=8.8Hz, 1H), 7.54(d, J=8.0Hz, 1H), 7.51(d, J=2.0Hz, 1H), 7.40(dd, J=8.0Hz, J=2.0Hz, 1H), 4.24(s, 2H) , 3.85(s, 3H).

Synthesis of intermediates 2-4

Intermediate 2-3 was used as raw material, and the method was the same as the synthesis of intermediate 1-4 in Example 1 to obtain intermediate 2-4 (460 mg, yield 91%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ10.85(s, 1H), 8.19(d, J=2.0Hz, 1H), 8.01(dd, J=8.8Hz, J=2.8Hz, 1H), 7.67( d, J=8.4Hz, 1H), 7.47(d, J=8.0Hz, 1H), 7.24-7.21(m, 2H), 4.31(s, 2H).

Synthesis of Intermediates 2-5

Intermediate 2-4 was used as raw material, and the method was the same as the synthesis of intermediate 1-5 in Example 1 to obtain intermediate 2-5 (390 mg, yield 100%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.13(d, J=3.0Hz, 1H), 8.01(dd, J=8.8Hz, J=3.0Hz, 1H), 7.81(d, J=8.0Hz, 1H), 7.78(d, J=8.8Hz, 1H), 7.39(d, J=8.4Hz, J=1.6Hz, 1H), 7.32(d, J=1.6Hz, 1H), 5.32(s, 2H) .

Synthesis of compound 2 (hydrochloride)

Using intermediate 2-5 as raw material, the method was the same as step a and step b of Example 1 to obtain compound 2 (hydrochloride) (47 mg, yield 12%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ14.75(brs, 4H), 8.49(d, J=2.0Hz, 1H), 8.31(d, J=8.8Hz, 1H), 8.24(d, J=10.8 Hz, 2H), 8.01(d, J=8.4Hz, 1H), 7.97(d, J=8.8Hz, 1H), 7.69(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.31( q, J=4.0Hz, 2H), 5.38(s, 2H), 5.1-5.14(m, 2H), 4.15-4.10(m, 2H), 3.92-3.86(m, 4H), 3.55(s, 6H ), 2.42-2.35(m, 2H), 2.25-2.12(m, 4H), 2.06-1.95(m, 4H), 0.85-0.78(m, 12H); ESI-LCMSm/z835.5(M+H) .

Example 3 Compound 3

Synthesis of Intermediate 3-1

Dissolve 5-bromo-2-hydroxyacetophenone (1.075g, 5mmol) and p-bromobenzaldehyde (0.925g, 5mmol) in absolute ethanol (30mL), add NaOH (0.6g, 15mmol), and stir at room temperature for 32 hours , TLC detection reaction is complete, and reaction solution is adjusted pH=6～7 with HCl aqueous solution (10%), separates out a large amount of yellow solids, suction filtration, gained solid is dissolved in ethyl acetate (250mL), dried over anhydrous sodium sulfate, filters, Concentrate to give yellow solid 3-1 (1.53g, yield: 80%) 

¹ HNMR (400MHz, CDCl ₃ ) δ12.68(s, 1H), 7.99(d, J=2.4Hz, 1H), 7.88(d, J=15.2Hz, 1H), 7.61-7.54(m, 6H), 6.95 (d, J=8.8Hz, 1H)

Synthesis of Intermediate 3-2

Add 3-1 (1.23g, 3.22mmol) into MeOH (50mL), add 10% NaOH solution (50mL) under ice-water bath, then drop 30% H ₂ O ₂ (35mL), remove the ice-water bath, and react at room temperature After 46 hours, TLC detected that the reaction was complete. The reaction solution was diluted with water (400 mL), adjusted to pH=4-5 by adding 10% HCl, extracted with dichloromethane (150 mL×2), combined the dichloromethane layers, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (PE:EA=20:1～5:1) to obtain light yellow solid 3-2 (200mg, yield: 15.7%)

¹ HNMR (400MHz, CDCl ₃ ) δ8.38(d, J=2.4Hz, 1H), 8.13(dd, J=6.8Hz, J=1.6Hz, 2H), 7.80(dd, J=8.8Hz, J= 2.4Hz, 1H), 7.67(dd, J=6.8Hz, J=1.6Hz, 2H), 7.50(d, J=8.8Hz, 1H), 7.03(brs, 1H)

ES-LCMSm/z395.1(M+H). 

Synthesis of Intermediate 3-3

3-2 (200 mg, 0.5 mmol) was dissolved in DMF (dimethylformamide) (7 mL), and K ₂ CO ₃ (345 mg, 2.5 mmol), iodomethane (284 mg, 2.0 mmol) were added. After reacting at room temperature for 16 hours, TLC detected that the reaction was complete. The reaction solution was poured into dilute hydrochloric acid (0.26%, 70 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, and washed with saturated brine (50 mL×5). Dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (PE:EA=200:1～40:1) to give light yellow solid 3-3 (145mg, yield: 70%)

¹ HNMR (400MHz, CDCl ₃ ) δ8.39(d, J=2.4Hz, 1H), 7.98(dt, J=8.8Hz, J=2.0Hz, 2H), 7.77(dd, J=8.8Hz, J= 2.4Hz, 1H), 7.67(dt, J=8.8Hz, J=2.0Hz, 2H), 7.44(d, J=8.8Hz, 1H), 3.90(s, 3H)

ES-LCMSm/z409.0(M+H). 

Synthesis of intermediates 3-4

3-3 (1.48g, 3.61mmol) was dissolved in benzene (200mL), under the protection of nitrogen, the high-pressure mercury lamp (1000W) was irradiated with ultraviolet light for 4 hours. The light was stopped, TLC detected that the reaction was complete, the reaction solution was concentrated, and purified by column chromatography (dichloromethane/ethyl acetate=10/1～5/1) to obtain yellow solid product 3-4 (460 mg, yield 31.2%), which was directly for the next reaction. the

¹ HNMR (400MHz, CDCl ₃ ) δ8.45(d, J=2.4Hz, 1H), 7.77(dd, J=8.8Hz, J=2.0Hz, 1H), 7.71(d, J=8.4Hz, 1H) ,7.62(dd,J=8.0Hz,J=1.6Hz,1H),7.46(d,J=8.8Hz,1H),7.40(brs,1H),5.27(s,2H)

Synthesis of compound 3 (hydrochloride)

Using intermediate 3-4 as raw material, the method was the same as step a and step b of Example 1 to obtain compound 3 (hydrochloride) (140 mg, yield: 27.6%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ15.39-14.83(m, 4H), 8.55(d, J=1.6Hz, 1H), 8.34-8.29(m, 2H), 8.20(s, 1H), 8.11 (d, J=7.6Hz, 1H), 8.02(d, J=8.0Hz, 1H), 7.98-7.94(m, 2H), 7.33(t, J=7.6Hz, 2H), 5.35(s, 2H) , 5.18(q, J=7.2Hz, 2H), 4.13(t, J=7.6Hz, 2H), 3.99-3.83(m, 4H), 3.55(s, 6H), 2.41-2.38(m, 2H), 2.23-2.18(m, 4H), 2.08-2.04(m, 4H), 0.85-0.77(m, 12H); ESI-LCMSm/z835.5(M+H).

Example 4 Compound 4

Synthesis of Intermediate 4-1

2,5-dimethoxy-α-chloroacetophenone (8g, 37.3mmol), methyl 4-methoxysalicylate (7.47g, 41.03mmol), cesium carbonate Cs ₂ CO ₃ (42.5g , 130.55mmol), sodium iodide (4.47g, 29.84mmol) and DMF (180mL) were mixed, heated to 100°C for 1.5 hours under nitrogen protection, and the reaction was stopped. Cool the reaction solution to room temperature, add dilute hydrochloric acid (0.3N, 1.2L), extract with ethyl acetate (600mL×2), combine the ethyl acetate layers, wash with saturated brine (300mL×5), and dry over anhydrous sodium sulfate , concentrated, and the crude product was purified by silica gel column chromatography (PE/EA10:1～1:2) to obtain light yellow product 4-1 (5.2g, yield: 42.5%)

¹ HNMR (400MHz, DMSO-d ₆ ) δ7.74 (d, J=8.4Hz, 1H), 7.13(d, J=1.6Hz, 1H), 7.06(d, J=8.8Hz, 1H), 7.01( dd, J=8.8Hz, J=2.8Hz, 1H), 6.91(dd, J=8.8Hz, J=1.6Hz, 1H), 6.87(d, J=3.2Hz, 1H), 3.82(s, 3H) , 3.73(s, 3H), 3.68(s, 3H)

ESI-LCMSm/z329.1(M+H). 

Synthesis of Intermediate 4-2

Using intermediate 4-1 as a raw material, the method is the same as the synthesis of intermediate 1-4 in Example 1 to obtain intermediate 4-2 (2g, yield: 47.8%). the

Synthesis of Intermediate 4-3

4-2 (2 g, 6.99 mmol) was dissolved in EtOH (35 mL), p-toluenesulfonic acid monohydrate (266.3 mg, 1.4 mmol) was added, refluxed overnight under nitrogen protection, and the reaction was complete as detected by TLC. After cooling to room temperature, insoluble matter was precipitated, filtered with suction, and the resulting solid was washed with ethanol (10mL) and dichloromethane (10mL) to give product 4-3 (400mg, yield: 21.3%)

¹ HNMR (400MHz, DMSO-d ₆ ) δ10.62(s, 1H), 10.08(s, 1H), 7.88(d, J=8.8Hz, 1H), 7.71(d, J=8.8Hz, 1H), 7.53(d, J=2.8Hz, 1H), 7.27(dd, J=8.8Hz, J=2.8Hz, 1H), 7.12(d, J=2.0Hz, 1H), 7.01(dd, J=8.8Hz, J=2.0Hz, 1H)

ESI-LCMSm/z269.1(M+H). 

Synthesis of Intermediate 4-4

Using intermediate 4-3 as raw material, the method was the same as the synthesis of intermediate 1-6 in Example 1 to obtain intermediate 4-4 (330 mg, yield: 33.3%). the

Synthesis of compound 4 (hydrochloride)

Using intermediate 4-4 as raw material, the method was the same as step a and step b of Example 1 to obtain compound 4 (hydrochloride) (63 mg, yield: 19%). the

¹ HNMR (400MHz, DMSO-d ₆ ) δ15.05-14.61 (m, 4H), 8.72 (d, J=2.0Hz, 1H), 8.40 (s, 1H), 8.35-8.26 (m, 4H), 8.09 (d, J=9.2Hz, 1H), 8.04(d, J=8.8Hz, 1H), 7.33(q, J=4.0Hz, 2H), 5.18(q, J=7.2Hz, 2H), 4.13(t , J=6.8Hz, 2H), 3.93-3.88(m, 4H), 3.55(s, 6H), 2.43-2.38(m, 2H), 2.21-2.15(m, 4H), 2.08-2.02(m, 4H ), 0.87-0.79(m, 12H).

ESI-LCMSm/z821.4(M+H). 

Formula (ii), prepared according to WO2012041014;

Formula (iii), prepared according to WO2011079327;

Formula (iv), prepared according to WO2010132601;

Formula (V), prepared according to WO2012040924

Compounds shown in Table 1 were obtained by synthesizing the intermediate compounds of Examples 1-4 and one or both of the above-mentioned compounds of formulas (ii)-(v) according to steps a and b. the

Compounds 5-13 in Table 1

Effect Example 1

HCV Replicon Experiment

According to the literature (Science.1999Jul2; 285 (5424): 110-3 and J. Virol. 2003, Mar; 77 (5): 3007-19 method described in the preparation, implementation and verification. Compounds 1-4 were tested with HCV genotype GT1a, GT1b and GT2a replicon cells, and HCV1b wild-type cells and Y93H, L31F, P32L, I302V resistant cells. GT1a and GT1b are hepatitis C replicon systems (HCV RepliconSystem) transfected with HCV1a, 1b, and 2a genotypes respectively. This system contains the G418 resistance gene NEO and the luciferase reporter gene. Detecting the content of NEO and detecting the expression level of luciferase gene by chemiluminescence can be used to determine the level of replication of hepatitis C and evaluate the effect of compounds 1-4 on HCV virus replication. the

experimental method:

HCV replicon transfected cells: Huh7.5.1 cells transfected with HCV replicon (wild type 1b). The transfected cells were seeded in 96-well plates, 8000 cells per well, and cultured at 37°C, S%CO ₂ for 24 hours.

Sample treatment: Add different concentrations of compound 1-4 samples to Huh7.5.1 cells transfected with HCV replicon, set up duplicate wells for each concentration, and set up no-sample control wells. Starting from the highest concentration of the test sample, use the POD810 automatic microplate pretreatment system to add different concentrations of compounds to the cells; 3-fold dilution of 10 concentrations; continue to culture for 72 hours. the

Compound activity and cytotoxicity assay:

CellTiter-fluor (Promega) was added to measure the fluorescence signal, and the obtained data (RFU) was calculated with GraphPad Prism software to calculate the EC ₅₀ of the compound.

The ranges of EC ₅₀ against HCV1b are as follows: a means: 0.0001nM≤EC ₅₀ ≤0.100nM; b means: 0.100nM<EC ₅₀ ≤10.00nM; c means: 10.00nM<EC ₅₀ ≤100.0nM; d means: EC ₅₀ >100nM.

Table 2 Compounds 1-4 against the EC ₅₀ value of HCV1b genotype replicon

Claims (10)

1. A cyclic flavone or isoflavone compound shown in formula (I), or its nitrogen oxide, hydrate, solvate, metabolite or pharmaceutically acceptable salt or prodrug, wherein, When A ₁ is -C(O)-, A ₂ is -O-; when A ₁ is -O-, A ₂ is -C(O)-; Q is -O-, -S-, -C(R ₄ R ₅ )-, -C(R ₄ R ₅ )O-, -OC(R ₄ R ₅ )-, -C(R ₄ R ₅ )N (R ₆ )-, -N(R ₆ )C(R ₄ R ₅ )-, -N(R ₆ )-, -C(R ₄ R ₅ )C(R ₄ R ₅ )-, -C(R ₄ R ₅ )-S- or -SC(R ₄ R ₅ )-; W is -(NHC(O)) _1~2- , -(C ₁ -C ₃ )alkylene-(NHC(O)) _1~2- , Or _R can be connected with W to form an imidazole ring; R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently H, D, OH, halogen, CN, amino, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto , C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, surrounded by 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _1-2 amino substituted C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl , C ₆ -C ₁₀ aryloxy, glycosyloxy, or C ₁ -C ₈ alkyl substituted by 1 to 5 oxygens; R ₆ is H, D, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkylformyl, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₃ -C ₈ Cycloalkyl, C ₂ -C ₈ heterocycloalkyl or C ₆ -C ₁₀ aryl; R ₁ ' is independently H, D, OH, halogen, CN, amino, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : (C ₁ -C ₈ alkyl) _{1 -2} amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, with 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _{1- 2} Amino-substituted C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, Glycosyloxy, or C ₁ -C ₈ alkyl substituted by 1 to 5 oxygens; Or R ₁ ' on two adjacent carbon atoms and the two carbon atoms it connects together form a C ₃ -C ₇ carbon ring, or two R ₁ ' on the same carbon atom forms a carbon atom that can be connected to it. A 3-7-membered ring inserted by 0-2 heteroatoms selected from N, O and S, or R ₁ ' on 2 carbon atoms interspersed by 1 carbon atom forms C together with the 2 carbon atoms it is connected to ₃ -C ₇ carbon ring; R ₂ ' is selected from the following substituent groups that are unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ heterocycloalkane group or C ₆ -C ₁₀ aryl group; R ₃ ' is H, D, or selected from unsubstituted or C ₁ -C ₈ alkyl substituted by 1 to 5 R ₀ ; R ₄ ' is selected from the following substituent groups unsubstituted or substituted by 1 to 5 R ₀ : C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylformyl or C ₁ -C ₈ alkoxy Formyl; Or R ₃ ′, R ₄ ′ and the nitrogen atom connected to it form a 3-7 membered monocyclic ring, a 4-12-membered bicyclic ring or a 5- to 12-membered spirocycle; Wherein, R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxyformyl, (C ₁ -C ₈ alkyl ) _1-2 carbamoyl, C ₁ -C ₈ alkylmercapto, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, sugar oxy, or 1 ~5 oxygen substituted C ₁ -C ₈ alkyl groups. 2. The compound according to claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₁ ′ are independently H, D, OH, halogen, CN, amino, or independently is selected from the following substituent groups that are unsubstituted or substituted by 1 to 3 R ₀ : (C ₁ -C ₆ alkyl) ₁ -amino, C ₁ -C ₆ alkoxyformyl, (C ₁ - C ₆ alkyl) _1-2 carbamoyl, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C 1 -C 6 alkoxy substituted by 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _1-2 amino groups, _{C 3 -C 7} ring Alkyl, C ₂ -C ₆ heterocycloalkyl, C ₆ -C ₈ aryl, C ₆ -C ₈ aryloxy, sugar oxy, or C ₁ -C ₆ substituted by 1 to 3 oxygen alkyl; R ₆ is H, D, or selected from the following substituent groups that are unsubstituted or substituted by 1 to 3 R ₀ : C ₁ -C ₆ alkylformyl, C ₁ -C ₆ alkoxyformyl, (C ₁ -C ₆ alkyl) _1-2 carbamoyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkyl, C ₃ -C ₇ Cycloalkyl, C ₂ -C ₆ heterocycloalkyl or C ₆ -C ₈ aryl; R2' is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ heterocycloalkyl or C ₆ -C ₈ unsubstituted or substituted by 1 to 3 R ₀ Aryl; R ₃ ' is H, D, or C ₁ -C ₆ alkyl unsubstituted or substituted by 1 to 3 R ₀ ; R ₄ ' is C ₁ -C ₆ alkyl, C ₁ -C 6 alkyl formyl or C _{1 -C 6 alkoxy} formyl unsubstituted or substituted by 1 to 3 R ₀ ; R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ alkoxyformyl, (C ₁ -C ₆ alkyl) _{1 -2} carbamoyl, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C 1 -C ₆ alkyl, C _{1 -C 6} alkane Oxygen, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, C ₆ -C ₈ aryl, C ₆ -C ₈ aryloxy, sugar oxy, or by 1 to 3 Oxygen substituted C ₁ -C ₆ alkyl. 3. The compound of claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₁ ′ are independently H, D, OH, halogen, CN, amino, or independently is selected from the following groups of substituents unsubstituted or substituted by 1 R ₀ : (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxyformyl, (C ₁ -C ₄ alkyl) _1-2 carbamoyl, C ₁ -C ₄ alkylmercapto, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, _C 1 -C 4 alkoxy substituted by 1 to 2 hydroxyl groups or 1 to 2 (C ₁ -C ₂ alkyl) _1-2 amino groups, C _{3 -C 7} cycloalkane radical, C ₂ -C ₅ heterocycloalkyl, benzene, phenoxy, glycosyloxy or C ₁ -C ₄ alkyl substituted by 1 oxygen; R ₆ is H, D, or selected from the following substituent groups that are unsubstituted or substituted by 1 R ₀ : C ₁ -C ₄ alkylformyl, C ₁ -C ₄ alkoxyformyl, (C ₁ -C ₄ alkyl) _1-2 carbamoyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkane radical, C ₂ -C ₅ heterocycloalkyl or phenyl; R ₂ ' is C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkyl or phenyl which is unsubstituted or substituted by 1 R ₀ ; R ₃ ' is H, D, or C ₁ -C ₄ alkyl unsubstituted or substituted by 1 R ₀ ; R ₄ ' is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylformyl or C ₁ -C ₄ alkoxyformyl unsubstituted or substituted by 1 R ₀ ; R ₀ is H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxyformyl, (C ₁ -C ₄ alkyl) _{1 -2} carbamoyl, C ₁ -C ₄ alkylmercapto, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C 1 -C ₄ alkyl, C _{1 -C 4} alkane Oxygen, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, phenyl, phenoxy, glycosyloxy, or C ₁ -C ₄ alkyl substituted by 1 oxygen. 4. The compound according to claim 1, wherein the glycosyloxy group is glucosyloxy, ribosyloxy, arabinosyloxy, xylosyloxy or fructosyloxy. 5. the compound as claimed in claim 1, is characterized in that, in formula (I) One of the following substituents: Among them, R ₁₁ ' is C ₁ -C ₈ alkyl or C ₁ -C ₈ heteroalkyl substituted by O, S, N heteroatoms, preferably C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkane group, more preferably C ₁ -C ₄ alkyl or C ₁ -C ₄ heteroalkyl. 6. compound as claimed in claim 1, is characterized in that, this compound is: 7. Use of the compound of claim 1 in the preparation of medicines for treating HCV-infected diseases. 8. The application of the compound according to claim 1 in HCV-infected diseases. 9. Administration of an effective amount of the compound of claim 1 to a patient infected with HCV. 10. The compound of claim 1 is used in combination with HCVNS3/4a protease inhibitor, HCVNS5b polymerase inhibitor or other anti-hepatitis C drugs to treat patients infected with HCV.