CN104610272B - Ring-type flavones or isoflavonoid and application thereof - Google Patents

Ring-type flavones or isoflavonoid and application thereof Download PDF

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CN104610272B
CN104610272B CN201310542304.6A CN201310542304A CN104610272B CN 104610272 B CN104610272 B CN 104610272B CN 201310542304 A CN201310542304 A CN 201310542304A CN 104610272 B CN104610272 B CN 104610272B
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alkyl
alkoxyl
amino
unsubstituted
formoxyl
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CN104610272A (en
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张所明
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SHANGHAI TANGRUN PHARMACEUTICAL TECHNOLOGY Co Ltd
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SHANGHAI TANGRUN PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses the ring-type flavones or isoflavonoid or its nitrogen oxides, hydrate, solvate, metabolite or pharmaceutically acceptable salt or prodrug shown in a kind of formula (I), works as A1For C (O) when, A2For O;Work as A1For O when, A2For C (O);Q is O, S, C (R4R5)‑、‑C(R4R5)O‑、‑OC(R4R5)‑、‑C(R4R5)N(R6)‑、‑N(R6)C(R4R5)‑、‑N(R6)‑、‑C(R4R5)C(R4R5)‑、‑C(R4R5) S or S C (R4R5)‑;W is (NHC (O))1～2‑、‑(C1‑C3) alkylidene (NHC (O))1～2Or R1Can be connected to form imidazole ring with W.The ring-type flavones or isoflavonoid of the present invention has the effect of excellent anti-hepatitis C virus.

Description

Ring-type flavones or isoflavonoid and application thereof
Technical field
The invention belongs to the technical field of compound synthesis, particularly relates to a kind of ring-type flavones or osajin chemical combination Thing and application thereof.
Background technology
After HCV (HCV) is blood transfusion and sporadic hepatitis main pathogen, virion is spherical in shape, and diameter is little In 80nm (being 36～40nm in liver cell, be 36～62nm in blood), it is single strand plus RNA virus, outside nucleocapsid Cyst membrane of the wrapping containing lipid, has furcella on cyst membrane.HCV-RNA about 9500～10000bp are constituted, in 5 ' noncoding region downstreams Immediately one open reading frame (openreading frame, ORF), genome array order be 5 '-C-E1-E2-p7-NS2- NS3-NS4-NS5-3, encodes the single polyprotein precursor of 3014 amino acid, and Jing host signal skin enzymes and virus protease split Solve as structural proteins (C, E1, E2, P7) and non-structural protein (NS2, NS3, NS4 and NS5).Nonstructural gene NS5 areas are located at base Because organizing 6258-9374nt, NS5A and NS5B two parts are cracked into by NS3 serine proteases, cracking site is located at cys- Between 2420/ser2421, the cracking site and its flanking sequence of different HCV separation strains are guarded relatively.NS5A areas are located at 6258- 7601nt, encodes 1973-2420aa, and the relative molecular weight of albumen is 56KD (i.e. P56) and 58KD (i.e. P58), and P58 is P56 Peroxophosphoric acid form, in the case of NS3, NS4A and NS4B are present, P56 can just be transformed into P58.
Generally acknowledge to research of antiviral agents for hepatitis C active drug it is interferon (IFN) at present, but HCV infection person is to interferon The response for the treatment of differs, and average response rate is less than 50%, and recurrence rate is higher after being discontinued.FDA have approved two NS3/ in 2011 4A serpins Telaprevir and Boceprevir are listed, for hepatitis C treatment provide it is new effective Method.But the appearance of drug resistance and toxic and side effect so that the treatment of HCV virus still needs newtype drug, such as acts on new The inhibitor of type target spot NS5a.HCVNS5a inhibitor and NS3/4a and NS5b inhibitor drug combination can be used to treat infection The patient of the HCV virus of drug resistance.
The content of the invention
It is an object of the invention to provide the ring-type flavones or isoflavonoid shown in a kind of formula (I),
Or its nitrogen oxides, hydrate, solvate, metabolite or pharmaceutically acceptable salt or prodrug, wherein,
Work as A1For-C (O)-when, A2For-O-;Work as A1For-O- when, A2For-C (O)-;
Q is-O- ,-S- ,-C (R4R5)-、-C(R4R5)O-、-OC(R4R5)-、-C(R4R5)N(R6)-、-N(R6)C (R4R5)-、-N(R6)-、-C(R4R5)C(R4R5)-、-C(R4R5)-S- or-S-C (R4R5)-;
W is-(NHC (O))1～2-、-(C1-C3) alkylidene-(NHC (O))1～2-、
Or R1Can be connected to form miaow with W Azoles ring, i.e. R1, W and ring-type flavones or isoflavones form condensed cyclic structure together with the phenyl with it --- benzimidazole ring structure, A carbon atom on the imidazole ring between two nitrogen-atoms reconnects following formula group:
R1、R2、R3、R4、R5It independently is H, D, OH, halogen, CN, amino, or selected from unsubstituted or by 1～5 R0Substituted substituents group:(C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamyl Base, C1-C8Alkyl thiol, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1-C8Alkoxyl, by 1～2 Individual hydroxyl or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1-C8Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6- C10Aryl, C6-C10Aryloxy, glycosyl epoxide or the C replaced by 1～5 oxygen1-C8Alkyl;
R6For H, D, or selected from unsubstituted or by 1～5 R0Substituted substituents group:C1-C8Alkyl Base, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamoyl, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C3-C8Cycloalkyl, C2-C8Heterocyclylalkyl or C6-C10Aryl;
Wherein, R1' it independently is H, D, OH, halogen, CN, amino, or selected from unsubstituted or by 1～5 R0Replace Substituents group:(C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamoyl, C1-C8 Alkyl thiol, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1-C8Alkoxyl, by 1～2 hydroxyl or 1 ～2 (C1-C2Alkyl)1-2The C that amino replaces1-C8Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6-C10Aryl, C6- C10Aryloxy, glycosyl epoxide or the C replaced by 1～5 oxygen1-C8Alkyl;
Or the R on two neighboring carbon atom1' connected 2 carbon atoms form C together3-C7Carbocyclic ring, Huo Zhetong Two R on one carbon atom1' connected 1 carbon atom formed can by 0～2 selected from the insertion of N, O and S hetero atom 3～ 7 yuan of rings, or middle ware is separated with the R on 2 carbon atoms of 1 carbon atom1' connected 2 carbon atoms form C together3- C7Carbocyclic ring;
R2' it is selected from unsubstituted or by 1～5 R0Substituted substituents group:C1-C8Alkyl, C3-C7Cycloalkanes Base, C2-C7Heterocyclylalkyl or C6-C10Aryl;
R3' it is H, D, or selected from unsubstituted or by 1～5 R0Substituted C1-C8Alkyl;
R4' it is selected from unsubstituted or by 1～5 R0Substituted substituents group:C1-C8Alkyl, C1-C8Alkyl first Acyl group or C1-C8Alkoxyl formoxyl;
Or R3′、R4' connected nitrogen-atoms is formed containing 1 N atom and is selected from the miscellaneous original of N, O and S containing 0～2 3～7 unit monocycles of son, 4～12 membered bicyclics or 5～12 yuan of volutions;
Wherein, R0For H, D, OH, halogen, CN, amino, (C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8 Alkyl)1-2Carbamoyl, C1-C8Alkyl thiol, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1- C8Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6-C10Aryl, C6-C10Aryloxy, glycosyl epoxide or by 1～5 The C that oxygen replaces1-C8Alkyl.
In the present invention, it is preferred to be, R1、R2、R3、R4、R5、R1' H, D, OH, halogen, CN, amino independently are, or Independently selected from unsubstituted or by 1～3 R0Substituted substituents group:(C1-C6Alkyl)1-2Amino, C1-C6Alcoxyl Base formoxyl, (C1-C6Alkyl)1-2Carbamoyl, C1-C6Alkyl thiol, C1-C6Alkyl sulphonyl, C1-C6Alkyl sulfenyl Base, C1-C6Alkyl, C1-C6Alkoxyl, by 1～2 hydroxyl or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1-C6Alkoxyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl, C6-C8Aryl, C6-C8Aryloxy, glycosyl epoxide or the C replaced by 1～3 oxygen1- C6Alkyl.More preferably, R1、R2、R3、R4、R5、R1' it independently is H, D, OH, halogen, CN, amino, or independently selected from It is unsubstituted or by 1 R0Substituted substituents group:(C1-C4Alkyl)1-2Amino, C1-C4Alkoxyl formoxyl, (C1- C4Alkyl)1-2Carbamoyl, C1-C4Alkyl thiol, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkyl, C1-C4Alkoxyl, by 1～2 hydroxyl or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1-C4Alkoxyl, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl, benzene, phenoxy group, glycosyl epoxide or the C replaced by 1 oxygen1-C4Alkyl.
In the present invention, it is preferred to be, R6For H, D, or selected from unsubstituted or by 1～3 R0The following of replacement takes For base group:C1-C6Alkyl formyl radical, C1-C6Alkoxyl formoxyl, (C1-C6Alkyl)1, carbamoyl, C1-C6Alkyl sulfonyl Base, C1-C6Alkyl sulphinyl, C1-C6Alkyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl or C6-C8Aryl.More preferably, R6 For H, D, or selected from unsubstituted or by 1 R0Substituted substituents group:C1-C4Alkyl formyl radical, C1-C4Alkoxyl Formoxyl, (C1-C4Alkyl)1-2Carbamoyl, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkyl, C3-C7 Cycloalkyl, C2-C5Heterocyclylalkyl or phenyl.
In the present invention, it is preferred to be, R2' it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl, C3-C7Ring Alkyl, C2-C6Heterocyclylalkyl or C6-C8Aryl.More preferably, R2' it is unsubstituted or by 1 R0Substituted C1-C4Alkane Base, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl or phenyl.
In the present invention, it is preferred to be, R3' it is H, D, or it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl. More preferably, R3' it is H, D, or it is unsubstituted or by 1 R0Substituted C1-C4Alkyl.
In the present invention, it is preferred to be, R4' it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl, C1-C6Alkane Base formoxyl or C1-C6Alkoxyl formoxyl.More preferably, R4' it is unsubstituted or by 1 R0Substituted C1-C4Alkyl, C1-C4Alkyl formyl radical or C1-C4Alkoxyl formoxyl.
In the present invention, it is preferred to be, R0For H, D, OH, halogen, CN, amino, (C1-C6Alkyl)1-2Amino, C1-C6Alcoxyl Base formoxyl, (C1-C6Alkyl)1-2Carbamoyl, C1-C6Alkyl thiol, C1-C6Alkyl sulphonyl, C1-C6Alkyl sulfenyl Base, C1-C6Alkyl, C1-C6Alkoxyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl, C6-C8Aryl, C6-C8Aryloxy, glycosyl oxygen Base or the C replaced by 1～3 oxygen1-C6Alkyl.More preferably, R0For H, D, OH, halogen, CN, amino, (C1-C4Alkyl)1-2 Amino, C1-C4Alkoxyl formoxyl, (C1-C4Alkyl)1-2Carbamoyl, C1-C4Alkyl thiol, C1-C4Alkyl sulphonyl, C1- C4Alkyl sulphinyl, C1-C4Alkyl, C1-C4Alkoxyl, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl, phenyl, phenoxy group, glycosyl Epoxide or the C replaced by 1 oxygen1-C4Alkyl.
Preferably, in formula (I)For one of substituents:
R11' it is C1-C8Alkyl or the C replaced by O, S, N hetero atom1-C8Miscellaneous alkyl, preferably C1-C6Alkyl or C1-C6 Miscellaneous alkyl, more preferably C1-C4Alkyl or C1-C4Miscellaneous alkyl
In the present invention, described glycosyl epoxide can be any monose glycosyl or disaccharides glycosyl, such as be glucosyl group oxygen Base, ribosyl epoxide, aralino epoxide, xylosyl epoxide or fructosyl epoxide etc..
In structural formula shown in formula (I)It is expressed as singly-bound or double bond.
The present invention specifically includes following compound:
Another object of the present invention is to the ring-type flavones or isoflavonoid that provide shown in formula (I) are preparing treatment Purposes in the medicine of the disease of HCV infection.
A further object of the present invention is ring-type flavones or isoflavonoid shown in offer formula (I) in HCV infection Disease in terms of application.
Another object of the present invention is that the patient for giving HCV infection applies the ring-type flavones shown in the formula (I) of effective dose Or isoflavonoid.
It is still another object of the present invention to provide the ring-type flavones or isoflavonoid and HCVNS3/ shown in formula (I) The medication combined patient for treating HCV infection of 4a protease inhibitors, HCVNS5b AG14361s or other anti-hepatitis.
The synthesis flow of ring-type flavones or isoflavonoid shown in formula (I) of the present invention is as follows:
Step a:By ring-type flavones or osajin raw material with duplex pinacol borate in catalyst Pd (dppf) Cl2Under In Isosorbide-5-Nitrae-dioxane solvent, heating response obtains midbody compound.
Step b:Again by midbody compound with(wherein L is halogen or OTf) is in Isosorbide-5-Nitrae-dioxy Six rings/H2Pd (dppf) Cl is used in O solvents2Catalytic reaction obtains the target compound shown in formula (I).
Specific embodiment
1 compound 1 of embodiment
The synthesis of intermediate 1-1
By 4- bromo- 2- methoxyphenylacetic acids (147mg, 0.6mmol) with resorcinol (60mg, 0.54mmol) borontrifluoride It is well mixed in borate ether (1mL), is heated to 90 DEG C of reactions overnight, point plate detection reaction is complete.Reactant liquor is poured into water, second Acetoacetic ester is extracted.Ethyl acetate layer is washed with saturated sodium bicarbonate, and salt washing, anhydrous sodium sulfate drying, concentration prepare thin-layer chromatography Purifying (petrol ether/ethyl acetate=2/1) obtains 80mg yellow solid products 1-1.
1HNMR (400MHz, DMSO-d6) δ 12.36 (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).
The synthesis of intermediate 1-2
1-1 (1g, 2.97mmol) is well mixed in acetic anhydride (10mL) with sodium acetate (2.44g, 29.66mmol), Overnight, point plate detection reaction is complete for backflow.Reactant liquor is poured in frozen water, ethyl acetate extraction.Ethyl acetate layer saturated carbon Sour hydrogen sodium washing is multiple, then is washed with salt, anhydrous sodium sulfate drying, concentration, silica gel column chromatography purifying (petrol ether/ethyl acetate= 20/1～8/1) obtain the slightly yellow solid product 1-2 of 800mg.
1HNMR (400MHz, DMSO-d6) δ 8.06 (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)
The synthesis of intermediate 1-3
1-2 (100mg, 0.25mmol) is dissolved in carbon tetrachloride (2mL), be dividedly in some parts dibenzoyl peroxide (12mg, 0.16mmol) with N- bromo-succinimides (138mg, 0.78mmol), overnight, point plate shows that reaction is complete for reaction backflow.Instead Liquid is answered to be quenched with water, dichloromethane extraction.Dichloromethane layer is washed with water, and salt washing, anhydrous sodium sulfate drying are concentrated to give crude product, Prepare Thin Layer Chromatography (petroleum ether/dichloromethane/ethyl acetate=15/15/1) and obtain 60mg white solid products 1-3.
1HNMR (400MHz, CDC13) δ 8.24 (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).
The synthesis of intermediate 1-4
1-3 (50mg, 0.1mmol) is dissolved in dichloromethane (1mL), at 0 DEG C be added dropwise Boron tribromide (39mg, 0.16mmol), it is stirred overnight at room temperature, point plate detection reaction is complete.Reactant liquor is quenched with methyl alcohol, and concentration prepares Thin Layer Chromatography (methylene chloride/methanol=15/1) obtains 40mg white solid products 1-4.
1HNMR (400MHz, CDCl3) δ 10.91 (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).
The synthesis of intermediate 1-5
During 1-4 (40mg, 0.094mmol) is dissolved in DMF (dimethylformamide) (1mL), potassium carbonate is dividedly in some parts (20mg, 0.14mmol), is stirred overnight at room temperature, and point plate detection reaction is complete.Reactant liquor is poured into water, and pH is acidified with 1N hydrochloric acid To 2, ethyl acetate is extracted.Ethyl acetate washed with water is washed, and saturated sodium bicarbonate is washed, and salt washing, anhydrous sodium sulfate drying are concentrated to give To 30mg product as off-white solid 1-5.
1HNMR (400MHz, DMSO-d6) δ 10.93 (brs, 1H), 8.62 (d, J=8.8Hz, 1H), 8.00 (d, J= 9.2Hz, 1H), 7.27 (dd, J=8.4Hz, 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).
The synthesis of intermediate 1-6
1-5 (320mg, 0.93mmol) is suspended in dichloromethane (10mL), sequentially add at 0 DEG C pyridine (147mg, 1.85mmol) with trifluoromethanesulfanhydride anhydride (Tf2O) (314mg, 1.11mmol), is stirred at room temperature two hours, and point plate detection has been reacted Entirely.Reactant liquor is quenched with water, dichloromethane extraction.Dichloromethane layer 1N salt pickling, sodium acid carbonate are washed, salt washing, anhydrous sulphur Sour sodium is dried, and is concentrated to give 430mg yellow solid products 1-6.
The synthesis of compound 1 (hydrochloride)
Step a
Intermediate 1-6 (2g), duplex pinacol borate (4eq), KOAc (5eq), Pd (dppDCl2([1,1 '-bis- (two Phenyl phosphorus) ferrocene] palladium chloride) (0.1eq) 80 DEG C are heated to overnight in Isosorbide-5-Nitrae-dioxane (40mL), add water and be quenched, Ethyl acetate is extracted, column chromatography (PE/EA (petrol ether/ethyl acetate) 100:1～10:1) purifying obtains 1.75g borates.
Step b
Compound (WO2011079327) shown in borate (100mg) that step a is obtained, formula (i) (2eq), Na2CO3 (6eq) with Pd (dppDCl2(0.2eq) in Isosorbide-5-Nitrae-dioxane/H2It is stirred overnight at 80 DEG C in O (2/1,3mL), point plate shows instead Should be complete.The mixture water and dichloromethane extraction, dichloromethane layer salt water washing, are dried, concentration, column chromatography (dichloromethane Alkane/methyl alcohol, 200:1～100:1) the faint yellow products of 80mg are obtained.Crude product is prepared after plate (EA/MeOH=50/1) is separated and is obtained 30mg faint yellow solids.Then it is dissolved in methyl tertiary butyl ether(MTBE)/Isosorbide-5-Nitrae-dioxane (1/1,1.5mL), HCl/1,4- bis- is added dropwise Six rings of oxygen (4.5N), is stirred overnight at room temperature, and stands 1 hour, and supernatant liquor is siphoned away, and solid is drained, then the room in ethyl acetate Temperature stirring two hours, filters, and (170mg, yield is 23%) to be dried to obtain compound 1 (hydrochloride).
1HNMR (400MHz, DMSO-d6) δ 15.16 (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).
2 compound 2 of embodiment
The synthesis of intermediate 2-1
The bromo- 2- hydroxypropiophenonepreparations (4.9g, 21.4mmol) of 5- and the bromo- Benzaldehyde,2-methoxies of 4- (4.6g, 21.4mmol) It is dissolved in absolute ethyl alcohol (50mL), is subsequently adding KOH (7.2g, 12.8mmol), reaction in 18 hours is stirred at room temperature completely, reaction Liquid pours water (150mL) into, adjusts pH5-7 with hydrochloric acid, filters, and filter cake washing, petroleum ether are washed, and are dried, crude product ethyl acetate: Petroleum ether (1:1) (6.4g, yield is 70%) to be recrystallized to give yellow solid intermediate 2-1.
1HNMR (400MHz, DMSO-d6) δ 10.27 (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).
The synthesis of intermediate 2-2
During intermediate 2-1 (3g, 7mmol) is dissolved in DMSO (dimethyl alum) (30mL), under room temperature, iodine is added (1.787g, 7mmol), is warmed up to 140 DEG C and stirs 1 hour, and reactant liquor hypo solution (20%) is quenched, and filters, Gu Body ethyl acetate dissolves, washing, saturated common salt washing, is dried, concentration, silica gel column chromatography (petrol ether/ethyl acetate=100/ 1) purifying obtains white solid 2-2 (1.6g, yield is 54%).
1HNMR (400MHz, DMSO-d6) δ 8.16 (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).
The synthesis of intermediate 2-3
Intermediate 2-2 is adopted for raw material, method obtains intermediate 2-3 with the synthesis of the intermediate 1-3 of embodiment 1 (150mg, yield is 63%).
1HNMR (400MHz, DMSO-d6) δ 8.20 (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).
The synthesis of intermediate 2-4
Intermediate 2-3 is adopted for raw material, method obtains intermediate 2-4 with the synthesis of the intermediate 1-4 of embodiment 1 (460mg, yield is 91%).
1HNMR (400MHz, DMSO-d6) δ 10.85 (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).
The synthesis of intermediate 2-5
Intermediate 2-4 is adopted for raw material, method obtains intermediate 2-5 with the synthesis of the intermediate 1-5 of embodiment 1 (390mg, yield is 100%).
1HNMR (400MHz, DMSO-d6) δ 8.13 (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).
The synthesis of compound 2 (hydrochloride)
Intermediate 2-5 is adopted for raw material, method obtains compound 2 (hydrochloride) with a the step of embodiment 1 and step b (47mg, yield is 12%).
1HNMR (400MHz, DMSO-d6) δ 14.75 (brs, 4H), 8.49 (d, J=2.0Hz, 1H), 8.31 (d, J= 8.8Hz, 1H), 8.24 (d, J=10.8Hz, 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).
3 compound 3 of embodiment
The synthesis of intermediate 3-1
5- bromo- 2- hydroxy acetophenones (1.075g, 5mmol) and p-bromobenzaldehyde (0.925g, 5mmol) are dissolved in into anhydrous second Alcohol (30mL), adds NaOH (0.6g, 15mmol), is stirred at room temperature 32 hours, and TLC detection reactions are complete, and reactant liquor is molten with HCl/water Liquid (10%) adjusts pH=6～7, separates out a large amount of yellow solids, and suction filtration, gained solid are dissolved in ethyl acetate (250mL), anhydrous sulphur Sour sodium is dried, and filters, is concentrated to give yellow solid 3-1 (1.53g, yield:80%)
1HNMR (400MHz, CDCl3) δ 12.68 (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)
The synthesis of intermediate 3-2
3-1 (1.23g, 3.22mmol) is added in MeOH (50mL), 10%NaOH solution (50mL) under ice-water bath, is added, 30%H is instilled again2O2(35mL) ice-water bath is removed, is reacted 46 hours under room temperature, TLC detection reactions are complete, and reactant liquor adds water (400mL) dilute, plus 10%HCl adjusts pH=4-5, is extracted with dichloromethane (150mL × 2), dichloromethane layer merges, anhydrous Sodium sulphate is dried, and is concentrated to give crude product, Jing silica gel column chromatographies purifying (PE:EA=20:1～5:1) obtain light yellow solid 3-2 (200mg, yield:15.7%)
1HNMR (400MHz, CDCl3) δ 8.38 (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).
The synthesis of intermediate 3-3
During 3-2 (200mg, 0.5mmol) is dissolved in DMF (dimethylformamide) (7mL), K is added2CO3(345mg, 2.5mmol), iodomethane (284mg, 2.0mmol).Room temperature reaction 16 hours, TLC detection reactions are complete, reactant liquor are poured into dilute In hydrochloric acid (0.26%, 70mL), extracted with ethyl acetate (50mL × 3), organic phase merges, saturated aqueous common salt (50mL × 5) is washed, Anhydrous sodium sulfate drying, concentration, silica gel column chromatography purifying (PE:EA=200:1～40:1) (145mg is received to obtain light yellow solid 3-3 Rate:70%)
1HNMR (400MHz, CDCl3) δ 8.39 (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).
The synthesis of intermediate 3-4
3-3 (1.48g, 3.61mmol) is dissolved in benzene (200mL), under nitrogen protection, high-pressure sodium lamp (1000W) is ultraviolet Irradiation 4 hours.Stop illumination, TLC detection reactions are complete, reactant liquor concentration, column chromatography (dichloromethane/ethyl acetate=10/1～ 5/1) purify yellow solid product 3-4 (460mg, yield 31.2%), be directly used in next step reaction.
1HNMR(400MHz,CDCl3)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)
The synthesis of compound 3 (hydrochloride)
Intermediate 3-4 is adopted for raw material, method obtains compound 3 (hydrochloride) with a the step of embodiment 1 and step b (140mg, yield:27.6%).
1HNMR (400MHz, DMSO-d6) δ 15.39-14.83 (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).
4 compound 4 of embodiment
The synthesis of intermediate 4-1
2,5- dimethoxys-alpha-chloro acetophenone (8g, 37.3mmol), 4- methoxysalicylic acid methyl esters (7.47g, 41.03mmol), cesium carbonate Cs2CO3(42.5g, 130.55mmol), sodium iodide (4.47g, 29.84mmol) and DMF (180mL) Mixing, is warming up to 100 DEG C under nitrogen protection and reacts 1.5 hours, stop reaction.Reactant liquor is cooled to room temperature, adds watery hydrochloric acid 0.3N, Extract in 1.2L), with ethyl acetate (600mL × 2), combined ethyl acetate layer is washed with saturated aqueous common salt (300mL × 5), nothing Aqueous sodium persulfate is dried, concentration, crude on silica gel column chromatography (PE/EA10：1～1：2) purify faint yellow product 4-1 (5.2g, Yield:42.5%)
1HNMR (400MHz, DMSO-d6) δ 7.74 (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).
The synthesis of intermediate 4-2
Intermediate 4-1 is adopted for raw material, synthesis of the method with the intermediate 1-4 of embodiment 1, obtain intermediate 4-2 (2g, Yield:47.8%).
The synthesis of intermediate 4-3
4-2 (2g, 6.99mmol) is dissolved in into EtOH (35mL), add p-methyl benzenesulfonic acid monohydrate (266.3mg, 1.4mmol), night is flow through in nitrogen protection next time, and TLC detection reactions are complete.It is cooled to room temperature, has insoluble matter to separate out, suction filtration, gained is solid Body is washed with ethanol (10mL), dichloromethane (10mL) washing, obtains product 4-3 (400mg, yield:21.3%)
1HNMR (400MHz, DMSO-d6) δ 10.62 (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).
The synthesis of intermediate 4-4
Intermediate 4-3 is adopted for raw material, synthesis of the method with 1 intermediate 1-6 of embodiment, obtain intermediate 4-4 (330mg, Yield:33.3%).
The synthesis of compound 4 (hydrochloride)
Intermediate 4-4 is adopted for raw material, method obtains compound 4 (hydrochloride) with a the step of embodiment 1 and step b (63mg, yield:19%).
1HNMR (400MHz, DMSO-d6) δ 15.05-14.61 (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), prepares according to WO2012041014;
Formula (iii), prepares according to WO2011079327;
Formula (iV), prepares according to WO2010132601;
Formula (V), prepares according to WO2012040924
By one of the midbody compound of embodiment 1～4 and above-mentioned formula (ii)～formula (v) or two compound according to The method synthesis of step a and step b obtains the compound shown in table 1.
1 compound 5～13 of table
Effect example 1
HCV replicons are tested
According to document (Science.1999Jul2;285(5424):110-3 and J.Viro1.2003, Mar;77(5): Method described in 3007-19) prepares, carries out and verify.Tested with HCV genotype GT1a, GT1b and GT2a replicon cells Compound 1～4, and HCV1b wild-type cells and Y93H, L31F, P32L, I302V resisting cell test compound 1～4. GT1a and GT1b are the Replicate Sub-systems (HCVRepliconSystem) of the hepatitis that transfection respectively has HCV1a, 1b, 2a genotype, The system contains G418 resistant genes NEO and luciferase reporter gene, is examined by realtime quantitative inspection (qPCR) The expression height of the content and chemoluminescence method detection luciferase gene of NEO is surveyed, the levels of replication of hepatitis is may be used to determine Height, assess the action effect that 1～4 pair of HCV virus of compound are replicated.
Experimental technique:
HCV replicon transfectional cells:The Huh7.5.1 cells that HCV replicons (wild type 1b) are transfected.Transfectional cell is connect Plant in 96 orifice plates, 8000 cell per wells, in 37 DEG C, S%CO2Culture 24 hours.
Sample treatment:1～4 sample of compound of variable concentrations is added in the Huh7.5.1 cells of HCV replicons transfection, Each concentration sets two multiple holes, and sets n.s control wells.Given the test agent is from the beginning of tested maximum concentration, automatically micro- with POD810 Orifice plate pretreatment system adds variable concentrations compound into cell;3 times of dilutions, 10 concentration;Continue culture 72 hours.
The activity of compound and CTA:
CellTiter-fluor (Promega) is added to determine fluorescence signal, the data (RFU) of acquisition use GraphPad Prism softwares calculate the EC of compound50。
For the EC of HCV1b50Scope difference is as follows:A is represented:0.0001nM≤EC50≤0.100nM;B is represented: 0.100nM ＜ EC50≤10.00nM;C is represented:10.00nM ＜ EC50≤100.0nM;D is represented:EC50＞ 100nM.
EC of 2 compound 1～4 of table for HCV1b genocopies50Value

Claims (9)

1. the ring-type flavones or isoflavonoid shown in a kind of formula (I),
Or its pharmaceutically acceptable salt, wherein,
Work as A1For-C (O)-when, A2For-O-；Work as A1For-O- when, A2For-C (O)-；
Q is-O- ,-S- ,-C (R4R5)-、-C(R4R5)O-、-OC(R4R5)-、-C(R4R5)N(R6)-、-N(R6)C(R4R5)-、-N (R6)-、-C(R4R5)C(R4R5)-、-C(R4R5)-S- or-S-C (R4R5)-；
W is-(NHC (O))1～2-、
Or R1Can be connected to form imidazole ring with W；
R1、R2、R3、R4、R5It independently is H, D, OH, halogen, CN, amino, or selected from unsubstituted or by 1～5 R0Take The substituents group in generation：(C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamoyl, C1-C8Alkyl thiol, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1-C8Alkoxyl, by 1～2 hydroxyl Base or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1-C8Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6-C10Virtue Base, C6-C10Aryloxy, glycosyl epoxide or the C replaced by 1～5 oxygen1-C8Alkyl；
R6For H, D, or selected from unsubstituted or by 1～5 R0Substituted substituents group：C1-C8Alkyl formyl radical, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamoyl, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1- C8Alkyl, C3-C8Cycloalkyl, C2-C8Heterocyclylalkyl or C6-C10Aryl；
R1' it independently is H, D, OH, halogen, CN, amino, or selected from unsubstituted or by 1～5 R0The following of replacement takes For base group：(C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8Alkyl)1-2Carbamoyl, C1-C8Alkyl mercapto Base, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1-C8Alkoxyl, by 1～2 hydroxyl or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1-C8Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6-C10Aryl, C6-C10Virtue Base epoxide, glycosyl epoxide or the C replaced by 1～5 oxygen1-C8Alkyl；
Or the R on two neighboring carbon atom1' connected 2 carbon atoms form C together3-C7Carbocyclic ring, or same carbon Two R on atom1' connected 1 carbon atom is formed can be by 0～2 3～7 yuan selected from the insertion of N, O and S hetero atom Ring, or middle ware is separated with the R on 2 carbon atoms of 1 carbon atom1' connected 2 carbon atoms form C together3-C7's Carbocyclic ring；
R2' it is selected from unsubstituted or by 1～5 R0Substituted substituents group：C1-C8Alkyl, C3-C7Cycloalkyl, C2- C7Heterocyclylalkyl or C6-C10Aryl；
R3' it is H, D, or selected from unsubstituted or by 1～5 R0Substituted C1-C8Alkyl；
R4' it is selected from unsubstituted or by 1～5 R0Substituted substituents group：C1-C8Alkyl, C1-C8Alkyl formyl radical Or C1-C8Alkoxyl formoxyl；
Or R3'、R4' connected nitrogen-atoms formation is containing 1 N atom and contains 0～2 selected from N, O and S heteroatomic 3 ～7 unit monocycles, 4～12 membered bicyclics or 5～12 yuan of volutions；
Wherein, R0For H, D, OH, halogen, CN, amino, (C1-C8Alkyl)1-2Amino, C1-C8Alkoxyl formoxyl, (C1-C8Alkane Base)1-2Carbamoyl, C1-C8Alkyl thiol, C1-C8Alkyl sulphonyl, C1-C8Alkyl sulphinyl, C1-C8Alkyl, C1-C8 Alkoxyl, C3-C10Cycloalkyl, C2-C8Heterocyclylalkyl, C6-C10Aryl, C6-C10Aryloxy, glycosyl epoxide or by 1～5 oxygen Substituted C1-C8Alkyl.
2. compound as claimed in claim 1, it is characterised in that R1、R2、R3、R4、R5、R1' independently be H, D, OH, halogen, CN, amino, or independently selected from unsubstituted or by 1～3 R0Substituted substituents group：(C1-C6Alkyl)1-2Ammonia Base, C1-C6Alkoxyl formoxyl, (C1-C6Alkyl)1-2Carbamoyl, C1-C6Alkyl thiol, C1-C6Alkyl sulphonyl, C1-C6 Alkyl sulphinyl, C1-C6Alkyl, C1-C6Alkoxyl, by 1～2 hydroxyl or 1～2 (C1-C2Alkyl)1-2What amino replaced C1-C6Alkoxyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl, C6-C8Aryl, C6-C8Aryloxy, glycosyl epoxide or by 1～3 The C that individual oxygen replaces1-C6Alkyl；
R6For H, D, or selected from unsubstituted or by 1～3 R0Substituted substituents group：C1-C6Alkyl formyl radical, C1-C6Alkoxyl formoxyl, (C1-C6Alkyl)1-2Carbamoyl, C1-C6Alkyl sulphonyl, C1-C6Alkyl sulphinyl, C1- C6Alkyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl or C6-C8Aryl；
R2' it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl or C6-C8's Aryl；
R3' it is H, D, or it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl；
R4' it is unsubstituted or by 1～3 R0Substituted C1-C6Alkyl, C1-C6Alkyl formyl radical or C1-C6Alkoxyl formyl Base；
R0For H, D, OH, halogen, CN, amino, (C1-C6Alkyl)1-2Amino, C1-C6Alkoxyl formoxyl, (C1-C6Alkyl)1-2Ammonia Base formoxyl, C1-C6Alkyl thiol, C1-C6Alkyl sulphonyl, C1-C6Alkyl sulphinyl, C1-C6Alkyl, C1-C6Alkoxyl, C3-C7Cycloalkyl, C2-C6Heterocyclylalkyl, C6-C8Aryl, C6-C8Aryloxy, glycosyl epoxide or the C replaced by 1～3 oxygen1- C6Alkyl.
3. compound as claimed in claim 1, it is characterised in that R1、R2、R3、R4、R5、R1' independently be H, D, OH, halogen, CN, amino, or independently selected from unsubstituted or by 1 R0Substituted substituents group：(C1-C4Alkyl)1-2Amino, C1-C4Alkoxyl formoxyl, (C1-C4Alkyl)1-2Carbamoyl, C1-C4Alkyl thiol, C1-C4Alkyl sulphonyl, C1-C4Alkane Base sulfinyl, C1-C4Alkyl, C1-C4Alkoxyl, by 1～2 hydroxyl or 1～2 (C1-C2Alkyl)1-2The C that amino replaces1- C4Alkoxyl, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl, benzene, phenoxy group, glycosyl epoxide or the C replaced by 1 oxygen1-C4Alkyl；
R6For H, D, or selected from unsubstituted or by 1 R0Substituted substituents group：C1-C4Alkyl formyl radical, C1-C4 Alkoxyl formoxyl, (C1-C4Alkyl)1-2Carbamoyl, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkane Base, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl or phenyl；
R2' it is unsubstituted or by 1 R0Substituted C1-C4Alkyl, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl or phenyl；
R3' it is H, D, or it is unsubstituted or by 1 R0Substituted C1-C4Alkyl；
R4' it is unsubstituted or by 1 R0Substituted C1-C4Alkyl, C1-C4Alkyl formyl radical or C1-C4Alkoxyl formoxyl；
R0For H, D, OH, halogen, CN, amino, (C1-C4Alkyl)1-2Amino, C1-C4Alkoxyl formoxyl, (C1-C4Alkyl)1-2Ammonia Base formoxyl, C1-C4Alkyl thiol, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkyl, C1-C4Alkoxyl, C3-C7Cycloalkyl, C2-C5Heterocyclylalkyl, phenyl, phenoxy group, glycosyl epoxide or the C replaced by 1 oxygen1-C4Alkyl.
4. compound as claimed in claim 1, it is characterised in that described glycosyl epoxide is glucosyl group epoxide, ribosyl Epoxide, aralino epoxide, xylosyl epoxide or fructosyl epoxide.
5. compound as claimed in claim 1, it is characterised in that in formula (I)
For one of substituents：
Wherein, R11' it is C1-C8Alkyl.
6. compound as claimed in claim 5, it is characterised in that R11' it is C1-C6Alkyl.
7. compound as claimed in claim 6, it is characterised in that R11' it is C1-C4Alkyl.
8. compound as claimed in claim 1, it is characterised in that the compound is：
9. the compound described in claim 1 treats the purposes in the medicine of the disease of HCV infection in preparation.
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JP2020505357A (en) 2017-01-20 2020-02-20 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Inhibitor of N-terminal domain of androgen receptor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100509784C (en) * 2003-12-11 2009-07-08 先灵公司 Inhibitors of hepatitis C virus ns3/ns4a serine protease
CN100522991C (en) * 2000-08-31 2009-08-05 弗特克斯药品有限公司 Peptidomimetic protease inhibitors
CN102596936A (en) * 2009-05-13 2012-07-18 吉里德科学公司 Antiviral compounds

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101301287A (en) * 2008-06-12 2008-11-12 上海双科医药科技有限公司 Use of composition of isoflavonoids from Belamcanda chinensis in preparing anti-hepatitis medicament
CN101744830B (en) * 2008-06-17 2012-09-05 上海医药工业研究院 Flavonoid compound and application of plant extract containing same
CN101822372A (en) * 2009-03-05 2010-09-08 财团法人工业技术研究院 Medical compound for curing hepatitis B and health food for inhibiting hepatitis B virus
CN101955478B (en) * 2010-05-25 2013-08-07 大理学院 Preparation of brominated flavanonollignan and application in medicine for treating viral hepatitis B
WO2012040924A1 (en) * 2010-09-29 2012-04-05 Merck Sharp & Dohme Corp. Fused tetracyclic heterocycle compounds and methods of use thereof for treatment of viral diseases
FR2973249B1 (en) * 2011-03-28 2014-02-07 Centre Nat Rech Scient USE OF EPIGALLOCATECHIN GALLATE AS AN ANTIVIRAL AGENT FOR HEPATITIS C VIRUS INFECTIONS
CN102247395A (en) * 2011-05-20 2011-11-23 中国人民解放军第二军医大学 Application of isoflavonoids compounds to preparation of antihepatitis drug
CN102379888B (en) * 2011-06-29 2013-04-24 江西中医学院 Application of flavone glycoside compounds in preparing medicament for treating and preventing hepatitis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100522991C (en) * 2000-08-31 2009-08-05 弗特克斯药品有限公司 Peptidomimetic protease inhibitors
CN100509784C (en) * 2003-12-11 2009-07-08 先灵公司 Inhibitors of hepatitis C virus ns3/ns4a serine protease
CN102596936A (en) * 2009-05-13 2012-07-18 吉里德科学公司 Antiviral compounds

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