WO2015180593A1 - Benzo heterocyclic diallyl derivatives having antiviral activity - Google Patents

Abstract

Disclosed are benzo heterocyclic diallyl derivatives represented by formula (I), wherein when A₁ is O or S, A₂ is CR₂ and A₃ is C(R₇)(R₈); when A₂ is O or S, A₁ is C(R₇)(R₈) and A₃ is CR₂; when A₃ is O or S, A₁ is C(R₇)(R₈) and A₂ is CR₂; and Z₁, Z₂ are independently or are linked with the neighboring R₁ to together form an aromatic ring, a heteroaromatic ring, a naphthenic ring, a heteronaphthenic ring or are linkages. The benzo heterocyclic diallyl derivatives of the present invention have excellent activity of anti-hepatitis c virus.

Description

Benzocyclohexadiene derivative having antiviral activity Technical field

The present invention relates to a class of benzocyclohexadiene derivatives having antiviral activity.

Background technique

A virus is a non-cellular form of parasitic living organism composed of a nucleic acid molecule (DNA or RNA) and a protein or only a protein. Hepatitis C virus (HCV), a single-stranded positive-strand RNA virus, includes a 5' non-coding region (5'-UTR), an open reading frame (ORF), and a 3' non-coding region (3'-UTR). The ORF translation produces a polypeptide chain that is subsequently processed into at least 10 different proteins, including a shell (core) protein, two envelope proteins (E1 and E2) and non-structural proteins (NS2, NS3, NS4a, NS4b, NS5a and NS5b). Although there are many studies on NS3/4Aa protease inhibitors, the first-generation protease inhibitors can reduce the HCV RNA load in patients to a certain extent, but the emergence of drug resistance and toxic side effects makes the treatment of HCV virus still need new drugs. . Hepatitis C virus NS5a protein is another anti-hepatitis C drug target. The first inhibitor of HCV NS5a protein against this target is BMS-790052, which has strong inhibitory activity against hepatitis C virus and its EC ₅₀ can reach the skin. The molar grade is one of the most potent inhibitors of HCV replication reported so far.

Benzocyclohexadiene is a 10-membered fused ring compound containing a hetero atom, such as chromene (also known as benzopyran) or isochromene (isochromene). , thiochromene (also known as benzothiopyran) and isothiochromene (also known as isobenzothiopyran) and so on. The (iso)(thio)chromenes are not important in themselves, but some of their derivatives are important. For example, vitamin E belongs to the dihydride of chromene, that is, a chroma derivative; benzo-α-pyrone, also known as coumarin, is widely present in plants, and some are active ingredients of Chinese herbal medicine. Benzo-γ-pyrone is also known as chromone. The 2- or 3-position phenyl substituted ketone is the core of an important plant component, and 2-phenyl chromone is called flavonoid. Flavone), 3-phenyl chromone is called isoflavone, and plant components containing such nucleus are commonly referred to as flavonoids. There are many reports on (iso)(thio)chromene derivatives in antiviral, antifungal and anticancer effects.

The present invention aims to find a novel (iso)(thio)chromene derivative as an inhibitor of HCV NS5a protein for use in anti-hepatitis C virus in order to cope with the resistance and side effects of existing anti-HCV drugs. Appearance.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (I) having antiviral activity,

among them,

When A ₁ is O or S, A ₂ is CR ₂ , A ₃ is C(R ₇ )(R ₈ ); when A ₂ is O or S, A ₁ is C(R ₉ )(R ₁₀ ), A ₃ is CR ₂ ; when A ₃ is O or S, A ₁ is C(R ₉ )(R ₁₀ ), and A ₂ is CR ₂ ;

Each A _{4 is} independently a bond or C(O);

Z ₁ and Z _{2 are} independently 6 to 10 membered aromatic rings, 5 to 10 members are contained in 1 to 2 heteroaromatic rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, and 3 to 7 members. Containing 1 to 2 heterocycloalkyl rings selected from N, O and S heteroatoms, or Z ₁ and Z _{2 are} independently bonded to the ortho R ₁ to form a 6 to 10 membered aromatic ring, 5 to 10 members. 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, 3 to 7 members having 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, Or, Z ₂ is a connection key;

Each R _{1 is} independently H, D or halogen;

Each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxycarbonyl, (C ₁ -C ₈ alkyl) _1-2 aminocarbonyl, C ₁ -C ₈ alkyldecyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkane Oxyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C ₁ -C ₈ alkyl group;

Each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxycarbonyl, (C ₁ -C ₈ alkyl) _1-2 aminocarbonyl, C ₁ -C ₈ alkyldecyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkane Oxyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C ₁ -C ₈ alkyl group;

Or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are bonded form a C ₃ -C ₇ carbocyclic ring, or two R ₃ on the same carbon atom may form a carbon atom ～2 3- to 7-membered rings selected from N, O, and S heteroatoms, or R ₃ on two carbon atoms separated by one carbon atom, together with two carbon atoms to form C ₃ -C ₇ carbon rings;

Each R _{4 is} independently C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ heterocycloalkyl or C ₆ -C ₁₀ aryl;

Each R ₅ and R _{6 is} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ - a C ₈ alkyl group, or R ₁ ', R ₂ ' together with a N atom to form a 3 to 10 membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;

Each of R ₇ , R ₈ , R ₉ , R _{10 is} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₈ alkyl, C ₃ -C ₇ naphthenic a group, a C ₂ -C ₇ heterocycloalkyl group, a 6 to 10 membered aryl group, and a 5 to 10 membered member having 1 to 2 heteroaryl groups selected from N, O and S hetero atoms, or R ₇ and R ₈ Or R ₉ and R ₁₀ together form a 3 to 12 membered cycloalkane ring which may be optionally substituted by deuterium, halogen or 1 to 2 selected from N, O and S heteroatoms, or Both R ₇ and R ₈ together form an oxo group (i.e., =0).

In the present invention, it is preferred that Z ₁ and Z _{2 are} independently a 6- to 8-membered aromatic ring, and a 5- to 8-membered heteroaryl ring having 1 to 2 hetero atoms selected from N, O and S hetero atoms, 3 to 3 a 6-membered cycloalkane ring, 3 to 6 members containing 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, or Z ₁ and Z _{2 are} independently bonded to the ortho R ₁ to form a 6 to 6 8-membered aromatic ring, 5-8 yuan containing 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, 3 to 6-membered cycloalkane rings, 3 to 6 members containing 1 to 2 selected from N, O And a heteroatom ring of the S hetero atom, or Z ₂ is a linkage; preferably Z ₁ is a benzene ring or Z ₁ is bonded to the ortho position R ₁ to form a benzene ring, Z ₂ is a linkage or Z ₂ is adjacent The R _{1 of the} position is bonded to form a benzene ring.

In a preferred embodiment of the present invention, A ₄ is a linkage, Z ₁ is a benzene ring, Z ₂ is a linkage, R ₁ is H, and formula (I) is formed into formula (Ia);

In another preferred embodiment of the present invention, A ₄ is a linkage, Z ₁ is bonded to the ortho R ₁ to form a benzene ring, Z ₂ is a linkage, and Z ₂ is R ₁ is H. (I) is formed into the formula (Ib);

In still another preferred embodiment of the present invention, A ₄ is a linking bond, Z ₁ is a benzene ring, R _{1 in the} Z ₁ ortho is H, and Z ₂ is bonded to the R _{1 in the} ortho position to form a benzene ring. (I) is formed into the formula (Ic);

In still another preferred embodiment of the present invention, A ₄ is a linkage, Z ₁ , Z ₂ are respectively bonded to the ortho position R ₁ to form a benzene ring, and the general formula (I) is formed into the general formula (Id);

In the present invention, preferably, each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ alkoxycarbonyl (C ₁ -C ₆ alkyl) _1-2 aminocarbonyl, C ₁ -C ₆ alkyl fluorenyl, 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, a glycosyloxy group or a C ₁ -C ₆ alkyl group substituted with 1 to 3 oxygens;

Preferably, each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxycarbonyl, (C ₁ -C ₄ Alkyl) _1-2 aminocarbonyl, C ₁ -C ₄ alkyl fluorenyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or C substituted by 1 oxygen _1- C ₄ alkyl;

More preferably, each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₂ alkyl) _1-2 amino, C ₁ -C ₂ alkoxycarbonyl, (C ₁ -C ₂ alkyl) _1-2 aminocarbonyl, C ₁ -C ₂ alkyl fluorenyl, C ₁ -C ₂ alkylsulfonyl, C ₁ -C ₂ alkylsulfinyl, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or substituted by 1 oxygen C ₁ -C ₂ alkyl. Wherein the glycosyloxy group is a glucosyloxy group, a ribosyloxy group, an arabinosyloxy group, a xylosyloxy group or a fructosyloxy group.

In the present invention, preferably, each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ alkoxycarbonyl (C ₁ -C ₆ alkyl) _1-2 aminocarbonyl, C ₁ -C ₆ alkyl fluorenyl, 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, a glycosyloxy group, or a C ₁ -C ₆ alkyl group substituted by 1 to 3 oxygens; or R ₃ on two adjacent carbon atoms together with 2 carbon atoms to form a C ₃ -C ₇ carbocyclic ring , or two R _3s on the same carbon atom and one carbon atom to which they are attached form a 3 to 7 membered ring which may be inserted by 0 to 2 hetero atoms selected from N, O and S, or 1 carbon atom in between. R ₃ on two carbon atoms together with two carbon atoms to form a C ₃ -C ₇ carbon ring;

Preferably, each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxycarbonyl, (C ₁ -C ₄ Alkyl) _1-2 aminocarbonyl, C ₁ -C ₄ alkyl fluorenyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or C substituted by 1 oxygen ₁ -C ₄ alkyl; or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are bonded form a C ₃ -C ₆ carbocyclic ring, or two R ₃ groups on the same carbon atom One carbon atom forms a 3 to 6 membered ring which may be inserted by 0 to 2 hetero atoms selected from N, O and S, or 2 carbons to which R ₃ is bonded to 2 carbon atoms separated by 1 carbon atom. The atoms together form a C ₃ -C ₆ carbon ring;

More preferably, each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₂ alkyl) _1-2 amino, C ₁ -C ₂ alkoxycarbonyl, (C ₁ -C ₂ alkyl) _1-2 aminocarbonyl, C ₁ -C ₂ alkyl fluorenyl, C ₁ -C ₂ alkylsulfonyl, C ₁ -C ₂ alkylsulfinyl, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or substituted by 1 oxygen C ₁ -C ₂ alkyl; or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are attached form a C ₃ -C ₆ carbocycle, or two R ₃ on the same carbon atom are attached thereto One carbon atom forms a 3- to 6-membered ring which can be inserted by 0 to 2 hetero atoms selected from N, O and S, or 2 of R ₃ connected to 2 carbon atoms in the middle of one carbon atom. form C ₃ -C ₆ carbocyclic ring together with the carbon atoms. Wherein the glycosyloxy group is a glucosyloxy group, a ribosyloxy group, an arabinosyloxy group, a xylosyloxy group or a fructosyloxy group.

In the present invention, preferably, each R ₄ is a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group or a C ₆ -C ₈ aryl group; R ₅ and R _{6 are} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C _{a 6-} alkyl group, or R ₁ ', R ₂ ' and a N atom together form a 3- to 8-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;

Preferably, R ₄ is C ₁ -C ₄ alkyl, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl or C ₆ aryl; R ₅ , R _{6 are} independently H, D , N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C ₄ alkyl, or R ₁ ', R ₂ And a N- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;

More preferably, R ₄ is C ₁ -C ₂ alkyl, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl or C ₆ aryl; R ₅ and R _{6 are} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C ₂ alkyl, or R ₁ ', R ₂ ' together with the N atom forms a 3- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S.

In the present invention, it is preferred that R ₇ , R ₈ , R ₉ and R _{10 are} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₆ alkane a C ₃ -C ₇ cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a 6- to 8-membered aryl group, and a 5- to 8-membered heteroaryl group having 1 to 2 hetero atoms selected from N, O and S hetero atoms. Or, both R ₇ and R ₈ or both R ₉ and R ₁₀ together form a 3 - optionally substituted by deuterium, halogen or 1 to 2 heteroatoms selected from N, O and S. a 10-membered cycloalkane ring, or both R ₇ and R ₈ together form an oxo group;

Preferably, R ₇ , R ₈ , R ₉ , R _{10 are} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₄ alkyl, C ₃ -C ₆ a cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 2 hetero atoms selected from N, O and S, or R ₇ and R ₈ Or R ₉ and R ₁₀ together form a 3- to 8-membered cycloalkane ring which may be optionally substituted by deuterium, halogen or by 1 to 2 heteroatoms selected from N, O and S, or R ₇ and R ₈ together form an oxo group;

More preferably, R ₇ , R ₈ , R ₉ , R _{10 are} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₂ alkyl, C ₃ -C _{a 6-} cycloalkyl group, a C ₂ -C ₅ heterocycloalkyl group or a 6-membered aryl group, or both R ₇ and R ₈ or both R ₉ and R ₁₀ together form a ring which may be optionally substituted by hydrazine or halogen. Or a 3- to 6-membered cycloalkane ring inserted from 1 to 2 hetero atoms selected from N, O and S, or both R ₇ and R ₈ together form an oxo group.

In the present invention, preferably, in the formula (I)

Independently:

Wherein R ₃ 'is a C ₁ -C ₈ alkyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group, most preferably a C ₁ -C ₂ alkyl group.

In the formula of the present invention,

Indicates that it can be either a single key or a double key, that is,

Can be

Can also be

In the present invention, the term "oxo" means "=O".

In the present invention, the term "optionally substituted" means that it may or may not be substituted with a substituent; the term "optionally inserted" means that it may be inserted by a hetero atom or may be free of a hetero atom. . For example, the term "a 3 to 12 membered cycloalkane ring which may be optionally substituted by deuterium, halogen or substituted by 1 to 2 heteroatoms selected from N, O and S" means a 3 to 12 membered cycloalkane ring. It may or may not be substituted by hydrazine and/or halogen; a 3 to 12 membered cycloalkane ring may be inserted by a hetero atom or may be free of a hetero atom; or, at the same time, it may be substituted by hydrazine and/or halogen. Atomic insertion; or, ie, not substituted by a substituent and without a hetero atom.

In the present invention, the term "independently" means that each substituent may be arbitrarily selected among the substituent groups, independent of each other, and may be the same or different. Taking "each R ₁ independently H, D or halogen" as an example, it is assumed that when one of R ₁ is H, the other R ₁ may be H or not H such as D or halogen, two R ₁ can be arbitrarily selected in the substituent group without affecting each other.

Particular compounds of the invention include the following compounds:

Another object of the present invention is to provide a use of the compound of the formula (I) of the present invention for the preparation of a medicament for preventing or treating a viral infection or a medicament for antiviral, the virus being preferably a hepatitis virus, particularly preferably hepatitis C virus.

A further object of the present invention is to provide the use of a compound of formula (I) for the treatment of HCV-infected diseases.

A further object of the present invention is to provide a method of treating a patient infected with HCV, comprising the step of administering an effective amount of the compound of claim 1 to a patient infected with HCV.

A further object of the present invention is to provide a compound of formula (I) for use in combination with an HCV NS3/4a protease inhibitor, an HCV NS5b polymerase inhibitor or other anti-HCV agent for the treatment of HCV infection.

The synthetic scheme of the compound represented by the formula (I) of the present invention is as follows:

Synthesis process one:

Synthesis process two:

Synthesis process three:

Step A: heating the starting material A or the intermediate 2 and the bispinacol borate in the catalyst Pd(dppf)Cl ₂ and KOAc in a 1,4-dioxane solvent under a nitrogen atmosphere to 80 ° C, The reaction is continued overnight to give Intermediate 1 or Intermediate 3.

Step B: Further intermediate 1 or intermediate 3 with starting material Bi (where i = 1, 2, 3, ...) under the catalyst Pd(dppf)Cl ₂ and in 1,4-dioxane and KCO ₃ The mixed solution of the aqueous solution is heated to 80 ° C under a nitrogen atmosphere, and reacted overnight to obtain the target compound represented by the intermediate 2 or the formula (I).

detailed description

Synthesis of Compound 1 of Example 1

Compound 1-A

To a 100 mL reaction flask was added p-bromophenylacetic acid (10 g, 46.37 mmol), and a solution of 2M diisopropylamine lithium (52 mL) in tetrahydrofuran was added under ice bath. After 1 h at room temperature, anhydrous magnesium chloride (4.88 g, 51.4 mmol) was added. After stirring for 0.5 h, acetone (2.98 g, 51.4 mmol) was added at -70 ° C and allowed to react overnight at room temperature. The reaction solution was poured into water (60 mL) and neutralized with hydrochloric acid to pH = 3-4. Methyl tert-butyl ether (200 mL) was extracted, washed with brine, dried over anhydrous sodium sulfate.

Compound 1-B

Add compound 1-A (11.0g) to a 500mL reaction flask, add dichloromethane (100mL) to dissolve, then add concentrated sulfuric acid (55g) at 15-20 ° C, stir for 20 minutes, remove the solvent under reduced pressure at room temperature, continue stirring for 2h . About 250 g of ice was added, and the solid was precipitated, filtered, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate.

Compound 1-C

Compound 1-B (1.4 g, 5.35 mmol), m-diphenol (1.2 g, 11.0 mmol) and methanesulfonic acid (8.4 mL) were added to a 100 mL reaction flask, and the mixture was heated to 70 ° C for 2 h. After completion of the reaction, the mixture was diluted with methylene chloride, washed with saturated sodium hydrogen sulfate, washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6. , J=8.8, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 5.69 (s, 1H), 3.64 (s, 1H), 1.49 (s, 3H), 1.28 (s, 3H) .

Compound 1-D

Compound 1-C (1.3 g, 3.18 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The reaction was quenched with EtOAc (EtOAc)EtOAc.

Compound 1-E

Compound 1-D (1.3g, 3.17mmol) was dissolved in dichloromethane (20mL) in an ice salt bath was added triethylamine (1.28g, 12.7mmol), followed by dropwise addition of triflic anhydride (Tf ₂ O , 2.2 g, 7.93 mmol), reacted at room temperature overnight. Dichloromethane (30 mL) was diluted with water, washed with sodium sulfate, washed with brine, dried over anhydrous sodium sulfate.

Compound 1-F

Compound 1-E (350 mg, 0.5 mmol), potassium acetate (245 mg, 2.5 mmol), bis-pinacol borate (306 mg, 2.0 mmol), [1,1'-bis(diphenylphosphine) dioxin A mixture of iron]palladium dichloride (Pd(dpPf)Cl ₂ , 29 mg, 0.04 mmol) and dioxane (5 mL) was degassed and reacted overnight at 80 ° C under nitrogen. The organic layer was concentrated to dryness under reduced pressure. methylene chloride / methanol (10/1).

Compound 1

A 100 mL reaction flask was charged with a solution of compound 1-F (170 mg, 0.5 mmol), potassium carbonate (289 mg, 2 mmol) in water (1 mL), and starting material B1 (

420 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.04 mmol) and dioxane (5 mL). The mixture was degassed and allowed to react overnight at 80 ° C under nitrogen. The organic layer was concentrated to dryness (EtOAc m.

Compound 1 (HCl salt): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.2-15.4 (brs, 4H), 8.09 (brs, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.50 -7.65 (m, 3H), 7.30-7.44 (m, 4H), 6.61 (s, 1H), 5.13 (m, 2H), 4.10-4.20 (m, 2H), 3.82-4.00 (m, 4H), 3.56 (s, 6H), 2.36-2.44 (m, 2H), 1.90-2.20 (m, 8H), 1.55 (s, 6H), 0.83 (dd, J = 6.4, 2.0 Hz, 6H), 0.79 (d, J =6.4Hz, 6H);

ESI-LC/MS: m/z 822.5 (M+H).

Synthesis of Compound 2 of Example 2

Compound 2-A

6-Hydroxy-4,4-dimethylbenzoin-2-one (3.4 g, 17.47 mmol) was added to a 100 mL reaction flask, and imidazole (1.42 g, 20.96 mmol) and tert-butyl were added at 0 °C. Dimethylchlorosilane (3.15 g, 20.96 mmol) was stirred at room temperature overnight. The mixture was quenched with EtOAc EtOAc (EtOAc m. -A (4.1g).

Compound 2-B

Compound 2-A (1.58 g, 5.16 mmol) and tetrahydrofuran (15.6 mL) were added to a 100 mL reaction flask, and a solution of 2M sodium bis(trimethylsilyl)amide (NaHMDS) in tetrahydrofuran (3.09 mL) was added at 0 ° C, and stirred. After 25 min, N-bistrifluoromethanesulfonylaniline (2.02 g, 5.67 mmol) was added and stirred at room temperature for 2 h. The organic layer was concentrated to dryness (EtOAc mjjjjjjjjj

Compound 2-C

To a 50 mL reaction flask was added compound 2-B (603 mg, 1.37 mmol), potassium carbonate (475 mg, 3.45 mmol) in water (3 mL), and starting material B2 (

570 mg, 1.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41 mg, 0.06 mmol), lithium chloride (145 mg, 3.45 mmol) and dioxane (15 mL) ). The reaction mixture was degassed and reacted at 100 ° C for 2 h under nitrogen. The organic layer was concentrated to dryness (EtOAc mjjjjjjjjj

Compound 2-D

Compound 2-C (570 mg, 0.881 mmol), tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (555 mg, 1.76 mmol) were added to a 50 mL reaction flask and stirred at room temperature for 2 h. Diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and evaporated.

Compound 2-E

Compound 2-D (300 mg, 0.54 mmol), dichloromethane (9 mL) and triethylamine (276 mg, 2.7 mmol) were added to a 50 mL reaction flask, and trifluoromethanesulfonic anhydride (390 mg, 1.38 mmol) was added dropwise at 0 °C. Stir at room temperature for 1.5 h. After adding 4.2 mL of 1N aqueous sodium hydroxide solution and 8 mL of methanol, the mixture was stirred for 30 min, diluted with methylene chloride, washed with water, brine, dried over anhydrous sodium sulfate.

Compound 2-F

The procedure was the same as the synthesis of the compound 1-F except that the compound 2-E (200 mg, 0.355 mmol) was used instead of the compound 1-E to give the compound 2-F (220 mg).

Compound 2

The procedure was the same as that of the compound 1, except that the compound 2-F (220 mg, 0.355 mmol) was used instead of the compound 1-F to obtain 80 mg of the compound 2.

Compound 2 (HCl salt): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.04-15.06 (m, 4H), 8.11 (s, 1H), 8.04 (s, 1H), 8.00-8.03 (s, 1H) ), 7.88-7.96 (m, 4H), 7.68 (dd, J = 8.8, 1.6 Hz, 1H), 7.26-7.36 (m, 3H), 5.85 (s, 1H), 510-5.20 (m, 2H), 4.10-4.20 (m, 2H), 3.82-4.00 (m, 4H), 3.56-3.67 (m, 6H), 2.36-2.44 (m, 2H), 2.00-2.20 (m, 8H), 1.52 (s, 3H) ), 1.50 (s, 3H), 0.84 (d, J = 6.4 Hz, 6H)), 0.78 (d, J = 6.4 Hz, 6H);

ESI-LC/MS: m/z 925.6 (M+H).

Synthesis of Compound 3 of Example 3

Compound 3-A

The method was the same as the synthesis of the compound 1-F except that 7-bromo-3-(4-bromophenyl)benzopyran-2-one (150 mg, 0.3947 mmol) was used instead of the compound 1-E to obtain the compound 3. -A (95 mg). ESI-LC/MS: m/z 474 (M).

Compound 3

The procedure was the same as the synthesis of Compound 1, except that Compound 3-A (95 mg, 0.200 mol) was used instead of Compound 1-F to give Compound 3 (50 mg).

Compound 3 (HCl salt): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 15.1 (brs, 2H), 14.85 (brs, 2H), 8.40 (s, 1H), 8.25 (brs, 1H), 8.18 (s, 1H), 7.90 to 8.00 (m, 7H), 7.33 (dd, J = 8.0, 8.0 Hz, 2H), 5.17 (t, J = 6.8 Hz, 2H), 4.13 (t, J = 7.2 Hz, 2H), 3.83 to 4.00 (m, 4H), 3.57 (s, 6H); 2.33 to 2.43 (m, 2H), 2.12 to 2.22 (m, 4H), 1.98 to 2.10 (m, 4H), 0.751 to 0.864 ( m,12H);

ESI-LC/MS: m/z 807 (M+1).

Synthesis of Compound 4 of Example 4

Compound 4-A

Sodium hydride (2.468 g, 61.7 mmol) was added to a solution of ethyl p-bromophenylacetate (10 g, 41.1 mmol) in tetrahydrofuran (200 mL), and stirred for 30 min, then diethyl carbonate (9.71 g, 82.2 mmol), and the mixture was poured to EtOAc EtOAc (EtOAc) Purification afforded the compound 4-A (12.5 g, yield: 96%).

Compound 4-B

Add compound 4-A (4g, 12.7mmol), m-bromophenol (2.196g, 12.7mmol) and diphenyl ether (30mL) to a single-mouth bottle, stir to 250 ° C for 1 hour, distillate diphenyl ether at atmospheric pressure The temperature was raised to 290 ° C, stirred for 3 hours, cooled to room temperature, toluene was added, filtered, and the filter cake was washed with petroleum ether and dried to give compound 4-B (2.1 g, 42%).

Compound 4-C

Compound 4-B (2 g, 5 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydrogen hydride (303 mg, 7.6 mmol) was added, and the mixture was stirred for 30 minutes, and iodomethane (1.08 g, 7.6) was added. Ment), heated to 60 ° C for 5 hours, poured into ice water, extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated, then purified by silica gel column chromatography (ethyl ether: ethyl acetate = 100:1) Compound 4-C (630 mg, yield 31%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.67-7.65 (dt, J = 2.0, 8.8 Hz, 2H), 7.61 ( Dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.42-7.40 (dt, J = 2.0, 8.8 Hz, 2H), 3.56 (s, 3H).

Compound 4-D

The procedure was the same as the synthesis of the compound 1-F except that the compound 4-C (500 mg, 1.2 mmol) was used instead of the compound 1-E to give the crude product of the compound 4-D (700 mg).

Compound 4

The procedure was the same as the synthesis of Compound 1, except that Compound 4-D (700 mg, 1.2 mmol) was used instead of Compound 1-F to give Compound 4 (130 mg).

Compound 4 (hydrochloride): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.22 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 ( s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.29-7.33 (m, 2H) ), 5.15-5.17 (m, 2H), 4.10-4.14 (t, J = 8.0 Hz, 2H), 3.85-3.90 (m, 4H), 3.63 (s, 3H), 3.39 (s, 6H), 2.34 2.45 (m, 2H), 1.95-2.22 (m, 8H), 0.85 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H), 0.78 (d, J = 6.8 Hz, 6H) ).

ESI-LC/MS m/z: 419.4 (M/2+H).

Synthesis of Compound 5 of Example 5

Compound 5-A

Add Mg (179 mg, 7.36 mmol) and tetrahydrofuran (30 mL) to a dry reaction flask, add 1,4-dibromobutane (0.795 g, 3.68 mmol) and a catalytic amount of iodine under nitrogen, and heat to reflux. The hour to magnesium shavings basically disappeared. 7-Bromo-3-(4-bromophenyl)-benzopyran-2-one (1 g, 2.63 mmol) was dissolved in tetrahydrofuran (20 mL), and slowly added to the above-prepared reagent in an ice bath. After being allowed to warm to room temperature, the reaction mixture was stirred for 3 hr. 1) Purification afforded Compound 5-A (500 mg, yield: 43%).

^{1 H NMR (400MHz, DMSO-} d 6) δ10.14 (s, 1H), 7.54-7.49 (m, 3H), 7.41 (d, J = 8.4Hz, 2H), 6.99 (d, J = 2.0Hz, 1H), 6.96 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.23 (s, 1H), 4.94 (s, 1H), 1.58-1.56 (m, 4H), 1.36-1.31 (m, 4H).

Compound 5-B

Compound 5-A (800 mg, 1.8 mmol) and acetic acid (10 mL) were added to a single-necked flask, refluxed for 3 hours, the reaction solution was cooled to room temperature, poured into water, filtered, and the filter cake was dissolved in ethyl acetate. The mixture was washed with sodium hydrogencarbonate, and brine (MgSO4)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.8 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.54 (s, 1H), 2.05-2.01 (m, 2H), 1.83-1.76 (m, 4H) , 1.71-1.64 (m, 2H).

Compound 5-C

The method was the same as the synthesis of the compound 1-F except that the compound 5-B was used instead of the compound 1-E to give the compound 5-C. ESI-LC/MS: m/z 515 (M+1).

Compound 5

The method was the same as the synthesis of Compound 1, except that Compound 5-C was used instead of Compound 1-F to give Compound 5. ESI-LC/MS: m/z 847 (M+1).

Synthesis of Compounds 6-17

Raw material Bi (where i = 1, 2, 3....) is commercially available or can be synthesized according to the following literature

Compound 1-E synthesized in Example 1

Or the compound 2-B synthesized in Example 2

As the raw material A, and selecting the corresponding raw material Bi, the target compound shown in Table 1 can be prepared according to the synthesis scheme 1 or the synthesis scheme 3.

Table 1 compounds 6 to 17

Effect Example HCV replicon cell inhibitory activity

The HCV genotype GT1b replicon cell system was used according to the method described in the literature (Science. 1999 Jul 2; 285 (5424): 110-3 and J. Virol. 2003, Mar; 77(5): 3007-19). Huh7 cells transfected with the HCV 1b replicon) were tested for inhibitory activity of the HCV 1b replicon on compounds 1 to 5.

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, 5% CO _{2 for} 24 hours.

Sample treatment: Different concentrations of Compound 1-5 samples were added to Huh7.5.1 cells transfected with HCV replicon, two duplicate wells were set for each concentration, and no sample control wells were set. The test sample was started from the highest concentration tested, and the POD810 automatic microplate pretreatment system was added to the cells with different concentrations of the compound; the concentration was diluted 3 times; the culture was continued for 72 hours.

Compound activity and cytotoxicity assay:

The fluorescence signal was measured by adding Cell Titer-fluor (Promega), and the obtained data (RFU) was calculated using the GraphPad Prism software to calculate the EC _{50 of the} compound.

Compounds 1 to 5 all showed an activity of inhibiting the HCV GT1b genotype, and the EC ₅₀ values of the compounds 1 to 5 are shown in Table 1.

Table 1 compounds 1 to ₅₅₀ of HCV 1b genotype values replicon EC

Wherein A represents EC ₅₀ ≤ 0.010 nM; and B represents 0.010 nM < EC ₅₀ ≤ 10 nM.

Industrial applicability

The benzohexadiene derivative of the present invention has an excellent anti-hepatitis C virus effect and has a very good industrial application prospect.

Claims (12)

1. a compound of the formula (I),

   

   among them,

   When A ₁ is O or S, A ₂ is CR ₂ , A ₃ is C(R ₇ )(R ₈ ); when A ₂ is O or S, A ₁ is C(R ₉ )(R ₁₀ ), A ₃ is CR ₂ ; when A ₃ is O or S, A ₁ is C(R ₉ )(R ₁₀ ), and A ₂ is CR ₂ ;

   Each A _{4 is} independently a bond or C(O);

   Z ₁ and Z _{2 are} independently 6 to 10 membered aromatic rings, 5 to 10 members are contained in 1 to 2 heteroaromatic rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, and 3 to 7 members. Containing 1 to 2 heterocycloalkyl rings selected from N, O and S heteroatoms, or Z ₁ and Z _{2 are} independently bonded to the ortho R ₁ to form a 6 to 10 membered aromatic ring, 5 to 10 members. 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, 3 to 7 members having 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, Or, Z ₂ is a connection key;

   Each R _{1 is} independently H, D or halogen;

   Each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxycarbonyl, (C ₁ -C ₈ alkyl) _1-2 aminocarbonyl, C ₁ -C ₈ alkyldecyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkane Oxyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C ₁ -C ₈ alkyl group;

   Each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₈ alkyl) _1-2 amino, C ₁ -C ₈ alkoxycarbonyl, (C ₁ -C ₈ alkyl) _1-2 aminocarbonyl, C ₁ -C ₈ alkyldecyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkane Oxyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C ₁ -C ₈ alkyl group;

   Or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are bonded form a C ₃ -C ₇ carbocyclic ring, or two R ₃ on the same carbon atom may form a carbon atom ～2 3- to 7-membered rings selected from N, O, and S heteroatoms, or R ₃ on two carbon atoms separated by one carbon atom, together with two carbon atoms to form C ₃ -C ₇ carbon rings;

   Each R _{4 is} independently C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ heterocycloalkyl or C ₆ -C ₁₀ aryl;

   Each R ₅ and R _{6 is} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ - a C ₈ alkyl group, or R ₁ ', R ₂ ' together with a N atom to form a 3 to 10 membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;

   Each of R ₇ , R ₈ , R ₉ , R _{10 is} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₈ alkyl, C ₃ -C ₇ naphthenic a group, a C ₂ -C ₇ heterocycloalkyl group, a 6 to 10 membered aryl group, and a 5 to 10 membered member having 1 to 2 heteroaryl groups selected from N, O and S hetero atoms, or R ₇ and R ₈ Or R ₉ and R ₁₀ together form a 3 to 12 membered cycloalkane ring which may be optionally substituted by deuterium, halogen or 1 to 2 selected from N, O and S heteroatoms, or Both R ₇ and R ₈ together form an oxo group.
2. The compound according to claim 1, wherein Z ₁ and Z _{2 are} independently a 6- to 8-membered aromatic ring, and a 5- to 8-membered heteroaryl ring having 1 to 2 hetero atoms selected from N, O and S hetero atoms. a 3- to 6-membered cycloalkane ring, 3 to 6 members having 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, or Z ₁ and Z ₂ independently bonded to the ortho R ₁ a 6-8-membered aromatic ring, 5-8 yuan containing 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, a 3-6-membered cycloalkane ring, and 3 to 6 members containing 1 to 2 selected from 1 to 2 a heterocycloalkane ring of N, O and S heteroatoms, or Z ₂ is a linkage; preferably Z ₁ is a benzene ring or Z ₁ is bonded to the ortho position R ₁ to form a benzene ring, and Z ₂ is a linkage or Z ₂ is bonded to the R _{1 of the} ortho position to form a benzene ring.
3. The compound according to claim 2, wherein A ₄ is a linking bond, Z ₁ is a benzene ring, Z ₂ is a linking bond, R ₁ is H, and formula (I) is formed into formula (Ia);

   

   Alternatively, A ₄ is a linkage, Z ₁ is bonded to the ortho R ₁ to form a benzene ring, Z ₂ is a linkage, and Z ₂ is R ₁ is H, and the general formula (I) is formed into the formula (Ib). ;

   

   Alternatively, A ₄ is a linkage, Z ₁ is a benzene ring, R _{1 in the} Z ₁ ortho is H, Z ₂ is bonded to the ortho R ₁ to form a benzene ring, and the general formula (I) is formed into the general formula (Ic) ;

   

   Or, A ₄ is a linkage, Z ₁ , Z ₂ are respectively bonded to the ortho position R ₁ to form a benzene ring, and the general formula (I) is formed into the formula (Id);

   
4. The compound according to claim 1, wherein each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ Alkoxycarbonyl, (C ₁ -C ₆ alkyl) _1-2 aminocarbonyl, C ₁ -C ₆ alkyl fluorenyl, 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 aryl An oxy group, a glycosyloxy group, or a C ₁ -C ₆ alkyl group substituted with 1 to 3 oxygens;

   Preferably, each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxycarbonyl, (C ₁ -C ₄ Alkyl) _1-2 aminocarbonyl, C ₁ -C ₄ alkyl fluorenyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or C substituted by 1 oxygen _1- C ₄ alkyl;

   More preferably, each R _{2 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₂ alkyl) _1-2 amino, C ₁ -C ₂ alkoxycarbonyl, (C ₁ -C ₂ alkyl) _1-2 aminocarbonyl, C ₁ -C ₂ alkyl fluorenyl, C ₁ -C ₂ alkylsulfonyl, C ₁ -C ₂ alkylsulfinyl, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or substituted by 1 oxygen C ₁ -C ₂ alkyl.
5. The compound according to claim 1, wherein each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₆ alkyl) _1-2 amino, C ₁ -C ₆ Alkoxycarbonyl, (C ₁ -C ₆ alkyl) _1-2 aminocarbonyl, C ₁ -C ₆ alkyl fluorenyl, 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 aryl An oxy group, a glycosyloxy group, or a C ₁ -C ₆ alkyl group substituted by 1 to 3 oxygen atoms; or R ₃ on two adjacent carbon atoms together with 2 carbon atoms to which they are bonded form a C ₃ -C ₇ a carbocyclic ring, or two R _3s on the same carbon atom and a carbon atom to which they are attached form a 3 to 7 membered ring which may be inserted by 0 to 2 heteroatoms selected from N, O and S, or 1 in the middle. R ₃ on two carbon atoms of one carbon atom together with two carbon atoms to form a C ₃ -C ₇ carbon ring;

   Preferably, each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₄ alkyl) _1-2 amino, C ₁ -C ₄ alkoxycarbonyl, (C ₁ -C ₄ Alkyl) _1-2 aminocarbonyl, C ₁ -C ₄ alkyl fluorenyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or C substituted by 1 oxygen ₁ -C ₄ alkyl; or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are bonded form a C ₃ -C ₆ carbocyclic ring, or two R ₃ groups on the same carbon atom One carbon atom forms a 3 to 6 membered ring which may be inserted by 0 to 2 hetero atoms selected from N, O and S, or 2 carbons to which R ₃ is bonded to 2 carbon atoms separated by 1 carbon atom. The atoms together form a C ₃ -C ₆ carbon ring;

   More preferably, each R _{3 is} independently H, D, OH, halogen, CN, amino, (C ₁ -C ₂ alkyl) _1-2 amino, C ₁ -C ₂ alkoxycarbonyl, (C ₁ -C ₂ alkyl) _1-2 aminocarbonyl, C ₁ -C ₂ alkyl fluorenyl, C ₁ -C ₂ alkylsulfonyl, C ₁ -C ₂ alkylsulfinyl, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl, C ₆ aryl, C ₆ aryloxy, glycosyloxy, or substituted by 1 oxygen C ₁ -C ₂ alkyl; or R ₃ on two adjacent carbon atoms together with the two carbon atoms to which they are attached form a C ₃ -C ₆ carbocycle, or two R ₃ on the same carbon atom are attached thereto One carbon atom forms a 3- to 6-membered ring which can be inserted by 0 to 2 hetero atoms selected from N, O and S, or 2 of R ₃ connected to 2 carbon atoms in the middle of one carbon atom. form C ₃ -C ₆ carbocyclic ring together with the carbon atoms.
6. The compound according to claim 1, wherein each R ₄ is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl or C ₆ -C ₈ Aryl; R ₅ , R _{6 are} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C ₆ alkyl, or R ₁ ', R ₂ ' together with the N atom to form a 3-8 olefin having at least 1 N atom and optionally 0 to 2 heteroatoms selected from N, O and S ring;

   Preferably, R ₄ is C ₁ -C ₄ alkyl, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl or C ₆ aryl; R ₅ , R _{6 are} independently H, D , N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C ₄ alkyl, or R ₁ ', R ₂ And a N- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;

   More preferably, R ₄ is C ₁ -C ₂ alkyl, C ₅ -C ₆ cycloalkyl, C ₄ -C ₅ heterocycloalkyl or C ₆ aryl; R ₅ and R _{6 are} independently H, D, N(R ₁ ')(R ₂ ') or NHC(O)OR ₁ '; R ₁ ', R ₂ ' are independently H, D, C ₁ -C ₂ alkyl, or R ₁ ', R ₂ ' together with the N atom forms a 3- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S.
7. The compound according to claim 1, wherein R ₇ , R ₈ , R ₉ and R _{10 are} independently H, D or the following substituents which are optionally substituted by deuterium or halogen: C ₁ - a C ₆ alkyl group, a C ₃ -C ₇ cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a 6-8 membered aryl group, and a 5-8 member having 1 to 2 hetero atoms selected from N, O and S. a heteroaryl group, or both R ₇ and R ₈ or both R ₉ and R ₁₀ together form a ring which may be optionally substituted by deuterium, substituted by halogen or inserted by 1 to 2 heteroatoms selected from N, O and S a 3 to 1O unit cycloalkane ring, or both R ₇ and R ₈ together form an oxo group;

   Preferably, R ₇ , R ₈ , R ₉ , R _{10 are} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₄ alkyl, C ₃ -C ₆ a cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 2 hetero atoms selected from N, O and S, or R ₇ and R ₈ Or R ₉ and R ₁₀ together form a 3- to 8-membered cycloalkane ring which may be optionally substituted by deuterium, halogen or by 1 to 2 heteroatoms selected from N, O and S, or R ₇ and R ₈ together form an oxo group;

   More preferably, R ₇ , R ₈ , R ₉ , R _{10 are} independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocycloalkyl or 6-membered aryl, or both R ₇ and R ₈ or both R ₉ and R ₁₀ form a ring which may be optionally substituted by deuterium or halogen Or a 3- to 6-membered cycloalkane ring inserted from 1 to 2 hetero atoms selected from N, O and S, or both R ₇ and R ₈ together form an oxo group.
8. The compound of claim 1 which is in the formula (I)

   

   Independently:

   

   Wherein R ₃ 'is a C ₁ -C ₈ alkyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group, most preferably a C ₁ -C ₂ alkyl group.
9. The compound of claim 1 wherein said compound is one of the following compounds:

   

   
10. Use of the compound according to claim 1 for the preparation of a medicament for preventing or treating a viral infection or an antiviral medicament, preferably a hepatitis virus, particularly preferably a hepatitis C virus.
11. A method of treating a patient infected with HCV, comprising the step of administering an effective amount of the compound of claim 1 to a patient infected with HCV.
12. A method of treating a patient infected with HCV, characterized in that the compound of claim 1 is used in combination with an HCV NS3/4a protease inhibitor, an HCV NS5b polymerase inhibitor or other anti-HCV drug for the treatment of a patient with HCV infection.