WO2016091036A1 - Hepatitis c virus protease inhibitor and synthesis method therefor - Google Patents

Abstract

Provided are a compound represented by general formula (I) and pharmaceutically acceptable salts thereof, and a perpetration method and a usage in preparing medicines for resisting a hepatitis virus and especially a usage in resisting a hepatitis C virus. The general formula shows a compound (I).

Description

Hepatitis C virus protease inhibitor and synthesis method thereof Technical field

The present invention relates to a class of compounds having anti-hepatitis C virus protease activity and methods for their synthesis.

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, is a major cause of post-transfusion and sporadic hepatitis. At present, the effective drug for anti-viral treatment of hepatitis C is interferon (IFN), but HCV-infected patients have different responses to interferon therapy, the average response rate is less than 50%, and the recurrence rate after drug withdrawal is higher. The FDA approved two NS3/4A serine protease inhibitors, Telaprevir and Boceprevir, in 2011, providing a new and effective method for the treatment of hepatitis C. In 2013, the FDA approved the launch of Sofosbuvir and Simeprevir. However, the response rate has not reached 100%, and the emergence of drug resistance and side effects has made the treatment of HCV virus still require new drugs.

PCT/CN2012/078990 discloses an HCV protease inhibitor having the structural formula:

A ₃ is NH or CH ₂ , Re is a substituted or unsubstituted C ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkyl-NHCO, (C ₁ -C ₁₀ alkyl) ₂ NCO An aryl group, a heteroaryl group or a 3- to 7-membered cycloalkyl group, a heterocycloalkyl group or a cycloalkoxy group-substituted formyl group.

Summary of the invention

It is an object of the present invention to provide an HCV NS3/4a protease inhibitor which is very effective against hepatitis C virus (HCV), or a pharmaceutically acceptable salt thereof, which has a structure as shown in the general formula (I).

Wherein A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₆ alkyl or C ₃ -C which is unsubstituted or substituted by 1 to 9 halogens or 1 to 6 Ra' _{a 7-} cycloalkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or C ₁ -C _{6 which} is unsubstituted or substituted by 1 to 9 halogens An alkyl group or a C ₃ -C ₇ cycloalkyl group;

A ₂ is N, O or a connection key;

Ar is a 6- to 10-membered aryl group which is unsubstituted or substituted by 1 to 6 R ₁ or a heteroaryl group of 5 to 10 members which has 1 to 3 hetero atoms selected from N, O and S;

Each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or is 1~ 3 R _m 'substituted substituents selected from the group consisting of (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ - C ₇ ) cycloalkyl, (C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ )alkyl, 6-10 membered aryl or containing 1 to 3 independently selected from N, O and S heteroatoms 5- to 10-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₆ )alkyl or (C ₃ -C ₆ ) unsubstituted or substituted with 1 to 9 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ ) optionally substituted by -O-(C ₁ -C ₆ )alkyl or -O-(C ₃ -C ₆ )cycloalkyl a cycloalkyl group, a (C ₁ -C ₆ ) alkoxy group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH ( C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ;

R ₂ is a substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, which is unsubstituted or substituted by 1 to 3 R ₂ '. C ₆ -C ₁₀ aryl, (C ₆ -C ₁₀ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl)C ₁ -C ₂ alkane a C ₃ -C ₇ cycloalkenyl group, a (C ₃ -C ₇ cycloalkenyl) C ₁ -C ₂ alkyl group, having 3 to 3 units independently selected from N, O and S heteroatoms a heterocyclic group, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, having 1 to 3 independently selected from N, O And a 5- to 10-membered heteroaryl group of the S hetero atom and (containing 1 to 3 5- to 10-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ;

R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₉ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be independently selected from NR _p by 1 to 3 , S or O heteroatoms are inserted, or the hydrocarbon chain may be unsubstituted or substituted by 1-9 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p and R _{q are} independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ₄ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl which is unsubstituted or substituted by 1 to 3 R ₄ ' a 3- to 7-membered heterocyclic group independently selected from N, O and S heteroatoms, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (C ₃ -C ₇ Cycloalkenyl) C ₁ -C ₄ alkyl, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₄ alkyl, C ₂ -C ₆ alkanoyl, (C ₁ -C ₄ alkyl) _1-2 (C ₃ -C ₇ )cycloalkyl or (C ₁ -C ₆ alkyl) _1-2 amino; R ₄ ' is selected from the group consisting of Substituents: halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: optionally -O-(C ₁ -C ₆ Alkyl or -O-(C ₃ -C ₆ )cycloalkyl substituted (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₆ )alkoxy a 6- to 10-membered aryl group having 1 to 3 5- to 10-membered heteroaryl groups independently selected from N, O and S heteroatoms, -NH(C ₁ -C ₆ )alkyl, and -N((C) ₁ -C ₆ )alkyl) ₂ .

In a preferred embodiment of the invention, Ar is a 6-membered aryl group substituted or unsubstituted by 1 to 5 R ₁ or 5 to 6 members having 1 to 3 hetero atoms selected from N, O and S hetero atoms. An aryl group; R ₃ and R _{4 are} covalently bonded to form a saturated hydrocarbon chain of C ₅ , and the general formula (I) is a general formula (II a) shown below,

When Z ₁ is a linkage, Z _{2 is} selected from O, S and N(R ₁ ), and Z _{3 is} selected from N and C(R ₁ );

When Z ₃ is a linkage, Z _{1 is} selected from O, S and N(R ₁ ), and Z _{2 is} selected from N and C(R ₁ );

When Z ₃ is N or C(R ₁ ), Z ₁ and Z _{2 are} independently selected from N and C(R ₁ ).

是一芳香取代基，该芳香取代基中的

是一芳香环，该芳香取代基是具有芳香性的6元芳基或5～6元杂芳基，Z₁、Z₂、Z₃可以独立地选自连接键、N、O、S等杂原子，但需满足该环具有芳香性的特征即可。芳香取代基上的“-R₁”表示R₁可以取代芳香环上的任意氢原子。在芳香取代基中，与大环基连接的连接键也可以是芳香环上的任意位置。In the present invention, a substituent

Is an aromatic substituent in the aromatic substituent

Is an aromatic ring, the aromatic substituent is a 6-membered aryl group or a 5- to 6-membered heteroaryl group having an aromaticity, and Z ₁ , Z ₂ and Z ₃ may be independently selected from a bonding bond, N, O, S, etc. An atom, but it is necessary to satisfy the aromatic character of the ring. "-R ₁ " on the aromatic substituent means that R ₁ may be substituted for any hydrogen atom on the aromatic ring. In the aromatic substituent, the linking bond to the macrocyclic group may also be any position on the aromatic ring.

Macrocyclic base:

”表示该键可以是单键，也可以是双键，但前提需满足该环具有芳香性。On the aromatic ring

"It means that the key can be a single bond or a double bond, but it is necessary to satisfy the aromaticity of the ring.

”表示该键可以是单键，也可以是双键。On the large ring base

"This indicates that the key can be a single button or a double button.

In a preferred embodiment of the invention, A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C( R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or C ₁ -C which is unsubstituted or substituted by 1 to 6 halogens or 1 to 4 Ra' _{a 4-} alkyl or C ₃ -C ₆ cycloalkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or unsubstituted or 1 to 6 Halogen-substituted C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

Preferably, A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C( R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₂ alkyl group or C ₅ - which is unsubstituted or substituted by 1 to 3 halogens or 1 to 2 Ra' C ₆ cycloalkyl; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or C ₁ -C which is unsubstituted or substituted by 1 to 3 halogens ₂ alkyl or C ₅ -C ₆ cycloalkyl.

In a preferred embodiment of the invention, each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -) which is unsubstituted or substituted by 1 to 2 R _m ' C ₆ ) alkynyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ cycloalkyl)(C ₁ -C ₄ )alkyl, 6-8 membered aryl or containing 1 to 3 independent a 5- to 8-membered heteroaryl group selected from the group consisting of N, O and S heteroatoms; R _n is hydrogen, or unsubstituted or substituted by 1 to 6 halogen, amino, hydroxy or cyano groups (C ₁ -C ₄ An alkyl or (C ₃ -C ₆ )cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or unsubstituted or 1 to 6 halogen, amino, hydroxy or cyano group consisting of: optionally substituted -O- (C ₁ -C ₄₎ alkyl, or -O- (C ₃ -C ₆₎ cycloalkyl substituted (C ₁ -C ₄₎ An alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a (C ₁ -C ₄ )alkoxy group, a 6- to 8-membered aryl group, and 1 to 3 independently selected from N, O and S heteroatoms ～8-membered heteroaryl, —NH(C ₁ -C ₄ )alkyl and -N((C ₁ -C ₄ ) Alkyl) ₂ ;

Preferably, each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or a substituent selected from the group consisting of (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, (C ₅ ) substituted with 1 R _m ' -C ₆ ) cycloalkyl, (C ₅ -C ₆ cycloalkyl)(C ₁ -C ₂ )alkyl, 6-membered aryl or containing 1 to 2 independently selected from N, O and S heteroatoms 5- to 6-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₂ )alkyl or (C ₅ -C ₆ ) unsubstituted or substituted with 1 to 3 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 3 halogen, amino, hydroxy or cyano groups: selectively -O- (C ₁ -C ₂₎ alkyl, or -O- (C ₅ -C ₆₎ cycloalkyl substituted (C ₁ -C ₂₎ alkyl, (C ₅ -C ₆₎ cycloalkyl An alkyl group, a (C ₁ -C ₂ ) alkoxy group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH(C ₁ - C ₂ ) alkyl and -N((C ₁ -C ₂ )alkyl) ₂ .

In a preferred embodiment of the invention, R ₂ is a substituent selected from the group consisting of unsubstituted or substituted by 1 to 2 R ₂ ': C ₁ -C ₄ alkyl, C ₂ -C ₄ olefin , C ₂ -C ₄ alkynyl, C ₆ -C ₈ aryl, (C ₆ -C ₈ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ Cycloalkyl)C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkenyl, (C ₃ -C ₆ cycloalkenyl)C ₁ -C ₂ alkyl, containing 1 to 3 independently selected from N, a 3- to 6-membered heterocyclic group of O and S heteroatoms, (containing 1 to 3 3- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, containing 1 ～5 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms and (containing 1 to 3 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' is selected from the group consisting of unsubstituted or substituted (C ₁ -C ₄ )alkyl substituted by amino, hydroxy, cyano or 1-6 halogen, (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, (C ₁ -C ₄ )alkoxy, -NH(C ₁ -C ₄ )alkyl and -N((C ₁ -C _{4 )} )alkyl) ₂ ;

Preferably, R ₂ is a substituent selected from the group consisting of C ₁ -C ₂ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, unsubstituted or substituted by 1 R ₂ ' , C ₆ aryl, (C ₆ aryl) C ₁ -C ₂ alkyl, C ₅ -C ₆ cycloalkyl, (C ₅ -C ₆ cycloalkyl)C ₁ -C ₂ alkyl, C ₅ - C ₆ cycloalkenyl, (C ₅ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl, having 1 to 2 5- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms, a 5- to 6-membered heterocyclic)C ₁ -C ₂ alkyl group having 1 to 2 independently selected from N, O and S heteroatoms, containing 1 to 2 independently selected from N, O and S heteroatoms. a 5- to 6-membered heteroaryl group and (containing 1 to 2 5- to 6-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' is selected from the group consisting of Substituent: (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen Alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ .

In a preferred embodiment of the invention, R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₇ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be 1 to 3 are independently selected from NR _p , S or O heteroatom insertions, or the hydrocarbon chain may be unsubstituted or substituted by 1 to 6 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p And R _{q are} independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;

Preferably, R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₆ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be independently selected from 1 to 2 Inserted from NR _p , S or O heteroatoms, or the hydrocarbon chain may be unsubstituted or substituted by 1 to 3 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p and R _{q are} independently hydrogen , C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl.

In a preferred embodiment of the invention, R ₄ is C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₆ naphthenic, unsubstituted or substituted by 1 to 2 R ₄ ' a C ₃ -C ₆ cycloalkenyl group having 3 to 3 membered heterocyclic groups independently selected from N, O and S heteroatoms, (C ₃ -C ₆ cycloalkyl) C ₁ -C _4- alkyl, (C ₃ -C ₆ cycloalkenyl) C ₁ -C ₄ alkyl, (containing 1 to 3 3- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₄ alkyl, C ₂ -C ₄ alkanoyl, (C ₁ -C ₄ alkyl) _1-2 (C ₃ -C ₆ )cycloalkyl or (C ₁ -C ₄ alkyl) _1-2 amino ; R ₄ ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 6 halogen, amino, hydroxy or cyano groups: optionally substituted -O- (C ₁ -C ₄₎ alkyl, or -O- (C ₃ -C ₆₎ cycloalkyl (C ₁ -C ₄₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₁ -C ₄ )alkoxy, 6- to 8-membered aryl, 5- to 5-membered heteroaryl optionally containing N, O and S heteroatoms, -NH(C ₁ -C ₄ ) alkyl and -N((C ₁ -C ₄ )alkyl) ₂ ;

Preferably, R ₄ is C ₁ -C ₂ alkyl, C ₂ -C ₃ alkenyl, C ₅ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkene which is unsubstituted or substituted by 1 R ₄ ' a 5- to 6-membered heterocyclic group independently selected from N, O and S heteroatoms, (C ₅ -C ₆ cycloalkyl) C ₁ -C ₂ alkyl, (C ₅ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl, (containing 1 to 2 5- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, C ₂ - C ₃ alkanoyl, (C ₁ -C ₂ alkyl) _1-2 (C ₅ -C ₆ )cycloalkyl or (C ₁ -C ₂ alkyl) _1-2 amino; R ₄ ' is selected from the group consisting of Substituents: halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 3 halogen, amino, hydroxy or cyano groups: optionally -O-(C ₁ -C ₂ ) alkyl or -O-(C ₅ -C ₆ )cycloalkyl substituted (C ₁ -C ₂ )alkyl, (C ₅ -C ₆ )cycloalkyl, (C ₁ -C ₂ )alkoxy a 6-membered aryl group having 1 to 2 5- to 6-membered heteroaryl groups independently selected from N, O and S heteroatoms, -NH(C ₁ -C ₂ )alkyl, and -N((C _{1 )} -C ₂ )alkyl) ₂ .

The compounds of the invention include the following compounds:

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

It is still another object of the present invention to provide a method of synthesizing a compound of the formula (II),

或O(CH₃)₃；Where R _y is

Or O(CH ₃ ) ₃ ;

That is, the compound of formula (II) consists of a two-part compound of formula (II a) and formula (II b),

Wherein the compound of the formula (II a) further comprises a compound of the formula (II a1) and the formula (II a2)

Wherein the compound of the formula (II b) further comprises a compound of the formula (II b1) and the formula (II b2)

among them,

When Z ₁ is a linkage, Z _{2 is} selected from O, S and N(R ₁ ), and Z _{3 is} selected from N and C(R ₁ );

When Z ₃ is a linkage, Z _{1 is} selected from O, S and N(R ₁ ), and Z _{2 is} selected from N and C(R ₁ );

When Z ₃ is N or C(R ₁ ), Z ₁ and Z _{2 are} independently selected from N and C(R ₁ );

A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₆ alkyl or C ₃ -C ₇ ring which is unsubstituted or substituted with 1 to 9 halogens or 1 to 6 Ra' An alkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with 1 to 9 halogens Or a C ₃ -C ₇ cycloalkyl group;

A ₂ is N, O or a connection key;

Each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or is 1~ Three R _m 'substituted substituents selected from the group consisting of (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ - C ₇ ) cycloalkyl, (C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ )alkyl, 6-10 membered aryl or containing 1 to 3 independently selected from N, O and S heteroatoms 5- to 10-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₆ )alkyl or (C ₃ -C ₆ ) unsubstituted or substituted with 1 to 9 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ ) optionally substituted by -O-(C ₁ -C ₆ )alkyl or -O-(C ₃ -C ₆ )cycloalkyl a cycloalkyl group, a (C ₁ -C ₆ ) alkoxy group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH ( C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ;

R ₂ is a substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, which is unsubstituted or substituted by 1 to 3 R ₂ '. C ₆ -C ₁₀ aryl, (C ₆ -C ₁₀ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl)C ₁ -C ₂ alkane a C ₃ -C ₇ cycloalkenyl group, a (C ₃ -C ₇ cycloalkenyl) C ₁ -C ₂ alkyl group, having 3 to 3 units independently selected from N, O and S heteroatoms a heterocyclic group, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, having 1 to 3 independently selected from N, O And a 5- to 10-membered heteroaryl group of the S hetero atom and (containing 1 to 3 5- to 10-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ;

The method comprises the following steps:

Step 1, under the action of an organometallic base or sodium hydride, Compound 1 and Boc-L-4-hydroxyproline in a dimethyl sulfoxide organic solvent were stirred to obtain a compound 2;

在二氯甲烷、四氢呋喃或二甲基甲酰胺有机溶剂中经搅拌反应得到化合物3，其中，R_x为NHSO₂A₂R₂或OCH₂CH₃； Step 2, compound 2 and compound under the action of a condensing agent and an organic base

The compound 3 is obtained by stirring in an organic solvent of dichloromethane, tetrahydrofuran or dimethylformamide, wherein R _x is NHSO ₂ A ₂ R ₂ or OCH ₂ CH ₃ ;

Step 3, the compound 3 and the deBoc reagent in dichloromethane and / or dioxane organic solvent were stirred to obtain the compound 4;

Step 4, under the action of a condensing agent and an organic base, compound 4 and (S)-2-N-Boc 8-ene-n-fluorene amino acid in a dichloromethane organic solvent stirred to obtain a compound 5;

Step 5. Under the protection of an inert gas, compound 5 is reacted with Zhan catalyst in an organic solvent of toluene, and then 2-mercaptonicotinic acid is added to terminate the reaction to obtain compound 6 or a compound of formula (II b1).

In a preferred embodiment of the invention,

When R _x is NHSO ₂ A ₂ R ₂ , proceed to the following steps 6 and 7:

Step 6, the compound of the formula (II b1) and the de Boc reagent are hydrolyzed by stirring in dichloromethane and/or a dioxane organic solvent to obtain a compound 7;

在N，N-二甲基甲酰胺有机溶剂中经搅拌反应得到式(II a1)化合物，其中，X为卤素或羟基，当X为羟基时，反应液中还含有缩合剂。 Step seven, under the action of an organic base, compound 7 and

The compound of the formula (II a1) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent.

In another preferred embodiment of the invention, when R _x is OCH ₂ CH ₃ , compound 6 proceeds to the following steps a and b:

Step a, under the action of an inorganic base, compound 6 is stirred and hydrolyzed in a mixed solvent of water, tetrahydrofuran and methanol to form compound 8;

Step b, first stirring the compound 8 and N,N'-carbonyldiimidazole in an organic solvent of dichloromethane, and then adding H ₂ NSO ₂ A ₂ R ₂ and an organic base to continue the reaction to obtain a compound of the formula (II b1) .

In a further preferred embodiment of the above preferred embodiment, the compound of formula (II b) obtained in step b proceeds to step six and step seven:

Step 6, the compound of the formula (II b1) and the de Boc reagent are hydrolyzed by stirring in dichloromethane and/or a dioxane organic solvent to obtain a compound 7;

在N，N-二甲基甲酰胺有机溶剂中经搅拌反应得到式(II a1)化合物，其中，X为卤素或羟基，当X为羟基时，反应液中还含有缩合剂。Step seven, under the action of an organic base, compound 7 and

The compound of the formula (II a1) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent.

The synthesis of the compound of the formula (II) of the present invention is shown on the following page.

或O(CH₃)₃；Where R _y is

Or O(CH ₃ ) ₃ ;

)和式(II b)(其中，R_y为O(CH₃)₃)两部分化合物组成。That is, the compound of formula (II) is represented by formula (II a) (wherein R _y is

And a compound of the formula (II b) wherein R _y is O(CH ₃ ) ₃ ).

Wherein, the synthesis of the compound of the formula (II a1) and the formula (II b1) is as shown in the first scheme:

In another synthetic process of the invention,

When Rx is OCH ₂ CH ₃ ,

Compound 6 can proceed to step six' and step seven':

Step 6 ', compound 6 and de Boc reagent in dichloromethane and / or dioxane organic solvent by stirring hydrolysis reaction to obtain compound 9;

在N，N-二甲基甲酰胺有机溶剂中经搅拌反应得到化合物10，其中，X为卤素或羟基，当X为羟基时，反应液中还含有缩合剂；Step VII', under the action of an organic base, compound 9 and

The compound 10 is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

Compound 10 proceeds to step a' and step b',

Step a', under the action of an inorganic base, the compound 10 is stirred and hydrolyzed in a mixed solvent of water, tetrahydrofuran and methanol to form a compound 11;

Step b', first stirring the compound 11 with N,N'-carbonyldiimidazole in an organic solvent of dichloromethane, and then adding H ₂ NSO ₂ A ₂ R ₂ and an organic base to continue the reaction to obtain the formula (II a1). Compound,

Another synthetic scheme for the compound of formula (II a1) of the present invention is as follows:

The synthesis of the compounds of formula (II a2) and formula (II b2) is:

a compound of the formula (II b1) is reacted with hydrogen under the catalysis of a palladium-carbon catalyst to obtain a compound of the formula (II b2),

a compound of the formula (II a1) is reacted with hydrogen under the catalysis of a palladium-carbon catalyst to obtain a compound of the formula (II a2),

Alternatively, the compound of formula (II b2) continues the following reaction:

Compound (II b2) is reacted with a de Boc reagent to obtain compound 7';

在N，N-二甲基甲酰胺有机溶剂中经搅拌反应得到式(II a2)化合物，其中，X为卤素或羟基，当X为羟基时，反应液中还含有缩合剂；Under the action of an organic base, compound 7' and

The compound of the formula (II a2) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

Wherein, the synthesis of the compound of the formula (II a2) and the formula (II b2) is as shown in the second scheme:

是将

与对甲苯磺酸一水合物、盐酸或三氟乙酸在有机溶剂中反应制备得到的。具体地是，当R_x为NHSO₂A₂R₂时，步骤二中的化合物

是将

与TsOH·H₂O在乙酸乙酯有机溶剂中于43～48℃反应制备得到的；当Rx为OCH₂CH₃时，步骤二中的化合物

是将

与盐酸在二氧六环有机溶剂中于室温下搅拌反应制备得到的。In a preferred embodiment of the invention, the compound in step two

Is going to

Prepared by reacting with p-toluenesulfonic acid monohydrate, hydrochloric acid or trifluoroacetic acid in an organic solvent. Specifically, when R _x is NHSO ₂ A ₂ R ₂ , the compound in step two

Is going to

Prepared by reacting TsOH·H ₂ O in ethyl acetate organic solvent at 43-48 ° C; when Rx is OCH ₂ CH ₃ , the compound in step two

Is going to

Prepared by stirring with hydrochloric acid in a dioxane organic solvent at room temperature.

In the invention, the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzo Triazole-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), dicyclohexylcarbal Imine (DCC), 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide (EDCI) and/or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP); the inert gas is nitrogen.

In the present invention, the organometallic base is potassium t-butoxide and/or sodium t-butoxide, and the organic base is diisopropylethylamine, triethylamine and/or 1,8-diaza Bicyclo [5.4.0] undec-7-ene (DBU), The inorganic base is LiOH, NaOH and/or KOH, and the deBoc reagent is hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.

In a further preferred embodiment of the invention,

In the first step, the organometallic base is slowly added to the organic solvent of the dimethyl sulfoxide containing the compound 1 and Boc-L-4-hydroxyproline in an ice bath, and the stirring is continued for 5 to 30 minutes. Then, the reaction is further stirred at room temperature for 10 to 50 minutes to obtain a compound 2, wherein the organometallic base is potassium t-butoxide and/or sodium t-butoxide;

和有机碱，然后室温搅拌反应过夜得到化合物3，其中，R_x为NHSO₂A₂R₂或OCH₂CH₃，所述的缩合剂为HATU，所述的有机碱为二异丙基乙胺；In the second step, the condensing agent and the compound are added to the dichloromethane solution containing the compound 2 under stirring in an ice bath.

And the organic base, and then the reaction is stirred at room temperature overnight to obtain the compound 3, wherein R _x is NHSO ₂ A ₂ R ₂ or OCH ₂ CH ₃ , the condensing agent is HATU, and the organic base is diisopropylethylamine. ;

In the third step, the dioxane solution of the compound 3 is heated to 65 to 75 ° C, and then p-toluenesulfonic acid is added, and the reaction is further stirred for 3 to 6 hours to obtain a compound 4a; or a solution of the compound 3 in dichloromethane. Adding HCl in dioxane solution, stirring at room temperature overnight to obtain compound 4b;

Step 4 is specifically: adding a compound 4 and an organic base to a dichloromethane solution containing (S)-2-N-Boc 8-ene-n-amino acid and a condensing agent under stirring in an ice bath, and stirring at room temperature overnight. Obtaining compound 5, wherein the condensing agent is HATU, and the organic base is diisopropylethylamine;

Step 5 specifically, after degassing the toluene solution containing the compound 5, heating under an inert gas, stirring to 64-68 ° C, adding Zhan catalyst for 1.5 to 3 hours, then adding 2-mercaptonicotinic acid to continue stirring to terminate the reaction. Compound 6 or a compound of the formula (II b1) is obtained in 1.5 to 3 hours, and the inert gas is nitrogen.

In a further preferred embodiment: when R _x is NHSO ₂ A ₂ R ₂ , proceed to the following steps 6 and 7:

Step 6, adding a solution of hydrochloric acid in dioxane to the dichloromethane solution containing the compound of the formula (II b1), stirring at room temperature for 2 to 5 hours to obtain a compound 7a;

和有机碱，室温下搅拌反应过夜得到式(II a1)化合物，其中所述的有机碱为二异丙基乙胺，其中，X为卤素或羟基，当X为羟基时，反应液中还加入缩合剂，所述的缩合剂为2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯。 Step VII, adding to the solution of the compound 7a in N,N-dimethylformamide

And the organic base is stirred at room temperature overnight to obtain a compound of the formula (II a1), wherein the organic base is diisopropylethylamine, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid is further added. A condensing agent, which is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

When R _x is OCH ₂ CH ₃ , compound 6 proceeds to the following steps a and b:

In step a, an inorganic lye is added to a solution of the compound 6 in tetrahydrofuran and methanol, and stirred at 18 to 22 ° C overnight to form a compound 8, wherein the inorganic lye is a solution of LiOH, NaOH or KOH;

Step b, compound 8 and N,N'-carbonyldiimidazole are stirred at room temperature overnight in dichloromethane solvent, then H ₂ NSO ₂ A ₂ R ₂ and an organic base are added to carry out the condensation reaction for 2 to 5 hours to obtain the formula (II b1). a compound, the organic base being 1,8-diazabicyclo[5.4.0]undec-7-ene,

The obtained compound of the formula (II b1) is further subjected to the steps 6 and 7 to obtain the compound of the formula (II a1).

Step 6, adding a solution of hydrochloric acid in dioxane to the dichloromethane solution containing the compound of the formula (II b1), stirring at room temperature for 2 to 5 hours to obtain a compound 7a;

和有机碱，室温下搅拌反应过夜得到式(II a1)化合物，其中，所述的有机碱为二异丙基乙胺，X为卤素或羟基，当X为羟基时，反应液中还加入缩合剂，所述的缩合剂为2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯；Step VII, adding to the solution of the compound 7a in N,N-dimethylformamide

And the organic base is stirred at room temperature overnight to obtain a compound of the formula (II a1), wherein the organic base is diisopropylethylamine, X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid is further added to the reaction liquid. a mixture, the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

Further, a 10% palladium-carbon catalyst is added to a methanol solution of the compound of the formula (IIb1), replaced with hydrogen, and the reaction is stirred for several hours to obtain a compound of the formula (IIb2).

Further, a 10% palladium-carbon catalyst is added to a methanol solution of the compound of the formula (IIa1), replaced with hydrogen, and the reaction is stirred for several hours to obtain a compound of the formula (IIa2).

In the present invention,

The term "zhan'catalyst 1B" is also known as "zhan catalyst", the Chinese name Jen's catalyst, is a ruthenium complex, CAS accession number: 918870-76-5.

In the present invention, the hetero atom in the "heteroaryl", "heterocycloalkyl", "heterocyclenyl" and "heterocyclyl" refers to a hetero atom selected from N, O and S.

In the present invention, the abbreviation "TsOH" means p-toluenesulfonic acid, "TsO" means a portion in which p-toluenesulfonic acid does not contain a hydroxyhydrogen, and the abbreviation "TsOH·H2O" means p-toluenesulfonic acid. A monohydrate compound. The abbreviation "DBU" refers to an organic base, specifically 1,8-diazabicycloundec-7-ene, CAS accession number: 6674-22-2. The abbreviation "HATU" is a condensing agent, specifically 2-(7-azobenzotriene). Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The abbreviation "HBTU" specifically refers to O-benzotriazole-tetramethylurea hexafluorophosphate. The abbreviation "HCTU" refers to 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate. The abbreviation "DCC" refers to dicyclohexylcarbodiimide. The abbreviation "EDCI" refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide. The abbreviation "PyBOP" refers to benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate. The abbreviation "CDI" refers to N,N'-carbonyldiimidazole. The abbreviation "DMSO" refers to dimethyl sulfoxide. The abbreviation "THF" refers to tetrahydrofuran. The abbreviation "DMF" means N,N-dimethylformamide. The abbreviation "DCM" means dichloromethane. The abbreviations "DIEA" and "DIPEA" both refer to diisopropylethylamine. "t-BuOK" means potassium t-butoxide. The abbreviation "MTBE" refers to methyl tert-butyl ether. The abbreviation "PE" refers to petroleum ether.

The term "Boc" in the term "Boc-L-4-hydroxyproline" means a protecting group - tert-butoxycarbonyl, ie "Boc-L-4-hydroxyproline" means "tert-butoxycarbonyl- L-4-hydroxyproline". Similarly, "(S)-2-N-Boc8-ene-n-anthracene amino acid" means "(S)-2-N-tert-butoxycarbonyl-8-ene-n-amino acid."

In the method of the invention for synthesizing a compound of formula (II):

In a preferred embodiment of the invention, A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₄ alkyl group or C ₃ -C _{6 which} is unsubstituted or substituted by 1 to 6 halogens or 1 to 4 Ra' a cycloalkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or a C ₁ -C ₄ alkane which is unsubstituted or substituted by 1 to 6 halogens Or a C ₃ -C ₆ cycloalkyl group;

Preferably, A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₂ alkyl group or a C ₅ -C ₆ cycloalkyl group which is unsubstituted or substituted with 1 to 3 halogens or 1 to 2 Ra';Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or C ₁ -C ₂ alkyl or C ₅ -C _{6 which} is unsubstituted or substituted by 1 to 3 halogens Cycloalkyl.

In a preferred embodiment of the invention, each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -) which is unsubstituted or substituted by 1 to 2 R _m ' C ₆ ) alkynyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ cycloalkyl)(C ₁ -C ₄ )alkyl, 6-8 membered aryl or containing 1 to 3 independent a 5- to 8-membered heteroaryl group selected from the group consisting of N, O and S heteroatoms; R _n is hydrogen, or unsubstituted or substituted by 1 to 6 halogen, amino, hydroxy or cyano groups (C ₁ -C ₄ An alkyl group or a (C ₃ -C ₆ )cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or unsubstituted or 1 to 6 halogen, amino, hydroxy or cyano group consisting of: optionally substituted -O- (C ₁ -C ₄₎ alkyl, or -O- (C ₃ -C ₆₎ cycloalkyl substituted (C ₁ -C ₄₎ An alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a (C ₁ -C ₄ )alkoxy group, a 6- to 8-membered aryl group, and 1 to 3 independently selected from N, O and S heteroatoms ～8-membered heteroaryl, —NH(C ₁ -C ₄ )alkyl and -N((C ₁ -C ₄ ) Alkyl) ₂ ;

Preferably, each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or a substituent selected from the group consisting of (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, (C ₅ ) substituted with 1 R _m ' -C ₆ ) cycloalkyl, (C ₅ -C ₆ cycloalkyl)(C ₁ -C ₂ )alkyl, 6-membered aryl or containing 1 to 2 independently selected from N, O and S heteroatoms 5- to 6-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₂ )alkyl or (C ₅ -C ₆ ) unsubstituted or substituted with 1 to 3 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 3 halogen, amino, hydroxy or cyano groups: optionally substituted -O- (C ₁ -C ₂₎ alkyl, or -O- (C ₅ -C ₆₎ cycloalkyl substituted (C ₁ -C ₂₎ alkyl, (C ₅ -C ₆₎ cycloalkyl An alkyl group, a (C ₁ -C ₂ ) alkoxy group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH(C ₁ - C ₂ ) alkyl and -N((C ₁ -C ₂ )alkyl) ₂ .

In a preferred embodiment of the invention, R ₂ is a substituent selected from the group consisting of unsubstituted or substituted by 1 to 2 R ₂ ': C ₁ -C ₄ alkyl, C ₂ -C ₄ olefin , C ₂ -C ₄ alkynyl, C ₆ -C ₈ aryl, (C ₆ -C ₈ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ Cycloalkyl)C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkenyl, (C ₃ -C ₆ cycloalkenyl)C ₁ -C ₂ alkyl, containing 1 to 3 independently selected from N, a 3- to 6-membered heterocyclic group of O and S heteroatoms, (containing 1 to 3 3- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, containing 1 ～5 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms and (containing 1 to 3 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' is selected from the group consisting of unsubstituted or substituted (C ₁ -C ₄ )alkyl substituted by amino, hydroxy, cyano or 1-6 halogen, (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, (C ₁ -C ₄ )alkoxy, -NH(C ₁ -C ₄ )alkyl and -N((C ₁ -C _{4 )} )alkyl) ₂ ;

Preferably, R ₂ is a substituent selected from the group consisting of C ₁ -C ₂ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, unsubstituted or substituted by 1 R ₂ ' , C ₆ aryl, (C ₆ aryl) C ₁ -C ₂ alkyl, C ₅ -C ₆ cycloalkyl, (C ₅ -C ₆ cycloalkyl)C ₁ -C ₂ alkyl, C ₅ - C ₆ cycloalkenyl, (C ₅ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl, having 1 to 2 5- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms, a 5- to 6-membered heterocyclic)C ₁ -C ₂ alkyl group having 1 to 2 independently selected from N, O and S heteroatoms, containing 1 to 2 independently selected from N, O and S heteroatoms. a 5- to 6-membered heteroaryl group and (containing 1 to 2 5- to 6-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' is selected from the group consisting of Substituent: (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen Alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ .

detailed description

Example 1

Compound b1

A solution of the compound a1 (299 g, 0.906 mol) in ethyl acetate (2.4 L) was warmed to 45 ° C, then p-toluenesulfonic acid monohydrate (189 g, 0.996 mol) was added portionwise and maintained at 45 ° C for 5.5 hours. The precipitated solid was filtered, washed with ethyl acetate and dried to give 352 g of Compound b1 (yield: 96.7%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.61 (brs, 3H), 7.48 (d, J = 8.0Hz, 2H), 7.12 (d, J = 8.0Hz, 2H), 5.60-5.69 (m, 1H), 5.36 (d, J = 16.8 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 2.90-3.01 (m, 1H), 2.30 (s, 3H), 2.20-2.28 (m, 1H) ), 2.08-2.14 (m, 1H), 1.56 (dd, J = 7.2, 9.6 Hz, 1H), 1.00-1.14 (m, 4H).

Compound 2

In an ice water bath and mechanical stirring, 145.4 g of potassium t-butoxide (1.295 mol, 5 eq) was slowly added in portions (2S, 4R) Boc-L-4-hydroxyproline 60 g (0.259 mol, 1 eq) and compound 1 (M24 of Example 24 on page 48 of WO 2013/017026 A1) (74.7 g, 0.259 mol, 1 eq) in a mixture of dimethyl sulfoxide (1.6 L). After the addition was completed, the mixture was stirred for 10 minutes. After removing the ice water bath, stirring was continued for 20 minutes at room temperature until the reaction was completed.

The reaction solution was added to 9 L of ice water under stirring, and the pH was adjusted to 4-5 with dilute hydrochloric acid, filtered, and the filter cake was beaten with water, filtered, washed with water, and dried. The crude product was dissolved by heating with 10 times of absolute ethanol, and filtered, and the filtrate was cooled and crystallized to obtain 115 g of Compound 2 (yield: 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 to 8.37 (m, 2H), 8.06 to 8.10 (m 1H), 7.38 (m, 1H), 7.58 to 7.88 (m, 2H), 7.42 to 7.46 (m, 1H), 6.00 (brs, 1H), 4.62 to 4.77 (m, 1H), 3.91 to 4.06 (m, 2H), 2.83 to 2.90 (m, 1H), 2.61 to 2.75 (m, 1H); 1.49 (s, 9H). ES-LC/MS m/z 483 (M + 1).

Compound 3 (1)

To a solution of compound 2 (54.1 g, 0.112 mol) in dichloromethane (0.84 L), HATU) (46.9 g, 0.146 mol), compound b1 (49.52 g, 0.123 mol) and diisopropyl Ethylamine (36 g, 0.28 mol) was stirred at room temperature overnight. The reaction solution was poured into ice water (560 mL) with stirring, and then added with petroleum ether (1 L), stirred for 10 min, filtered, and the filter cake was dried. The crude product was recrystallized from ethanol (1.6 L) to give Compound 3 (1) (74 g, yield: 96%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (brs, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 1.6 Hz) , 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 9.2, 2.0 Hz) , 1H), 7.02 (brs, 1H), 6.05 (brs, 1H), 5.80-5.90 (m, 1H), 5.32 (d, J = 16.8 Hz, 1H), 5.19 (d, J = 11.2 Hz, 1H) , 4.44 (t, J = 7.6 Hz, 1H), 3.98 (dd, J = 8.0, 4.0 Hz, 1H), 3.89 (d, J = 8.4 Hz, 1H), 2.95-3.05 (m, 1H), 2.60- 2.70 (m, 2H), 2.14 (dd, J = 8.8, 9.2 Hz, 1H), 2.04 (dd, J = 8.0, 5.2 Hz, 1H), 1.52-1.68 (m, 1H), 1.48 (m, 9H) , 1.32-1.44 (m, 2H), 1.05-1.15 (2H). ES-LC/MS m/z 695 (M+1).

Compound 4 (1)

A solution of compound 3 (1) (44.5 g, 0.0641 mol) in dioxane (0.66 L) was heated to 70 °C. Then p-toluenesulfonic acid monohydrate (25.58 g, 0.137 mol) was added and stirred at 70 ° C for 4 h. The mixture was cooled to room temperature, concentrated to dryness under reduced pressure. <RTI ID=0.0>>>

Compound 5 (1)

To a solution of (S)-2-N-Boc 8-ene-n-amino acid (13.6 g, 0.0575 mol) and HATU (20.2 g, 0.063 mol) in dichloromethane (600 mL) 4(1) (47.2 g, 0.0523 mol) and diisopropylethylamine (23.6 g, 0.183 mol). The reaction solution was washed successively with water (400 mL), 1N hydrochloric acid (400 ml), saturated sodium hydrogen carbonate (400 mL) and brine (400 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated The crude product was recrystallized from dichloromethane and ethanol to afford compound 5 (1) (32 g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.45 (brs, 1H), 8.32 (d, J = 8.4Hz, 1H), 8.29 (d, J = 8.4Hz, 1H), 8.08 (d, J = 2.0Hz , 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.60-7.66 (m, 2H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (brs, 1H), 6.13 (brs, 1H), 5.77-5.90 (m, 2H), 5.35 (d, J = 8.4 Hz, 1H), 5.29 (dd, J = 17.2, 1.6 Hz, 1H), 5.17 (dd, J = 10.8, 1.6 Hz, 1H) ), 4.99 (dt, J = 14.8, 2.0 Hz, 1H), 4.95 (dt, J = 10.4, 1.2 Hz, 1H), 4.54-4.58 (dd, J = 7.2, 9.2 Hz, 1H), 4.40 - 4.85 ( m,1H), 4.34 (d, J = 12.0 Hz, 1H), 4.12 (dd, J = 4.4, 12.0 Hz, 1H), 2.94-3.00 (m, 1H), 2.63 - 2.73 (m, 2H), 2.00 -2.16(m,4H),1.70-1.76(m,1H),1.62-1.66(m,1H),1.27-1.51(m,18H),1.06-1.14(2H).ES-LC/MS:m/ z 848(M+1)

Compound of formula (II b1)(1)

A solution of the compound 5 (1) (45 g, 53.12 mmol) in toluene (9 L) was degassed, heated under stirring with nitrogen to 66 ° C, and then reacted with Zhan Catalyst-1B (0.9 g, 2.0 w%) for 2 hours. 2-Mercaptonicotinic acid was added, and the mixture was stirred for 2 hr. EtOAc (EtOAc m. Purification by silica gel column chromatography (DCM /MeOH)

_{^{1 H NMR (400MHz, CDCl 3}} , 298K) δ10.45 (brs, 1H), 8.35 (d, J = 8.0Hz, 1H), 8.26 (d, J = 8.4Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.55-7.62 (m, 2H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 6.71 (brs, 1H), 6.10 ( Brs,1H), 5.75 (q, J=9.2, 9.2, 8.4 Hz, 1H), 5.00-5.07 (m, 2H), 4.65-4.70 (m, 2H), 4.30-4.36 (m, 1H), 4.10- 4.16 (m, 1H), 2.90-3.00 (m, 1H), 2.73-2.90 (m, 2H), 2.60-2.65 (m, 1H), 2.30-2.37 (m, 1H), 1.80-2.00 (m, 3H) ), 1.60-1.66 (m, 1H), 1.42-1.56 (7H), 1.28-1.35 (m, 9H), 1.10.12.22 (m, 3H), 0.94-1.02 (1H). ES-LC/MS: m /z 820(M+1)

Compound 7a(1)

To a solution of the compound of formula (II b1) (1) (1 g, 1.22 mmol, 1 eq) in dichloromethane (20 ml), 10 ml of a 5 mol/L solution of hydrogen chloride dioxane was added and stirred at room temperature for 3 h. Concentration by pressure gave 1 g of crude compound 7a (1), which was used directly in the next step.

Compound of formula (II a1)(1)

To a solution of 1 g of compound 7a (1) in N,N-dimethylformamide (20 ml) at room temperature, was added 5-methyl-2-carboxypyrazine 168.5 mg (1.22 mmol, 1 eq), HATU 928 mg (2.44) Methyl ether (2 eq.) and 946.5 mg (7.32 mmol, 6 eq) of diisopropylethylamine. The reaction mixture was added to ice water, the pH was adjusted to 4 to 5 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography to afford 910 mg (II a1) 1) Compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.29 (s, 1H), 8.96 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.32 (d, J = 8.4 Hz) , 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 2.0, 1H), 7.76 (dd, J = 8.0, 7.2 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 8.0, 7.2 Hz, 1H), 7.450 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.88 (brs, 1H), 6.17 (brs, 1H), 5.75 to 5.82 (q, J = 9.2, 8.8, 10 Hz, 1H), 5.05 (dd, J = 8.8, 10.0 Hz, 1H), 4.744 to 4.795 (m, 1H), 4.72 (t, J = 8.0 Hz, 1H), 4.62 (d, J = 12 Hz, 1H), 4.23 (dd, J = 4.0, 12.0 Hz, 1H), 2.92 to 2.98 (m, 1H), 2.75 to 2.78 ( m, 2H), 2.66 (s, 3H), 2.54 to 2.63 (m, 1H), 2.34 (q, J = 8.4 Hz, 1H), 2.05 to 2.08 (m, 1H), 1.97 to 1.99 (m, 2H) , 1.74 to 1.81 (m, 1H), 1.59 to 1.63 (m, 8H), 1.52 to 1.56 (m, 6H), 1.33 to 1.47 (m, 3H), 1.27 (s, 3H), 1.10 to 1.24 (m, 3H), 0.95 to 1.01 (m, 1H). ES-LC/MS m/z 840 (M+1)

Compound of formula (II a1)(1)

Under a nitrogen atmosphere, a 10% palladium-carbon catalyst (10 mg) was added to a methanol solution (10 mL) of a compound of formula (II a1) (1) (100 mg), and hydrogen was replaced three times, and then the reaction was stirred for 2 hours. The catalyst was removed by filtration, and concentrated to dryness under reduced pressure to give a compound (yield of formula (II a2) (1). ES-LC/MS m/z 842 (M+1).

Example 2

Compound b2

Compound a2 (141 g, 0.552 mol) was dissolved in 6N hydrochloric acid / dioxane (500 mL), room temperature Stir for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound b2 (l.

Compound 3 (2)

To a solution of compound 2 (257.5 g, 0.533 mol), compound b2 (107.3 g, 0.559 mol) and HATU (243.2 g, 0.639 mol) in dichloromethane (3 L) below 20 ° C, DIEA (206.7) g, 1.599 mol), stirred at room temperature for 18 hours. The reaction mixture was poured into ice-hydrochloric acid (1M, 1.5L), and the methylene chloride layer was separated and washed with water (2L 2) and brine (2L). The organic layer was dried (MgSO4). ES-LC/MS m/z: 621.3 (M+H)

Compound 4 (2)

To a solution of the compound 3 (2) (223 g, 0.360 mol) in dichloromethane (2 L), EtOAc (EtOAc) 200 g, yield 100%).

^{1 H NMR: (400MHz, CDCl} 3) δ11.3 (brs, 1H), 9.30 (brs, 1H), 8.56 (brs, 1H), 8.39 (s, 1H), 8.05 (m, 1H), 7.81 (m , 1H), 7.59 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.15 (brs, 1H), 5.58 (brs, 1H), 5.40 -5.30(m,1H), 5.30-5.20(m,1H), 5.13(d,J=10.0Hz,1H), 4.25-4.12(m,2H),4.12-4.0(m,1H),3.85-3.96 (m, 1H), 3.09 (s, 1H), 2.72 (s, 1H), 2.42-2.30 (m, 1H), 1.81 (s, 1H), 1.55-1.49 (m, 1H), 1.25 (m, 3H) ).ES-LC/MS m/z 520.2(M+H)

Compound 5 (2)

Under 20 ° C, to compound 4 (2) (200 g, 0.359 mol), (S)-2-N-Boc 8-ene-n-amino acid (97.53 g, 0.359 mol) and HATU (163.9 g, 0.431 mol) In a dichloromethane (3 L) solution, DIEA (139.36 g, 1.078 mol) was added with stirring and stirred at room temperature for 18 hours. The reaction mixture was poured into EtOAc EtOAc (EtOAc m. The crude product was recrystallized from EtOAc (EtOAc) (EtOAc)

^{1 H NMR: (400MHz, CDCl} 3) δ8.33 (d, J = 8.4Hz, 1H), 8.26 (d, J = 8.0Hz, 1H), 8.06 (d, J = 1.6Hz, 1H), 7.85 ( t, J = 8.0 Hz, 1H), 7.70-7.50 (m, 3H), 7.45 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.07 (s, 1H), 5.85-5.71 (m, 2H) ), 5.35-5.31 (m, 1H), 5.17-5.14 (m, 2H), 4.99-4.89 (m, 3H), 4.45-4.35 (m, 1H), 4.24 - 4.13 (m, 4H), 3.05 - 2.93 (m, 1H), 2.59-2.51 (m, 1H), 2.25-2.15 (q, J = 8.8 Hz, 1H), 2.05-1.95 (m, 2H), 1.92-1.88 (dd, J = 8.0, 5.6 Hz , 1H), 1.82-1.55 (m, 3H), 1.54-1.50 (dd, J = 9.6, 5.6 Hz, 1H), 1.35-1.24 (m, 17H); ES-LC/MS m/z 773.3 (M+ H).

Compound 6 (2)

Add compound 5 (2) (50 g) and 1,2-dichloroethane (8 L) to a 10 L reaction flask, degas, heat to 66 ° C under nitrogen, add zhan catalyst (0.75 g), react for 1.5 h . After the TLC detection reaction was completed, 2-mercaptonicotinic acid (900 mg) was added, and heating was continued for 2 hours and then cooled. The solvent was concentrated under reduced pressure, and the mixture was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.35 (d, J = 8.4Hz, 1H), 8.27 (d, J = 8.4Hz, 1H), 8.03 (d, J = 2.0Hz, 1H), 7.86 (t , J=7.2 Hz, 1H), 7.59-7.68 (m, 2H), 7.45 (dd, J=8.8, 2.0 Hz, 1H), 7.06 (brs, 1H), 6.02 (m, 1H), 5.59-5.53 ( m, 1H), 5.37 (d, J = 8.4 Hz, 1H), 5.28 (d, J = 9.6 Hz, 1H), 5.02 (dd, J = 8.0, 4.0 Hz, 1H), 4.61 (t, J = 6.4) Hz,1H),4.10-4.32(m,4H),3.08-3.19(m,1H),2.44-2.56(m,1H),2.12-2.34(m,3H),1.88-2.04(m,2H), 1.70-1.82 (m, 1H), 1.58-1.64 (m, 1H), 1.44-1.54 (m, 3H), 1.24-1.42 (m, 15H). ES-LC/MS m/z 746.3 (M+H)

Compound 8 (2)

To a solution of compound 6 (2) (41.3 g, 0.067 mol) in THF (600 mL) and methanol (600 mL), water (300mL) and lithium hydroxide (1.41 g, 0.336 mol). The reaction mixture was stirred at 20 ° C overnight. The reaction solution was cooled to 5-8 ° C, and 1N hydrochloric acid solution was added to pH=3 with stirring, and concentrated to 500 mL under reduced pressure at 40 ° C, 1 L of water was added thereto, stirred, filtered, and dried to give 39 g of solid. 36.5 g of a white solid compound 8 (2) was obtained by filtration (yield: 92.4%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.30 (d, J = 8.0Hz, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.01 (d, J = 2.4Hz, 1H), 7.81 (t , J=7.2 Hz, 1H), 7.52-7.60 (m, 2H), 7.40 (dd, J=8.8, 2.0 Hz, 1H), 7.15 (brs, 1H), 6.01 (brs, 1H), 5.67 (q, J = 8.4 Hz, 1H), 5.25 (d, J = 7.6 Hz, 1H), 5.19 (t, J = 8.8 Hz, 1H), 4.86 (t, J = 7.2 Hz, 1H), 4.36-4.50 (m, 2H), 4.14 - 4.16 (m, 1H), 2.94 - 3.02 (m, 1H), 2.60 - 2.70 (m, 1H), 2.22 - 2.42 (m, 3H), 2.10 - 2.20 (m, 1H), 1.82 1.94 (m, 2H), 1.60-1.68 (m, 2H), 1.38-1.54 (4H), 1.32-1.38 (m, 10H). ES-LC/MS m/z 717.7 (M+H)

Compound of formula (II b1)(1)

To a solution of compound 8 (2) (20 g, EtOAc. Then cyclopropylsulfonamide (5.07 g, 41.85 mmol) and DBU (8.48 g, 55.78 mmol) were added and the reaction was continued for 3 h. The reaction mixture was washed with EtOAc EtOAc EtOAc EtOAc. Analytical purification (petroleum ether / acetic acid Ethyl ester = 1/1) gave 14.5 g of the compound of formula (II b1) (1) (yield: 64%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (brs, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 2.0 Hz) , 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.55-7.62 (m, 2H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 6.87 (brs, 1H), 6.08 (brs, 1H), 5.72 (dd, J=8.4, 8.8 Hz, 1H), 5.13 (d, J=7.2 Hz, 1H), 5.00 (dd, J=8.8, 9.6 Hz, 1H), 4.65-4.70 (m, 2H) ), 4.30-4.36 (m, 1H), 4.13 (dd, J = 7.2, 4.0 Hz, 1H), 2.90-3.00 (m, 1H), 2.73-2.90 (m, 2H), 2.55-2.65 (m, 1H) ), 2.30-2.37 (t, J = 8.8 Hz, 1H), 1.80-2.00 (m, 3H), 1.60-1.66 (m, 1H), 1.42-1.56 (m, 6H), 1.33-1.30 (m, 1H) ), 1.28-1.35 (m, 9H), 1.10-1.22 (m, 3H), 0.94-1.02 (1H). ES-LC/MS m/z 820.2 (M+H).

Compound 7a(1)

Synthesis of Compound 7a (1) of Example 1.

Compound of formula (II a1)(1)

Synthesis of the compound of the formula (II a1) (1) of Example 1.

Examples 3-7

Synthesis of Compounds of Formula (II a2~6)

参考WO2013/017026 A1第48页实施例24的M24Compound 1:

Reference is made to M24 of Example 24 on page 48 of WO 2013/017026 A1.

参考WO2013/017026 A1第47页实施例22的M22Compound 1':

Reference is made to M22 of Example 22 on page 47 of WO 2013/017026 A1.

为中间原料，可以制备下列化合物：According to the synthetic scheme and process conditions of the present invention, correspondingly using Compound 1 or Compound 1' as a starting material, and selecting

For intermediate materials, the following compounds can be prepared:

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). The Huh7 cells transfected with the HCV 1b replicon) were tested for the inhibitory activity of the HCV 1b replicon against the compounds of the formula (II a1) (1) and the formula (II b1) (1).

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: Add different concentrations of compound samples of formula (II a1) (1) and formula (II b1) (1) to Huh7.5.1 cells transfected with HCV replicon, set two duplicate wells for each concentration, and set no Sample control wells. 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.

The compounds of the formula (II a1) (1) and (II b1) (1) all exhibit an activity of inhibiting the HCV GT1b genotype, but the compound of the formula (II a1) (1) has a stronger activity and an EC ₅₀ value thereof. ≤0.1nM, see Table 1 for details.

Table 1 EC ₅₀ values of compounds of formula (II a1)(1) and (II b1)(1) for HCV 1b genotype replicons

Remarks: A indicates EC ₅₀ ≤ 0.1 nM; B indicates 0.1 nM < EC ₅₀ ≤ 10 nM.

Industrial applicability

The hepatitis C virus protease inhibitor of the invention has excellent anti-hepatitis C virus effect and is simple in synthesis method, and has very good industrial application prospect.

Claims (26)

a compound of the formula (I), and a pharmaceutically acceptable salt thereof,

A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₆ alkyl or C ₃ -C ₇ ring which is unsubstituted or substituted with 1 to 9 halogens or 1 to 6 Ra' An alkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with 1 to 9 halogens Or a C ₃ -C ₇ cycloalkyl group; A ₂ is N, O or a connection key; Ar is a 6- to 10-membered aryl group which is unsubstituted or substituted by 1 to 6 R ₁ or a heteroaryl group of 5 to 10 members which has 1 to 3 hetero atoms selected from N, O and S; Each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or is 1~ 3 R _m 'substituted substituents selected from the group consisting of (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ - C ₇ ) cycloalkyl, (C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ )alkyl, 6-10 membered aryl or containing 1 to 3 independently selected from N, O and S heteroatoms 5- to 10-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₆ )alkyl or (C ₃ -C ₆ ) unsubstituted or substituted with 1 to 9 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ ) optionally substituted by -O-(C ₁ -C ₆ )alkyl or -O-(C ₃ -C ₆ )cycloalkyl a cycloalkyl group, a (C ₁ -C ₆ ) alkoxy group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH ( C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ; R ₂ is a substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, which is unsubstituted or substituted by 1 to 3 R ₂ '. C ₆ -C ₁₀ aryl, (C ₆ -C ₁₀ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl)C ₁ -C ₂ alkane a C ₃ -C ₇ cycloalkenyl group, a (C ₃ -C ₇ cycloalkenyl) C ₁ -C ₂ alkyl group, having 3 to 3 units independently selected from N, O and S heteroatoms a heterocyclic group, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, having 1 to 3 independently selected from N, O And a 5- to 10-membered heteroaryl group of the S hetero atom and (containing 1 to 3 5- to 10-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ; R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₉ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be independently selected from NR _p by 1 to 3 , S or O heteroatoms are inserted, or the hydrocarbon chain may be unsubstituted or substituted by 1-9 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p and R _{q are} independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; R ₄ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl which is unsubstituted or substituted by 1 to 3 R ₄ ' a 3- to 7-membered heterocyclic group independently selected from N, O and S heteroatoms, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (C ₃ -C ₇ Cycloalkenyl) C ₁ -C ₄ alkyl, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₄ alkyl, C ₂ -C ₆ alkanoyl, (C ₁ -C ₄ alkyl) _1-2 (C ₃ -C ₇ )cycloalkyl or (C ₁ -C ₆ alkyl) _1-2 amino; R ₄ ' is selected from the group consisting of Substituents: halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: optionally -O-(C ₁ -C ₆ Alkyl or -O-(C ₃ -C ₆ )cycloalkyl substituted (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₆ )alkoxy a 6- to 10-membered aryl group having 1 to 3 5- to 10-membered heteroaryl groups independently selected from N, O and S heteroatoms, -NH(C ₁ -C ₆ )alkyl, and -N((C) ₁ -C ₆ )alkyl) ₂ . The compound according to claim 1, wherein Ar is a 6-membered aryl group substituted or unsubstituted with 1 to 5 R ₁ or 5 to 6 members having 1 to 3 selected from N, O and S a heteroaryl group of an atom; R ₃ and R _{4 are} covalently bonded to form a saturated hydrocarbon chain of C ₅ , and the general formula (I) is a general formula (II a) shown below,

Wherein, when Z ₁ is a linking bond, Z _{2 is} selected from the group consisting of O, S and N(R ₁ ), and Z _{3 is} selected from N and C(R ₁ ); When Z ₃ is a linkage, Z _{1 is} selected from O, S and N(R ₁ ), and Z _{2 is} selected from N and C(R ₁ ); When Z ₃ is N or C(R ₁ ), Z ₁ and Z _{2 are} independently selected from N and C(R ₁ ). The compound according to claim 1 or 2, wherein A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b O, C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or are unsubstituted or substituted by 1 to 6 halogens or 1 to 4 Ra' a C ₁ -C ₄ alkyl group or a C ₃ -C ₆ cycloalkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or unsubstituted or a C ₁ -C ₄ alkyl group or a C ₃ -C ₆ cycloalkyl group substituted by 1 to 6 halogens; Preferably, A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C( R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₂ alkyl group or C ₅ - which is unsubstituted or substituted by 1 to 3 halogens or 1 to 2 Ra' C ₆ cycloalkyl; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or C ₁ -C which is unsubstituted or substituted by 1 to 3 halogens ₂ alkyl or C ₅ -C ₆ cycloalkyl. A compound as claimed in claim 1 or 2, characterized in that: Each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or is 1~ 2 R _m 'substituted substituents selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₃ - C ₆ ) cycloalkyl, (C ₃ -C ₆ cycloalkyl)(C ₁ -C ₄ )alkyl, 6-8 membered aryl or containing 1 to 3 independently selected from N, O and S heteroatoms 5- to 8-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₄ )alkyl or (C ₃ -C ₆ ) unsubstituted or substituted with 1 to 6 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 6 halogen, amino, hydroxy or cyano groups: (C ₁ -C ₄ )alkyl, (C ₃ -C ₆ ) optionally substituted by -O-(C ₁ -C ₄ )alkyl or -O-(C ₃ -C ₆ )cycloalkyl a cycloalkyl group, a (C ₁ -C ₄ ) alkoxy group, a 6- to 8-membered aryl group, a 5- to 8-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH ( C ₁ -C ₄ )alkyl and -N((C ₁ -C ₄ )alkyl) ₂ ; Preferably, each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or a substituent selected from the group consisting of (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, (C ₅ ) substituted with 1 R _m ' -C ₆ ) cycloalkyl, (C ₅ -C ₆ cycloalkyl)(C ₁ -C ₂ )alkyl, 6-membered aryl or containing 1 to 2 independently selected from N, O and S heteroatoms 5- to 6-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₂ )alkyl or (C ₅ -C ₆ ) unsubstituted or substituted with 1 to 3 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 3 halogen, amino, hydroxy or cyano groups: optionally substituted -O- (C ₁ -C ₂₎ alkyl, or -O- (C ₅ -C ₆₎ cycloalkyl substituted (C ₁ -C ₂₎ alkyl, (C ₅ -C ₆₎ cycloalkyl An alkyl group, a (C ₁ -C ₂ ) alkoxy group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH(C ₁ - C ₂ ) alkyl and -N((C ₁ -C ₂ )alkyl) ₂ . A compound as claimed in claim 1 or 2, characterized in that: R ₂ is a substituent selected from the group consisting of C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, which is unsubstituted or substituted by 1 to 2 R ₂ '. C ₆ -C ₈ aryl, (C ₆ -C ₈ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ cycloalkyl)C ₁ -C ₂ alkane a C ₃ -C ₆ cycloalkenyl group, a (C ₃ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl group, having 3 to 3 units independently selected from N, O and S heteroatoms a heterocyclic group, (containing 1 to 3 3- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, having 1 to 3 independently selected from N, O And a 5- to 8-membered heteroaryl group of the S hetero atom and (containing 1 to 3 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' a substituent selected from the group consisting of (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkenyl, unsubstituted or substituted with amino, hydroxy, cyano or 1 to 6 halogen, (C _2- C ₄ ) alkynyl, (C ₁ -C ₄ )alkoxy, -NH(C ₁ -C ₄ )alkyl and -N((C ₁ -C ₄ )alkyl) ₂ ; Preferably, R ₂ is a substituent selected from the group consisting of C ₁ -C ₂ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, unsubstituted or substituted by 1 R ₂ ' , C ₆ aryl, (C ₆ aryl) C ₁ -C ₂ alkyl, C ₅ -C ₆ cycloalkyl, (C ₅ -C ₆ cycloalkyl)C ₁ -C ₂ alkyl, C ₅ - C ₆ cycloalkenyl, (C ₅ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl, having 1 to 2 5- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms, a 5- to 6-membered heterocyclic)C ₁ -C ₂ alkyl group having 1 to 2 independently selected from N, O and S heteroatoms, containing 1 to 2 independently selected from N, O and S heteroatoms. a 5- to 6-membered heteroaryl group and (containing 1 to 2 5- to 6-membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' is selected from the group consisting of Substituent: (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen Alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ . A compound as claimed in claim 1 wherein: R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₇ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be independently selected from NR _p by 1 to 3 , S or O heteroatoms are inserted, or the hydrocarbon chain may be unsubstituted or substituted by 1 to 6 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p and R _{q are} independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; Preferably, R ₃ is hydrogen; or R ₃ and R _{4 are} covalently bonded to form a C ₅ -C ₆ saturated or unsaturated hydrocarbon chain which may not be inserted by a hetero atom or may be independently selected from 1 to 2 Inserted from NR _p , S or O heteroatoms, or the hydrocarbon chain may be unsubstituted or substituted by 1 to 3 halogens, OR _p , SR _p or -NR _p R _q , wherein R _p and R _{q are} independently hydrogen , C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl. A compound as claimed in claim 1 wherein: R ₄ is C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl which is unsubstituted or substituted by 1 to 2 R ₄ ' a 3- to 6-membered heterocyclic group independently selected from N, O and S heteroatoms, (C ₃ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl, (C ₃ -C ₆ Cycloalkenyl) C ₁ -C ₄ alkyl, (containing 1 to 3 3- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₄ alkyl, C ₂ -C ₄ alkanoyl, (C ₁ -C ₄ alkyl) _1-2 (C ₃ -C ₆₎ cycloalkyl or (C ₁ -C ₄ alkyl) _1-2 amino; R ₄ 'is selected from the group consisting of Substituents: halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 6 halogen, amino, hydroxy or cyano groups: optionally -O-(C ₁ -C ₄ Alkyl or -O-(C ₃ -C ₆ )cycloalkyl substituted (C ₁ -C ₄ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₄ )alkoxy a 6-8 membered aryl group having 1 to 3 5- to 8-membered heteroaryl groups independently selected from N, O and S heteroatoms, -NH(C ₁ -C ₄ )alkyl, and -N((C) ₁ -C ₄ )alkyl) ₂ ; Preferably, R ₄ is C ₁ -C ₂ alkyl, C ₂ -C ₃ alkenyl, C ₅ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkene which is unsubstituted or substituted by 1 R ₄ ' a 5- to 6-membered heterocyclic group independently selected from N, O and S heteroatoms, (C ₅ -C ₆ cycloalkyl) C ₁ -C ₂ alkyl, (C ₅ -C ₆ cycloalkenyl) C ₁ -C ₂ alkyl, (containing 1 to 2 5- to 6-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, C ₂ - C ₃ alkanoyl, (C ₁ -C ₂ alkyl) _1-2 (C ₅ -C ₆ )cycloalkyl or (C ₁ -C ₂ alkyl) _1-2 amino; R ₄ ' is selected from the group consisting of Substituents: halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 3 halogen, amino, hydroxy or cyano groups: optionally -O-(C ₁ -C ₂ ) alkyl or -O-(C ₅ -C ₆ )cycloalkyl substituted (C ₁ -C ₂ )alkyl, (C ₅ -C ₆ )cycloalkyl, (C ₁ -C ₂ )alkoxy a 6-membered aryl group having 1 to 2 5- to 6-membered heteroaryl groups independently selected from N, O and S heteroatoms, -NH(C ₁ -C ₂ )alkyl, and -N((C _{1 )} -C ₂ )alkyl) ₂ . A compound according to claim 1, wherein the compound is one of the following compounds:

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. a method of synthesizing a compound of the formula (II),

Where R _y is

Or O(CH ₃ ) ₃ ; When Z ₁ is a linkage, Z _{2 is} selected from O, S and N(R ₁ ), and Z _{3 is} selected from N and C(R ₁ ); When Z ₃ is a linkage, Z _{1 is} selected from O, S and N(R ₁ ), and Z _{2 is} selected from N and C(R ₁ ); When Z ₃ is N or C(R ₁ ), Z ₁ and Z _{2 are} independently selected from N and C(R ₁ ); A ₁ is O, S, C(R _a R _b ), N(R _a ), OC(R _a R _b ), C(R _a R _b )O, C(R _a R _b )C(R _a R _b ), wherein R _a and R _{b are} independently hydrogen or a C ₁ -C ₆ alkyl or C ₃ -C ₇ ring which is unsubstituted or substituted with 1 to 9 halogens or 1 to 6 Ra' An alkyl group; Ra' is a substituent selected from the group consisting of OR _c , SR _c and N(R _c ) ₂ wherein R _c is H or a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with 1 to 9 halogens Or a C ₃ -C ₇ cycloalkyl group; A ₂ is N, O or a connection key; Each R _{1 is} independently hydrogen, halogen, cyano or -YR _m , Y is a linkage, O, S, SO, SO ₂ or NR _n ; R _m is hydrogen, or is unsubstituted or is 1~ 3 R _m 'substituted substituents selected from the group consisting of (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ - C ₇ ) cycloalkyl, (C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ )alkyl, 6-10 membered aryl or containing 1 to 3 independently selected from N, O and S heteroatoms 5- to 10-membered heteroaryl; R _n is hydrogen, or (C ₁ -C ₆ )alkyl or (C ₃ -C ₆ ) unsubstituted or substituted with 1 to 9 halogen, amino, hydroxy or cyano groups a cycloalkyl group; R _m ' is selected from the group consisting of halogen, amino, hydroxy or cyano, or the following groups which are unsubstituted or substituted by 1 to 9 halogen, amino, hydroxy or cyano groups: (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ ) optionally substituted by -O-(C ₁ -C ₆ )alkyl or -O-(C ₃ -C ₆ )cycloalkyl a cycloalkyl group, a (C ₁ -C ₆ ) alkoxy group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group having 1 to 3 independently selected from N, O and S heteroatoms, -NH ( C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ; R ₂ is a substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, which is unsubstituted or substituted by 1 to 3 R ₂ '. C ₆ -C ₁₀ aryl, (C ₆ -C ₁₀ aryl)C ₁ -C ₂ alkyl, C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl)C ₁ -C ₂ alkane a C ₃ -C ₇ cycloalkenyl group, a (C ₃ -C ₇ cycloalkenyl) C ₁ -C ₂ alkyl group, having 3 to 3 units independently selected from N, O and S heteroatoms a heterocyclic group, (containing 1 to 3 3- to 7-membered heterocyclic groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl, having 1 to 3 independently selected from N, O And a 5- to 10-membered heteroaryl group of the S hetero atom and (containing 5 to 10 membered heteroaryl groups independently selected from N, O and S heteroatoms) C ₁ -C ₂ alkyl; R ₂ ' a substituent selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, unsubstituted or substituted by amino, hydroxy, cyano or 1-9 halogen, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ; The method comprises the following steps: Step 1, under the action of an organometallic base or sodium hydride, Compound 1 and Boc-L-4-hydroxyproline in a dimethyl sulfoxide organic solvent were stirred to obtain a compound 2;

Step 2, compound 2 and compound under the action of a condensing agent and an organic base

The compound 3 is obtained by stirring in an organic solvent of dichloromethane, tetrahydrofuran or dimethylformamide, wherein R _x is NHSO ₂ A ₂ R ₂ or OCH ₂ CH ₃ ;

Step 3, the compound 3 and the deBoc reagent in dichloromethane and / or dioxane organic solvent were stirred to obtain the compound 4;

Step 4, under the action of a condensing agent and an organic base, compound 4 and (S)-2-N-Boc 8-ene-n-fluorene amino acid in a dichloromethane organic solvent stirred to obtain a compound 5;

Step 5, under the protection of an inert gas, the compound 5 is reacted with the Zhan catalyst in an organic solvent of toluene, and then the reaction is terminated by adding 2-mercaptonicotinic acid to obtain the compound 6 or the compound of the formula (II b1).

The method of claim 10 wherein when R _x is NHSO ₂ A ₂ R ₂ , proceeding to the following steps 6 and 7: Step 6, the compound of the formula (II b1) and the de Boc reagent are hydrolyzed by stirring in dichloromethane and/or a dioxane organic solvent to obtain a compound 7;

Step seven, under the action of an organic base, compound 7 and

The compound of the formula (II a1) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

The method of claim 10 wherein when R _x is OCH ₂ CH ₃ , compound 6 is subjected to the following steps a and b: Step a, under the action of an inorganic base, compound 6 is stirred and hydrolyzed in a mixed solvent of water, tetrahydrofuran and methanol to form compound 8;

Step b, first stirring the compound 8 and N,N'-carbonyldiimidazole in an organic solvent of dichloromethane, and then adding H ₂ NSO ₂ A ₂ R ₂ and an organic base to continue the reaction to obtain a compound of the formula (II b1) ,

The method of claim 12 wherein the compound of formula (II b1) obtained in step b proceeds to step six and step seven: Step 6, the compound of the formula (II b1) and the de Boc reagent are hydrolyzed by stirring in dichloromethane and/or a dioxane organic solvent to obtain a compound 7;

Step seven, under the action of an organic base, compound 7 and

The compound of the formula (II a1) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

The method of claim 10, wherein when Rx is OCH ₂ CH ₃ , Compound 6 proceeds to step six' and step seven': Step 6 ', compound 6 and de Boc reagent in dichloromethane and / or dioxane organic solvent by stirring hydrolysis reaction to obtain compound 9;

Step VII', under the action of an organic base, compound 9 and

The compound 10 is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

Compound 10 proceeds to step a' and step b', Step a', under the action of an inorganic base, the compound 10 is stirred and hydrolyzed in a mixed solvent of water, tetrahydrofuran and methanol to form a compound 11;

Step b', after reacting the compound 11 with N,N'-carbonyldiimidazole in an organic solvent of dichloromethane, the reaction is further carried out by adding H ₂ NSO ₂ A ₂ R ₂ and an organic base to obtain the formula (II a1). Compound,

The method according to claim 10 or 12, wherein the compound of the formula (II b1) is reacted with hydrogen under the catalysis of a palladium-carbon catalyst to obtain a compound of the formula (II b2),

The method of claim 11, 13 or 14, wherein the compound of formula (II a1) Reacting with hydrogen under the catalysis of a palladium-carbon catalyst to obtain a compound of the formula (II a2),

The method of claim 15 wherein the compound of formula (II b2) continues with the following reaction: The compound of the formula (II b2) is reacted with a de Boc reagent in dichloromethane and/or a dioxane organic solvent to obtain a compound 7';

Under the action of an organic base, compound 7' and

The compound of the formula (II a2) is obtained by stirring in an organic solvent of N,N-dimethylformamide, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid further contains a condensing agent;

The method according to any one of claims 10 to 17, wherein the organometallic base is potassium t-butoxide and/or sodium t-butoxide, and the organic base is diisopropylethylamine. Triethylamine and/or 1,8-diazabicyclo[5.4.0]undec-7-ene, the deBoc reagent is hydrogen chloride, p-toluenesulfonic acid or trifluoroacetic acid. The method according to claim 12 or 14, wherein the inorganic base is LiOH, NaOH and/or KOH. The method according to any one of claims 10 to 17, wherein said condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetrazole. Pyruvate hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluron hexafluorophosphate, Dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide and/or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, The inert gas is nitrogen. The method of claim 10 wherein: In the first step, the organometallic base is slowly added to the organic solvent of the dimethyl sulfoxide containing the compound 1 and Boc-L-4-hydroxyproline in an ice bath, and the stirring is continued for 5 to 30 minutes. Then, the reaction is further stirred at room temperature for 10 to 50 minutes to obtain a compound 2, wherein the organometallic base is potassium t-butoxide and/or sodium t-butoxide; In the second step, the condensing agent and the compound are added to the solution containing the compound 2 in dichloromethane, tetrahydrofuran or dimethylformamide under stirring in an ice bath.

And an organic base, followed by stirring at room temperature overnight to obtain compound 3, wherein R _x is NHSO ₂ A ₂ R ₂ or OCH ₂ CH ₃ , and the condensing agent is 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, the organic base is diisopropylethylamine; In the third step, the dioxane solution of the compound 3 is heated to 65 to 75 ° C, and then p-toluenesulfonic acid is added, and the reaction is further stirred for 3 to 6 hours to obtain a compound 4a; or a solution of the compound 3 in dichloromethane. Adding a solution of HCl to dioxane, stirring at room temperature overnight to obtain compound 4b;

Step 4 is specifically: adding a compound 4 and an organic base to a dichloromethane solution containing (S)-2-N-Boc 8-ene-n-amino acid and a condensing agent under stirring in an ice bath, and stirring at room temperature overnight. Obtaining compound 5, wherein the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, the organic base Is diisopropylethylamine; Step 5 specifically, after degassing the toluene solution containing the compound 5, heating under an inert gas, stirring to 64 to 68 ° C, adding a Zhan catalyst for 1.5 to 3 hours, and then adding 2-mercaptonicotinic acid to terminate the reaction 1.5 to Compound 6 or a compound of formula (II b1) is obtained in 3 hours, and the inert gas is nitrogen. The method of claim 21 wherein when R _x is NHSO ₂ A ₂ R ₂ , the following steps 6 and 7 are continued: The step 6 is specifically, adding a solution of hydrogen chloride in dioxane solution to the dichloromethane solution containing the compound of the formula (II b1), stirring at room temperature for 2 to 5 hours to obtain a compound 7a;

Step VII, adding to the solution of the compound 7a in N,N-dimethylformamide

And the organic base is stirred at room temperature overnight to obtain a compound of the formula (II a1), wherein the organic base is diisopropylethylamine, wherein X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid is further added. a condensing agent, wherein the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate;

The method of claim 22 wherein when R _x is OCH ₂ CH ₃ , compound 6 is subjected to the following steps a and b: In step a, an inorganic lye is added to a solution of the compound 6 in tetrahydrofuran and methanol, and stirred at 18 to 22 ° C overnight to form a compound 8, wherein the inorganic lye is a solution of LiOH, NaOH or KOH;

Step b, compound 8 and N,N'-carbonyldiimidazole are stirred at room temperature overnight in dichloromethane solvent, then H ₂ NSO ₂ A ₂ R ₂ and an organic base are added to carry out the condensation reaction for 2 to 5 hours to obtain the formula (II b1). a compound, the organic base being 1,8-diazabicyclo[5.4.0]undec-7-ene,

The method according to claim 23, wherein the obtained compound of the formula (II b1) is further subjected to the steps 6 and 7 to obtain a compound of the formula (II a1). Step 6, adding a solution of hydrochloric acid in dioxane to the dichloromethane solution containing the compound of the formula (II b1), stirring at room temperature for 2 to 5 hours to obtain a compound 7a;

Step VII, adding to the solution of the compound 7a in N,N-dimethylformamide

And the organic base is stirred at room temperature overnight to obtain a compound of the formula (II a1), wherein the organic base is diisopropylethylamine, X is a halogen or a hydroxyl group, and when X is a hydroxyl group, the reaction liquid is further added to the reaction liquid. a mixture, the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

The method according to claim 21 or 23, wherein a 10% palladium-carbon catalyst is added to a methanol solution of the compound of the formula (IIb1), replaced with hydrogen, and the reaction is stirred for several hours to obtain a compound of the formula (IIb2). The method according to claim 22 or 24, characterized in that a 10% palladium-carbon catalyst is added to a methanol solution of the compound of the formula (IIa1), replaced with hydrogen, and the reaction is stirred for several hours to obtain a compound of the formula (IIa2).