WO2014194826A1

WO2014194826A1 - Three-circle fused-heterocycle nucleoside phosphoramidate compound, preparation method therefor, and application thereof

Info

Publication number: WO2014194826A1
Application number: PCT/CN2014/079165
Authority: WO
Inventors: 王勇; 赵立文; 毕胜; 高毅平; 王德忠; 陈宏雁; 刘阳; 张仓; 张文萍; 郭啸; 南阳
Original assignee: 南京圣和药业有限公司
Priority date: 2013-06-06
Filing date: 2014-06-04
Publication date: 2014-12-11
Also published as: CN104231023B; CN104231023A

Abstract

The present invention provides a three-circle fused-heterocycle nucleoside phosphoramidate compound, a preparation method therefor, a composition containing the fused-heterocycle nucleoside phosphoramidate compound, and an application of the compound or composition serving as a medicine for curing the virus-infectious disease, and especially, an application of the compound or composition serving as a medicine for curing viral hepatitis.

Description

Tricyclic fused heterocyclic nucleoside phosphoramidate compound, preparation method and application thereof

Technical field

The invention belongs to the field of medical chemistry, and particularly relates to a class of tricyclic fused heterocyclic nucleoside phosphoramidate compounds, a preparation method thereof, a composition containing the nucleoside phosphoramidate compound, and the compound or composition as a virus infection The use of a therapeutic drug for sexually transmitted diseases, particularly as a therapeutic drug for viral hepatitis. Background technique

Hepatitis C virus (HCV) is the leading cause of most non-A, non-B hepatitis. Hepatitis C virus infection is a major health problem leading to chronic liver diseases such as cirrhosis and liver cancer. According to the World Health Organization, there are more than 200 million infected people in the world. Once infected, only about 20% of people can get rid of the virus, and the rest will carry HCV.

HCV is a virus belonging to the Flaviviridae family and is a enveloped positive-strand RNA virus in the flavivirus family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and contains a single open reading frame (ORF) encoding a large polyprotein of approximately 3000 amino acids.

The genetic structure of HCV and the other two genera of the Flaviviridae, prion and flavivirus, are similar. Currently, standard methods of treating HCV infection are interferon and a combination of interferon and ribavirin. However, only 50% of the responders responded to this method, and interferons had significant side effects such as pan-like symptoms, weight loss, and fatigue, while interferon and ribavirin combination therapy produced considerable Side effects, including hemolysis, anemia, and fatigue.

The development of novel anti-HCV drugs has been slow for a long time due to the lack of suitable cell models for in vitro viral replication. Until 1999, Lohmann established a subgenomic replication model (replicon) that can replicate autonomously at high levels in liver cancer cells. This model is a selective bicistronic subgenomic HCV RNA replication subsystem that is recognized as HCV RNA. In vitro replication model research has reached a milestone in breakthrough progress. The replicon is capable of high level of autonomous replication in the human hepatoma cell line Huh7. Studies have shown that replicon replication in cells has no significant effect on host cell growth and metabolism, and high-level replication is associated with adaptive mutations in the viral genome and host cell tolerance. These findings laid the foundation for the study of selective HCV full-sequence genomic replicons. Summary of the invention

An object of the present invention is to provide a tricyclic fused heterocyclic nucleoside phosphoramidate compound represented by the formula (I) for use in the treatment and/or prevention of HCV infection, a stereoisomer thereof, a prodrug, and a pharmaceutically Acceptable salts, hydrates, solvates,

P* represents a chiral phosphorus atom,

Wherein (1) is selected from the group consisting of H and an indenyl group, which is optionally selected from one or more of an indenyl group, an anthracenyloxy group, a phosphonium group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a decyl group, an amino group. An acyl, guanidinoyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl group;

(2) R _{2 is} selected from the group consisting of H, anthracenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more fluorenyl, decyloxy, halogen, hydroxy, amino, monodecylamino, Bis-amino, aryl or heteroaryl substituted;

(3) R ₃ is absent or selected from decyl, alkenyl, alkynyl, decyloxy, halogen, halodecyl, decylamino, decylsulfonyl, decylsulfonylamino, sulfamoyl Sulfhydryl, 3⁄4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino, ester, _CN, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aryl base;

(4) D is selected from _ (CR _al R _a 0-, - (CR _al RS -, _S0_, - S0 ₂ -, - CO-, - N (R _b ) -, - N (R _b ) - CO- , -CO ^) -, R _al wherein said each is hydrogen, alkyl with halogen, alkyl with haloalkyl, alkenyl or haloalkenyl, or R _al, they are attached to form a ring alkyl with C together with The m is 0 or 1, and the R _b is absent, hydrogen, sulfhydryl, decylsulfonyl or fluorenylcarbonyl, and each of the Rd, each of which is hydrogen, halogen, fluorenyl, halogenated fluorene group, alkenyl or haloalkenyl, or when Rd, R. ₂ are alkyl with time, C with Rd, R. ₂ constituting the embankment cycloalkyl group;

(5) D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0_, -S0 ₂ -, -CO-, -N (R _d ) -, - (CH) „-, wherein R _d is absent, hydrogen, Indenyl or halogenated fluorenyl, said n is 0, 1 or 2, said _ (CH) „ - optionally decyloxy, hydrazino, 3⁄4, hydroxy, amino, nitro, cyano , a mercapto acyl group, an aminoacyl group, a nonylamino group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;

(6) G and G ¹ are each -N- or -CH-;

(7) " = " is a single or double key, two of which are "one", or one "=" is a single key and the other is a double key;

(8) Ring T is selected from:

a, an aromatic ring or a heteroaryl ring, which may be substituted with an indenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a halogen, a halogenated fluorenyl group, a halogenated fluorenyl group, a hydroxy group, a nitro group, an amino group, a monodecylamino group, a bis-indolyl group, a decyl acyl group, an aminoacyl group, a decylamino group, an acylamino group, a _CN group, an aryl group or a heteroaryl group;

b. a cyclic anthracene or a heterocyclic anthracene, said cycloteronyl or heterocyclic anthracene may be substituted by R ₄ , wherein _3⁄4 is fluorenyl, alkenyl, alkynyl, decyloxy, halogen, halo fluorenyl , halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, nonylamino, acylamino, _CN, aryl or heteroaryl. Another object of the present invention is to provide a nucleoside phosphoramidate compound of the formula (I) of the present invention, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof. Methods.

A further object of the present invention is to provide a nucleoside phosphoramidate compound, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate or a solvate thereof and a medicament of the formula (I) of the present invention. An acceptable carrier composition and a nucleoside phosphoramidate compound of the formula (I) of the present invention, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate or a solvate thereof Another antiviral composition.

It is still another object of the present invention to provide a nucleoside phosphoramidate compound of the formula (I) of the present invention, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate thereof and/or Or a method for preventing hepatitis C virus infection and a nucleoside phosphoramidate compound of the formula (I) of the present invention and a stereoisomer, salt, hydrate, solvate or crystal thereof thereof for preparation for treatment and/or Prevention of hepatitis C The application of drugs for inflammation of the virus.

A further object of the present invention is to provide a method of inhibiting RNA-dependent RNA viral polymerase, particularly for inhibiting HCV NS5B polymerase.

It is also an object of the present invention to provide use in the treatment of RNA dependent RNA viral replication, particularly in the treatment of HCV replication.

Another object of the invention is also to provide use in the treatment of RNA dependent RNA viral infections, particularly in the treatment of HCV infection.

In view of the above object, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound, a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystallization thereof, The compound is as shown in the general formula (I):

P* represents a chiral phosphorus atom,

among them,

(1) selected from the group consisting of H and fluorenyl, optionally substituted by one or more fluorenyl, decyloxy, decylamino, halogen, hydroxy, amino, nitro, cyano, decanoyl, aminoacyl, Substituted with amidinoyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl;

(2) R _{2 is} selected from the group consisting of H, decyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more fluorenyl, decyloxy, halogen, hydroxy, amino, monodecylamino, Bis-amino, aryl or heteroaryl substituted;

(4) D is selected from _(CR _al R _a 0-, -(CH S -, -S0-, - S0 ₂ -, - CO-, - N(R _b )-, - N(R _b )- CO -, -CO ^)-, wherein R _al , each of which is hydrogen, fluorenyl, halogen, halodecyl, alkenyl or haloalkenyl, or R _al , together with the C to which they are attached, constitutes a ring Further, the m is 0 or 1, and the R _b is a non-existent hydrogen, a decyl group, a decylsulfonyl group or a fluorenylcarbonyl group, and each of the Rd, each of which is hydrogen, a halogen, a fluorenyl group, or a halogenated group. embankment, alkenyl or haloalkenyl, or when Rd, R. ₂ are alkyl with time, C may be, R. ₂ constituting the embankment cycloalkyl group Rd;

(5) D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0_, -S0 ₂ -, -CO-, -N(R _d ) -, - (CH) „-, wherein R _d is absent, hydrogen, Indenyl or halogenated fluorenyl, said n is 0, 1 or 2, said _(CH) „ - optionally decyloxy, hydrazino, 3⁄4, hydroxy, amino, nitro, cyano , a mercapto acyl group, an aminoacyl group, a nonylamino group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;

(6) G and G ¹ are each -N- or -CH-;

(7) "―" is a single key or a double key, two of which are "^" are single keys, or one "^" is a single Key, and the other is a double bond; and

(8) Ring T is selected from:

b. a cyclic anthracene or a heterocyclic anthracene, said cyclononan or heterocyclic anthracene may be substituted by R ₄ , wherein _3⁄4 is a fluorenyl, alkenyl, alkynyl, decyloxy, halogen, halogenated fluorenyl group , halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, nonylamino, acylamino, _CN, aryl or heteroaryl.

In some embodiments of the first aspect, the present invention provides a nucleoside phosphoramidate compound of the above formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate thereof Or crystallized,

D is selected from _ (CR _al R _a 0-, - (CR _al R _a2 ) „S -, -SO-, - S0 ₂ -, - CO-, - N (R _b ) -, - N (R _b ) - CO-, -CO -, wherein said IL, each of which is hydrogen, fluorenyl, halogen, halogenated d- ₆ fluorenyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl, or R _al And R _a2 together with the C to which they are attached constitute a C ₃ — _s ring fluorenyl group, said m is 0 or 1, said R _b being absent, hydrogen, d- ₆ fluorenyl, d- ₆ fluorenyl sulfonate An acyl group or a d- ₆ fluorenylcarbonyl group, each of which is hydrogen, halogen, d- ₆ fluorenyl, halogenated d- ₆ fluorenyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl, or when Rd, R. ₂ are alkyl with, C with Rd, ϋ ₂ configuration ₍₃ - ₈ cycloalkyl group embankment;

D ^{1 is} selected from the group consisting of oxygen, sulfur, _S0-, -S0 ₂ -, -CO-, -N (R _d ) -, _ (CH) „, wherein R _d is absent, hydrogen, d- ₆ Indenyl, halo d- ₆ fluorenyl, said n is 0, 1 or 2, said _ (CH) „ - optionally by (^ ₆ methoxy, d- ₆垸 amino, halogen, hydroxy Or an amino group, a nitro group, a cyano group, a d- ₆ fluorenyl group, an amino acyl group, a ( _-6垸 amino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group; and the ring T is selected from the group consisting of:

a, . An aromatic or heteroaryl ring, which may be substituted by R ₄ , wherein is d fluorenyl, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, d- ₆ decyloxy, halogen , halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino, mono ₆垸 amino, bis ₆垸 amino, d- ₆ decyl acyl, amino acyl, d- ₆ Amidinoyl, acylamino, _CN, aryl or heteroaryl;

b, . a cyclic anthracene or a heterocyclic anthracene, said cycloteronium or heterocycloalkyl hydrocarbon may be substituted by R ₄ , wherein _3⁄4 is ( _-6 fluorenyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, d - ₆ methoxy, halogen, halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino, mono- ₆垸 amino, bis- ₆垸 amino, d- ₆ decanoyl , aminoacyl, nonylacyl, acylamino, -CN, aryl or heteroaryl.

In still other embodiments of the first aspect, the present invention provides a nucleoside phosphoramidate compound of the above formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate Object or crystal, of which

3⁄4 is selected from the group consisting of 11 and ( ₆ fluorenyl), optionally substituted by one or more d- ₆ fluorenyl, d- ₆ methoxy, d- ₆垸amino, halogen, hydroxy, amino, nitro, a cyano group, a ( _-6- ylhydryl acyl group, an aminoacyl group, a d- ₆ hydrazinoyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;

Selected from H, d- ₆ fluorenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more d- ₆ fluorenyl, d- ₆ methoxy, halogen, hydroxy, amino, singly (^- ₆垸 amino, bis^ ₆垸 amino, aryl or heteroaryl substituted; and

Or absent, or selected from d- ₆ fluorenyl, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, d- ₆ methoxy, halogen, halogenated d- ₆ fluorenyl, d- ₆ decylamino , D- embankment ₆ alkylsulfonyl group, a sulfonylamino group D- embankment _6, sulfamoyl group D- embankment _6, halo (- embankment ₆ alkoxy, hydroxy, nitro, amino, mono (^ ₆ amino embankment, Bis(^- ₆垸amino, amide, ester , _CN C ₃ — _s cyclodecyl, C ₃ — _s heterocycloalkyl, aryl, heteroaryl, aryl (^ ₆ fluorenyl).

(1) selected from the group consisting of 11 and ₆ fluorenyl, optionally substituted by one or more d- ₆ methoxy, d- ₆垸amino, halogen, hydroxy, amino, nitro, cyano, ( ₆ mercaptoacyl, aminoacyl, d- ₆ acylamino, sulfonyl, sulfinyl, decyl, aryl or heteroaryl;

(2) R _{2 is} selected from the group consisting of H d- ₆ fluorenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more ( _-6 methoxy, halogen, hydroxy, amino, mono d — ₆垸 amino, double d- ₆垸 amino, aryl or heteroaryl substituted;

(3) R ₃ is absent or selected from d- ₆ fluorenyl, d- ₆ decyloxy, halogen, halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino , ₆垸 amino group, bis ₆垸 amino group, amide group, ester group, _CN ( ₃ - ₈ cyclodecyl group, hetero C ₃ - _s cyclodecyl group, aryl group, heteroaryl group, aryl d- ₆ fluorenyl group ;

(4) D is selected from _(CR _al R _a 0- -(CH S - -S0- - S0 ₂ - -CO- - N(R _b )- - N(R _b )- CO- -CO -, wherein Each of said ILs is hydrogen, fluorenyl, halogen, halogenated d- ₆ fluorenyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl, or R _al R _a2 together with the C to which they are attached constitutes C ₃ — _s ring fluorenyl, said m is 0 or 1, said R _b is absent, hydrogen, fluorenyl, decylsulfonyl or fluorenylcarbonyl, said Rd R. ₂ each being hydrogen, Halogen, decyl, alkenyl or haloalkenyl, or when Rd R. ₂ is a fluorenyl group, C may form a cyclodecyl group with R _cl ;

(5) D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0_ - S0 ₂ - -CO-, -N(R _d ) - - (CH) „-, said R _d is absent, hydrogen, d— ₆垸Or a halogenated d- ₆ fluorenyl group, said n being 0 1 or 2, said _(CH) „ optionally being d- ₆ methoxy, d- ₆垸amino, halogen, hydroxy, amino , nitro, cyano, d- ₆ decyl acyl, amino acyl, ( _-6垸 aminoacyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl substituted;

(6) GG ^{1 is} each -N- or -CH-;

(7) " = " is a single or double key, two of which are "one", or one "=" is a single key, and the other is a double key, and

a, when G is -CH -, and G is connected to G ¹ "" is a double bond, D is connected to G" is a single bond;

b. When G is -CH - -N - G ¹ is -N-, "" of G is connected to G ¹ as a single bond, and D is connected to G as a single bond; only when G is -CH - G ¹ is -N -, and when D is -N-, G is connected to G ¹ as a single bond, and D is connected to G as a double bond;

c. When G is NG ¹ is -CH-, G is connected to G ¹ as a single bond, and D is connected to G as a single bond;

(8) Ring T is selected from:

a, five- and six-membered aromatic or heteroaryl rings, said five- and six-membered aromatic or heteroaryl rings may be substituted by 3⁄4, wherein are fluorenyl, alkenyl, alkynyl, decyloxy, halogen, Halogenated fluorenyl, halodecyloxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, decylamino, acylamino, _CN, aryl or heteroaryl;

b C ₃ — _s cyclohydrocarbon or heterocyclic anthracene, said cycloteronium or heterocycloalkyl hydrocarbon may be substituted by R ₄ , wherein _3⁄4 is d- ₆ fluorenyl, alkenyl, alkynyl, decyloxy, Halogen, halodecyl, halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, hydrazinoyl, acylamino, _CN, aryl or heteroaryl .

In some preferred embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, Solvent Object or crystal, of which

3⁄4 is selected from the group consisting of H and d- ₆ fluorenyl;

Selected from ( _-6焼, ^3⁄4;

Or absent, or selected from d- ₆ fluorenyl, d- ₆ methoxy, fluoro, chloro, bromo, halogenated d- ₆ fluorenyl, halogenated (^ _-6 methoxy, hydroxy, nitro, amino , ( _{6 6} amino group, bis (^- ₆垸 amino group, acylamino group, ester group,

-CN, C ₃ - ₆ cyclodecyl, C ₃ - ₆ heterocycloalkyl, aryl, heteroaryl, aryl fluorenyl;

D is selected from _(CR _al R _a 0-, - (CR _al R _a2 ) „S -, -SO-, - S0 ₂ -, - CO-, - N(R _b )-, - N(R _b ) - CO-, -CO ^)-, wherein said IL, each is hydrogen or d- ₆ fluorenyl; said m is 0 or 1; said R _b is absent, hydrogen, d- ₆垸a d, _6- mercaptosulfonyl or d- ₆ fluorenylcarbonyl; each of the R, R. ₂ is hydrogen, halogen, fluorenyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl, or when Rd, are selected from the group firing d- _3, C with Rd, R. ₂ constituting the C ₃ - ₇ cycloalkyl group embankment;

D ^{1 is} selected from the group consisting of oxygen, sulfur, _S0-, -S0 ₂ -, -CO-, -N(R _d ) -, _(CH) „, said R _d is absent, hydrogen, sulfhydryl; Said n is 0, 1 or 2;

G, G ¹ are each -N- or -CH-;

Ring T is selected from:

(a) a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring containing at least one hetero atom, and the five- or six-membered heteroaryl ring or benzene ring may be substituted by R ₄ , wherein d- ₆ Indenyl, d- ₆ methoxy, halogen, halogenated ( _-6 fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino, mono (^ ₆垸 amino, double d- ₆垸 amino, Amido or -CN; and

(b), C ₃ - _s cyclononane or heterocyclic anthracene, said cyclononan or heterocycloalkyl hydrocarbon may be substituted by R ₄ , wherein is ₆ fluorenyl, d- ₆ methoxy, halogen, Halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino, mono- ₆ ylamino, bis- ₆ hydrazine amino, acylamino or _CN.

In still other preferred embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof Solvent or crystal, wherein

_{3⁄4 is} selected from the group consisting of H and d- ₄ fluorenyl;

Selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclopentyl, benzyl;

Is absent, or selected from alkyl with d- _4, (; _--4 embankment alkoxy, fluoro, chloro, bromo, and phenyl;

D is selected from _(CR _al R _a 0-, - (CR _al R _a2 ) „S -, -SO-, - S0 ₂ -, - CO-, - N(R _b )-, - N(R _b ) - CO-, -CO ^)-, wherein each of R _al and R _a2 is hydrogen, methyl or ethyl; said m is 0 or 1; said R _b is absent, hydrogen, A a group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a methylsulfonyl group or a methylcarbonyl group; each of said Rd, each being hydrogen, fluorine, methyl, ethyl, C ₂ - ₄ alkenyl or halogen a C ₂ - ₄ alkenyl group, or when both Rd and R. ₂ are methyl, C and Rd, ϋ ₂ constitute a cyclopropyl group;

D ^{1 is} selected from the group consisting of oxygen, sulfur, _S0-, -S0 ₂ -, -CO-, -N(R _d ) -, _(CH) „, wherein R _d is absent, hydrogen or ( ₄垸 base; the η is 0 or 1;

G, G ¹ are each N or - CH-;

Ring T is selected from:

(a) a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring containing at least one N, 0 or S hetero atom, and the five- or six-membered heteroaryl ring or benzene ring may be substituted by R ₄ . Wherein is (^ ₆ fluorenyl, d- ₆ decyloxy, halogen, halogenated d- ₆ fluorenyl, halogenated d- ₆ decyloxy, hydroxy, nitro, amino, mono-d- ₆ fluorenylamino, double d - ₆ hydrazine amino, formylamino, acetylamino or -CN; and

(b) a cyclopentanium, cyclohexanyl, cycloheptadine or a heterocyclic pentamidine, a heterocyclic hexanyl, or a heterocyclic ring of at least one ^ or S hetero atom.

In some further preferred embodiments, the invention provides a tricyclic fused heterocyclic nucleus of formula (I) An amino phosphoramidate compound, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein is selected from the group consisting of H and d- ₆ fluorenyl; and R _{2 is} selected from d- ₆ Anthracenyl, benzyl; R ₃ is absent or selected from the group consisting of fluorenyl, d- ₆ methoxy, fluoro, chloro, bromo, halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, Nitro, amino, monodecylamino, double d- ₆垸amino, -CN; D is selected from _ (CR _al R _a2 ) „0-, - (CR _al RS -, -S0-, - S0 ₂ -, - CO-, - N (R _b ) -, - N (R _b ) - CO-, - (CRd) -, wherein each of R _al and R _a2 is hydrogen or ₆ fluorenyl, and the m is 0 Or 1, wherein R _b is absent, hydrogen, d- ₆ fluorenyl, d- ₆ fluorenylsulfonyl or d- ₆ fluorenylcarbonyl, said Rd, each being hydrogen, halogen, d- ₆垸a C ₂ - ₆ alkenyl group or a halogenated C ₂ - ₆ alkenyl group, or when both Rd and ϋ ₂ are selected from the group consisting of d- ₃ fluorenyl groups, C and Rd, R. ₂ constitute a C ₃ _-7 cyclodecyl group; D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0-, -S0 ₂ -, -CO-, -NR _d -, _ (CH) „, wherein R _d is absent, hydrogen or d- ₆ fluorenyl Said n is 0, 1 or 2; G, G ¹ are each -N- or -CH-; and ring T is selected from: (a) a five-membered heteroaryl ring or a six-membered heteroaryl ring containing at least one hetero atom, benzene a ring, wherein the five- or six-membered heteroaryl or benzene ring may be substituted by R ₄ , wherein (^ ₆ fluorenyl, d- ₆ decyloxy, halogen, halogenated ( _-6 fluorenyl, halogenated) D- ₆ methoxy, hydroxy, nitro, amino, mono (^ ₆垸 amino, double d- ₆垸 amino, acylamino or -CN; and (b) C ₃ — _s cyclohydrocarbon or heterocycloalkyl The cyclononene or heterocyclic anthracene may be substituted, wherein is a fluorenyl group, a d- ₆ decyloxy group, a halogen, a halogenated d- ₆ fluorenyl group, a halogenated d- ₆ decyloxy group, a hydroxyl group, Nitro, amino, mono (^ ₆垸 amino, bis ₆垸 amino, amide or _CN.

In some further preferred embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof , solvate or crystalline, is selected from H and d- ₄ wherein embankment group; R ₂ is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclopentyl, benzyl; R ₃ is Not present, or selected from d- ₄ fluorenyl, d- ₄ methoxy, fluoro, chloro, bromo; D is selected from _ (CR _al R _a2 ) „0-, - (CR _al R _a2 ) „S -, -S0-, -S0 ₂ -, - CO-, - N (R _b ) -, - N (R _b ) - CO-, -CO ^) -, wherein each of R _al and R _a2 is hydrogen, Methyl or ethyl, said m is 0 or 1, said R _b is absent, hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, methylsulfonyl or methyl A carbonyl group, each of which is hydrogen, fluorine, methyl, ethyl, C ₂ - ₄ alkenyl or halogenated C ₂ - ₄ alkenyl, or as Rd, R. ₂ is a methyl group, C and Rd, R. ₂ constitutes a cyclopropyl group; D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0-, -S0 ₂ -, -CO-, -N (R _d ) -, _ (CH) „ -, wherein R _d is not Exist, hydrogen or d- ₄ fluorenyl, said n is 0 or 1; G, G ¹ are each -N- or -CH-; and ring T is selected from: (a), containing at least one N, 0 or a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring of the S hetero atom, wherein the five- or six-membered heteroaryl ring or benzene ring may be substituted by 3⁄4, wherein - ₆ fluorenyl, d- ₆ fluorene , halogen, halogenated d- ₆ fluorenyl, halogenated d- ₆ methoxy, hydroxy, nitro, amino, mono (^ ₆垸 amino, bis ₆垸 amino, formylamino, acetylamino or -CN And (b), cyclopentanyl, cyclohexanyl, cycloheptadine or heterocyclic pentylene, cyclohexanyl, cycloglycan having at least one ^ 0 or S hetero atom.

According to a first aspect of the invention, in some preferred embodiments, when D ¹ is _ (CH) „ -, wherein n is 0, ie, D ¹ is absent, D, G, G ¹ are attached to the benzene The ring constitutes a benzo five- or six-membered ring, as shown by the formula (Π)

(1) selected from the group consisting of 11 and ₆ fluorenyl, optionally substituted by one or more fluorenyl, decyloxy, hydrazino, halogen, hydroxy, amino, nitro, cyano, decanoyl, amino An acyl, guanidinoyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl group;

(2) R _{2 is} selected from the group consisting of H, d- ₆ fluorenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more fluorenyl, decyloxy, halogen, hydroxy, amino, mono embankment amino, bis embankment amino, aryl or heteroaryl group substituted, e.g. halo (^ ₆ embankment, benzyl;

(5) G and G ¹ are each -N- or -CH-;

(6) " = " is a single or double key, two of which are " single", or one " = " is a single key and the other is a double key;

(7) Ring T is selected from:

a, an aromatic ring or a heteroaryl group, for example, may be a 5-membered and a 6-membered aromatic ring or a heteroaryl ring, wherein the aromatic ring or heteroaryl ring may be substituted, wherein is an anthracenyl group, a decyloxy group, a halogen group, a halogenated group Base, halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino or -CN;

In some embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (Π), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate Object or crystal, of which

3⁄4 is selected from the group consisting of H and d- ₆ fluorenyl;

Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl;

Is absent, or is selected from the group consisting of d- ₄ fluorenyl, (; _-4 methoxy, fluoro, chloro, bromo, phenyl;

D is selected from - (CR _al R _a2 ) „0-, - (CR _al R _a2 ) „S -, -S0-, - S0 ₂ -, - CO-, - N (R _b )-, - N (R _b ) - CO-, -CO ^) -, wherein each of R _al , R _a2 is hydrogen, methyl or ethyl, the m is 0 or 1, and the R _b is absent, hydrogen , methyl, ethyl, propyl, isopropyl, cyclopropyl, methylsulfonyl or methylcarbonyl, said Rd, R. ₂ each is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl, or as Rd, R. _{When 2} is a methyl group, C may form a cyclopropyl group with Rd;

G, G ¹ are each -N- or -CH-;

It is a single key or a double key, two of which are single keys, or one is a single key and the other is a double key.

a, when 6, G ¹ are both -CH -, and G is connected to G ¹ as a double bond, D and G phase Connected to a single button, and

b. When G is -CH -, -N -, G ¹ is -N-, G is connected to G ¹ as a single bond, D is connected to G as a single bond; only when G is -CH -, G ¹ When -N -, and D is -N-, G is connected to G ¹ as a single bond, and D is connected to G as a double bond;

Ring T is selected from:

a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring containing at least one N, 0 or S hetero atom, and the five- or six-membered heteroaryl ring or benzene ring may be substituted by R ₄ , wherein ^ ₄ fluorenyl, d - ₄ methoxy, halogen, halogenated d- ₆ fluorenyl, halogenated d - ₄ methoxy, hydroxy, nitro, amino, mono d - ₄ fluorenyl, double d - ₄垸Amino, amide or -CN; and

b. Cyclopentanyl, cyclohexanyl, cycloheptadine or a heterocyclic pentamidine, a heterocyclic hexanyl group or a heterocyclic ring fluorene containing at least one ^ 0 or S hetero atom.

In some preferred embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (Π), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or crystal, wherein

_3⁄4 is 11, d- ₄垸 base;

Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, benzyl;

Is not present, or is selected from the group consisting of fluorine, chlorine, bromine, and phenyl;

D is selected from - (CR _al R _a2 ) „0-, - (CR _al R _a2 ) „S -, -S0-, - S0 ₂ -, - CO-, - N (R _b )-, - N (R _b ) - CO-, -CO ^) -, wherein each of R _al , R _a2 is hydrogen, methyl or ethyl, the m is 0 or 1, and the R _b is absent, hydrogen , methyl, ethyl, propyl, isopropyl, cyclopropyl, each of which is hydrogen, fluoro, methyl, ethyl, C ₂ - ₆ alkenyl or halogenated C ₂ - ₆ alkenyl , or when Rd, each is methyl or ethyl, C can be combined with Rd, R. ₂ constitutes a ring base;

G, G ¹ are each N or - CH-;

a, when 6, G ¹ are both -CH -, and G is connected to G ¹ as a double bond, D is connected to G as a single bond, and

b. When G is -CH -, N, and G ¹ is N, G is connected to G ¹ as a single bond, and " = " connected to D is a single bond; only when _G is - _CH -, G ¹ is _{When N} and D are -N-, G is connected to G ¹ as a single bond, and D is connected to G as a double bond;

Ring T is selected from:

a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring containing at least one N, 0 or S hetero atom, and the five- or six-membered heteroaryl ring or benzene ring may be substituted by R ₄ , wherein ^ ₄ fluorenyl, d - ₄ methoxy, halogen, halogenated d- ₆ fluorenyl, halogenated d - ₄ methoxy, hydroxy, nitro, amino, mono d - ₄ fluorenyl, double d - ₄垸Amino, formylamino, acetylamino or -CN; and

b, cyclopentanyl, cyclohexanyl, cycloheptadine or a heterocyclic pentylene having at least one ^ or S hetero atom, a heterocyclohexanyl, a heterocyclic heptane, the cyclodecyl or heterocycloalkyl Substituted, wherein _3⁄4 is d- ₄ fluorenyl, d- ₄ methoxy, halogen, halogenated d- ₆ fluorenyl, halogenated d- ₄ methoxy, hydroxy, nitro, amino, mono ( _-4垸) Amino, double d- ₄ amino, formylamino, acetylamino or _CN.

In still other preferred embodiments, the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (Π), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof Solvent or crystal, wherein

3⁄4 is 11, methyl, ethyl; R _{2 is} selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopentyl, benzyl;

For non-existence, or selected from fluorine, chlorine, and bromine;

D is selected from -0- - S - -S0- - S0 ₂ - -CO-, - N (R _b ) - - N (R _b ) - CO- - C (R _cl R _c2 ) - wherein R is _b is absent, hydrogen, methyl, ethyl, propyl, isopropyl, each of which is hydrogen, fluoro, methyl, ethyl, C ₂ - ₄ alkenyl, or as Rd R. _{2 When} each is a methyl group or an ethyl group, C and Rd R. ₂ constitutes a ring base;

GG ^{1 is} each -N- or -CH-;

a, when 6 G ¹ is -CH -, and G is connected to G ¹ as a double bond, D is connected to G as a single bond, and

b. When G is -CH - -N - G ¹ is N, "" of G is connected to G ¹ is a single bond, and "" connected to G is a single bond; only when G is - CH - G ¹ is -N -, and when D is -N-, G is connected to G ¹ as a single bond, and D is connected to G as a double bond;

Ring T is a benzene ring or a cyclohexanyl group, wherein the benzene ring or cyclohexanyl group may be substituted, wherein (^ ₄ fluorenyl group, decyloxy group, halogen, halogenated d- ₆ fluorenyl group, halogenated d- ₄₎ Alkoxy, hydroxy, nitro, amino, mono ( _-4垸 amino, bis d- ₄ -amino, formylamino, acetylamino or _CN

The present invention provides the following specific compounds and their diastereomers, prodrugs, and pharmaceutically acceptable

S9T6.0/M0ZN3/X3d 9Z8t6I/ 0Z OAV

S9T6.0/M0ZN3/X3d 9Z8t6I/ 0Z OAV

a) a compound of the formula (1) is reacted with phosphorus oxychloride under basic conditions, and then reacted with a compound of the formula (2), followed by addition of pentafluorophenol to obtain a compound of the formula (3);

b) The compound of the formula (3) is reacted with a compound of the formula (4) under low temperature conditions to obtain the target compound of the formula (5).

Wherein, R ₂ , D, D ¹ , G, G ¹ , " = ring T have the above definition.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) of the present invention, a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal .

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal, Also package One or more anti-HCV therapeutic agents comprising a composition selected from the group consisting of HCV NS3 protease inhibitors, HCV NS5B RNA-dependent RNA polymerase inhibitors, nucleoside analogs, interferon ct, pegylated interferon, Ribavirin, levovirin, verramidine, a TLR7 agonist, a TLR9 agonist, a cyclophilin inhibitor, an alpha glucosidase inhibitor, an NS5A inhibitor, and an NS3 helicase inhibitor.

The compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof of the present invention may be combined with a pharmaceutically acceptable carrier, diluent or The excipients are mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the pharmaceutical formulation art.

In a fourth aspect, the present invention provides a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystallization thereof or a pharmaceutical combination of the present invention of the present invention. A method of treating a subject infected with a Flaviviridae virus comprising administering to the subject a compound of formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvent Or a compound comprising a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, to effectively reduce the amount of the subject The amount of viral load of the virus. In some embodiments, the invention provides methods for treating and/or preventing an infection of an RNA virus, such as a Flaviviridae virus, comprising administering to a subject in need thereof a compound of the invention, a stereoisomer thereof, a salt, a hydrate thereof , solvate or crystal or a pharmaceutical composition thereof. In other embodiments, the invention provides a method of inhibiting an RNA virus, such as a Flaviviridae virus infection, comprising combining the virus with a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a salt, a hydrate, a solvent thereof Contact with the crystallization or its pharmaceutical composition.

"Rhuviridae" refers to any virus of the Flaviviridae family, including those that infect humans and non-human animals, such as flaviviruses, plague viruses, and hepatitis C virus. The compounds and compositions of the invention are particularly useful for the therapeutic or prophylactic treatment of HCV.

In another aspect, the present invention provides a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof of the present invention for use in the prevention or treatment of a viral infection. In particular, the use of a flavivirus-infected disease, and in the preparation of a medicament for preventing/treating a viral infection, particularly in the preparation of a medicament for preventing/treating an HCV viral infection, such as an HCV viral hepatitis disease. Definition of Terms

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning meaning meaning

As used herein, the term "stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers. All stereoisomers are within the scope of the invention.

As used herein, the term "prodrug" refers to any pharmaceutically acceptable form (e.g., an ester, an amide compound) of a compound of the invention when administered to a mammal to provide the active compound.

As used herein, the term "salt" refers to a pharmaceutically acceptable salt of a compound of the invention formed with an acid, such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, formamidinesulfonic acid or the like.

As used herein, the term "solvate" refers to a form of a compound of the invention which forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which they are coordinated with water. Within the scope of the invention, the solvate is preferably a hydrate.

As used herein, the term "crystalline" refers to the various solid forms formed by the compounds described herein, including crystalline forms, amorphous forms.

As used herein, the term "mercapto" refers to a straight-chain, branched or cyclic saturated hydrocarbon group, and "d-mercapto" refers to a saturated hydrocarbon group of 6 or less carbon atoms, including straight-chain or branched d- ₆ -fluorenyl. And d- ₆ ring fluorenyl. For example, suitable d- ₆ thiol groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, positive Pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl. The term includes substituted or unsubstituted indenyl groups which may be optionally substituted by one or more groups selected from the group consisting of fluorenyl, decyloxy, aryloxy, decylamino, arylamino, halogen. , hydroxy, amino, nitro, cyano, decyl acyl, amino acyl, decyl acyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.

As used herein, the term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon group containing one or more carbon-carbon double bonds (c=c), preferably an alkenyl group containing from 2 to 6 carbon atoms, more preferably containing The alkenyl group having 2 to 4 carbon atoms is most preferably an alkenyl group having 2 carbon atoms. The term "C ₂ - ₆ alkenyl" refers to an unsaturated hydrocarbon group containing one or two carbon-carbon double bonds and having from 2 to 6 carbon atoms. The term "C ₂ - ₄ alkenyl" refers to an unsaturated hydrocarbon group containing one or two carbon-carbon double bonds and having from 2 to 4 carbon atoms, and suitable alkenyl groups include, but are not limited to, ethenyl, propenyl. Similarly, the term "alkynyl" refers to a straight or branched chain unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds (C ≡ C), preferably an alkynyl group having 2 to 6 carbon atoms, more preferably 2 Alkynyl group up to 4 carbon atoms.

As used herein, the term "decyloxy" refers to -0-fluorenyl, preferably d- ₆ methoxy, and suitable oxiranyl groups include, but are not limited to, methoxy, ethoxy, and the like.

As used herein, the term "halogen" means fluoro, chloro, bromo, iodo.

As used herein, the term "haloindenyl" refers to a fluorenyl group substituted with at least one halogen atom, preferably halo ( _-6 fluorenyl).

As used herein, the term "mercaptosulfonyl" means "mercapto-S0 ₂ -", preferably d- ₆ fluorenyl-so ₂ -, suitable fluorenylsulfonyl groups include, but are not limited to, methylsulfonyl, B Sulfonyl.

As used herein, the term "mercaptocarbonyl" means "( _-6 -yl-C(=0)-", and suitable fluorenylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl.

As used herein, the term "aromatic ring" includes, but is not limited to, a benzene ring, a naphthalene ring, a biphenyl ring, an anthracene ring, a tetrahydronaphthalene ring, an anthracene ring, an indan ring, a biphenyl ring, and an anthracene ring, preferably a benzene ring. The term includes both substituted and unsubstituted groups. The aromatic ring may be optionally substituted by one or more groups selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, aryloxy, halogen, halodecyl, halodecyloxy, Hydroxy, nitro, amino, monodecylamino, bis-indolyl, arylamino, decyl acyl, aminoacyl, guanidinoyl, acylamino, _CN, aryl or heteroaryl.

As used herein, the term "heteroaryl ring" refers to a 3-10 membered heteroaromatic ring system containing 1-4 heteroatoms selected from N, 0 and S, hetero atoms, and preferably C ₃ - ₇ membered heteroaromatic ring system, Such as thiophene, pyridine, imidazole, furan, pyrrole, thiazole, 1, 2, 3-triazole, 1, 2, 4-triazole, 1, 2, 3-thiadiazole, oxazole, 1, 2, Suitable 4-arodiazoles, 1,3,4-oxadiazoles, etc., suitable heteroaryl rings include, but are not limited to, thiophene, pyridine, imidazole. The term includes both substituted and unsubstituted groups. The heteroaryl ring may be optionally substituted by one or more groups selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, an aryloxy group, a halogen, a halogenated fluorenyl group, a halogenated fluorenyloxy group. , hydroxyl, nitro, amino, single Amidino, bis-indenylamino, arylamino, decyl acyl, aminoacyl, decylamino, acylamino, _CN, aryl or heteroaryl.

As used herein, the term "heterocycle embankment hydrocarbon" means having at least one N, 0 or S ring heteroatom embankment hydrocarbons, preferably C ₃ - ₇ embankment heterocyclic hydrocarbons, including but not limited to heterocyclic embankment pentyl, hexyl heterocycle垸, heterocyclic 垸. The cyclic anthracene or heterocyclic anthracene hydrocarbon herein includes both substituted and unsubstituted groups. The cyclononene or heterocycloalkyl hydrocarbon may be optionally substituted by one or more groups selected from the group consisting of: an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, an aryloxy group, a halogen, a halogenated fluorenyl group, 3⁄4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, arylamino, decyl acyl, aminoacyl, hydrazinoyl, acylamino, _CN, aryl or heteroaryl.

As used herein, the term "amido" is "d-decyl-C0N" and suitable amido groups include, but are not limited to, formylamino, acetylamino,

The compounds of the present invention contain multiple asymmetric centers and, therefore, can be racemates and racemic mixtures, single enantiomers, diastereomers, diastereomer mixtures, and single diastereomers. The form exists. Detailed ways

The invention will be further illustrated in detail below with reference to the examples, but the invention is not limited to the examples. Unless otherwise indicated, the reagents and starting materials used in the present invention are commercially available.

Example 1 (2S)- 2-(((9 咔 azole-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3, 4-di) Hydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of (2S)-2-("pentafluorophenoxy)(9-oxazole-4-yloxy)phosphoryl)amino)propionic acid isopropyl ester

Add phosphorus oxychloride (0.84 g, 0. Olmol) to the reaction flask, add dichloromethane (DCM, 30 mL), cool to -60 ° C, add 4-hydroxycarbazole (1 g, 0.01 mol) And a solution of triethylamine (0.55 g, 0.01 mol) in dichloromethane, which was allowed to react at room temperature overnight. The mixture was cooled to -60 ° C, L-alanine isopropyl ester hydrochloride was added, and after stirring for 20 min, triethylamine (1.38 g, 0.025 mol) in dichloromethane was added dropwise, and the addition was completed. The temperature was raised to -5 ° C, and a solution of pentafluorophenol (lg, 10 mmol) and triethylamine (0.82 g, 0.015 mol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature. The reaction is complete, extracted with water, dried, concentrated and purified elut

Step 2, (2S) -2- ((carbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidine) Preparation of -1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

(2S)-2-((Pentafluorophenoxy)(9-oxazol-4-yloxy)phosphoryl)amino)propionic acid isopropyl ester (26 mg, 0.1 mmol) was added to the reaction flask, and sealed. Argon protection. Tetrahydrofuran (THF, 1.5 mL) was injected, and t-butylmagnesium chloride (0.3 mL) was injected under ice-cooling, and allowed to react at room temperature for 3 h. Under ice bath, a solution of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (70 mg, 0.15 mmol) in THF was injected, and the reaction was completed for 15 h. The mixture was quenched with EtOAc (EtOAc)EtOAc. 3⁄4匪R (300 MHz, DMS0-c _e ) δ ppm: 11. 46 (s, 1H), 11. 43 (s, 1H), 8. 19 (d, 1H), 7. 49 (d, 1H) , 7. 39 (t, 1H), 7. 32 (t, 1H), 7. 30 (t, 1H), 7. 16 (d, 1H), 7. 13 (t, 1H), 6. 18 ( t, 1H), 6. 01 (t, 1H), 5. 83 (d, 1H), 5. 24 (s, 1H), 4. 86 (q, 1H), 4. 44—4· 48 (m , 1H), 4. 32—4· 33 (m, 1H), 4. 05 (s, 1H), 4. 02 (q, 1H), 3. 84-3. 90 (m, 2H), 1. 24 (s, 3H), 1. 20 (d, 3H), 1. 13 (d, 6H).

ESI - MS m/z : [M+H] ⁺ = 619.

Example 2 (2S)-2-(((9-Methylcarbazole-4-yloxy)((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3) 4-Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1 Preparation of 4-hydroxy- 9-methyl-^ "carbazole

In a reaction flask, 4-hydroxycarbazole (2 g) was dissolved in DMF (15 mL), NaH (880 mg) was slowly added at 0 ° C, and then stirred at room temperature for 30 min. Further, Mel (1.5 g) was added, and the reaction was continued at room temperature for 1 h. TLC showed the reaction was completed, ethyl acetate (100 mL) was diluted, and the organic phase was washed successively with water, 10% LiCl aqueous solution and saturated brine, and dried to remove organic phase. The crude product was obtained. EtOAcjjjjjjj

3⁄4 匪R (400MHz, MSO-de) δ ppm: 10. 10 (s, 1H), 8. 16-8. 18 (d, 1H), 7. 50-7. 53 (d, 1H), 7. 38-7. 41 (t, 1H), 7. 14 -7. 26 (m, 2H) , 6. 99 -7. 01 (d, 1H), 6. 60 -6. 62 (d, 1H), 3. 81 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 198.

Step 2, (2S) -2- ((9-Methylcarbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, Preparation of 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

4-hydroxy-9-methyl-9 /-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400MHz, DMS0-c _e ) δ ppm: 11. 51 (s, 1H), 8. 22-8. 24 (d, 1H), 7. 61-7. 63 (m, 1H), 7 40 -7. 51 (m, 4H), 7. 17-7. 24 (m, 2H) , 6. 24-6. 33 (m, 1H), 5. 90-6. 05 (m, 2H) , 5. 15 (s, 1H), 4. 83-4. 89 (m, 1H), 4. 31-4. 48 (m, 2H) , 3. 93-4. 14 (m, 1H), 3 84-3. 93 (m, 5H), 1. 06-1. 22 (m, 12H).

LC-MS m/z: [M+H] ⁺ = 633.

Example 3 (2S)-2-(((9-isopropylcarbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3) , 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy) Phosphoryl)amino)propionic acid isopropyl ester

step

In the reaction flask, 4-hydroxycarbazole (lg, 5.46 mmol), THF (20 mL) was added, dissolved, cooled to -10 °C, NaH (0. 55 g, 14 mmol) was slowly added, and the mixture was stirred for 30 minutes. Add 2-bromopropene oxime 0. 74g (6mmol), add the mixture, react to room temperature for 3h, quench with water, extract with ethyl acetate, dry, concentrate, and concentrate, purified by preparative chromatography, PET: EA=10%, The title compound, a tan liquid.

Step 2, (2S) -2- (((9-isopropyl-^"oxazol-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) 3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester Preparation

4-hydroxy-9-isopropylcarbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro- Using 2'-methyluridine as a starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4匪R (500MHz, DMS0-c _e ) δ ppm: 11. 46 (s, 1H), 8. 20 (d, 1H), 7· 73- 7· 13 (m, 7H), 6. 27-5 . 67 (m, 3H), 5· 14- 4· 31 (m, 4H) , 4. 02-3. 80 (m, 4H), 1. 63 (d, 6 H) , 1. 26-1. 2 2 (m, 6H), 1. 16-1. 11 (m, 6H).

ESI - MS m/z : [M+H] ⁺ =661.

Example 4 (2S) -2- ((9-ethylcarbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 4-hydroxy-9-ethyl-^ "carbazole"

In the reaction flask, 4-hydroxycarbazole (1 g, 5.46 mmol) was added, dissolved in THF (20 mL), cooled to -10 ° C, NaH (0.55 g, 14 mmol), added, and stirred for 30 min. Afterwards, add bromoacetamidine (0.66 g, 6 mmol), add, and react at room temperature for 3 h. The reaction is completed, quenched with water, extracted with ethyl acetate, dried, concentrated and purified by preparative chromatography, PET: EA=10%, The title compound was obtained as a tan liquid.

Step 2, (2S) -2- ((9-ethylcarbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, Preparation of 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

4-hydroxy-9-ethyl-9/-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4 NMR (500 MHz, DMSO-c _s ) δ ppm: 11.47 (s, 1H), 7.61-8.23 (m, 3H), 7.15-7.50 (m, 5H), 5.96-6.02 (m, 2H), 5.64- 5.75 (m, 2H, ) , 5.16-5.32 (m, 2H), 4.84-4.88 (m, 1H), 4.44-4.48 (m, 2H, ), 4.30-4.37 (m, 1H), 4.05-408 (m , 1H), 3.61-3.65 (m, 1H), 1.21-1.33 (m, 9H), 1.12-1.17 (m, 6H).

ESI - MS m/z: [M+H] ⁺ = 647.2.

Example 5 (2S) -2- ((9-oxo- 9 芴- 2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3) , 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

2-hydroxy-9-fluorenone, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro-2'- The title compound was obtained by the same procedure as in Example 1 using methyl uridine as a starting material.

3⁄4匪R (300 MHz, DMS0-c _e ) δ: 11.43 (s, 1H), 7.96 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.59 (t, 2H), 7.41 -7.46 (m, 1H), 7.36 (t, 1H), 6.01 (d, 1H), 5.62-5.66 (m, 2H), 5.57 (d, 1H), 4.82-4.85 (m, 1H), 4.39-4.42 (m, 1H), 4.26-4.29 (m, 1H), 4.02—4.04 (m, 1H), 3.80—3.90 (m, 2H), 3.62-3.65 (m, 1H), 1.27 (d, 3H), 1.23 (d, 6H), 1.13 (dd, 3H).

ESI - MS m/z: [M+Na] ⁺ = 654.2.

Example 6 (2S)-2-((6, 7,8,9-tetrahydrodibenzo[b,d]furan-2-yloxy) ((2R, 3R, 4R, 5R)- 5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)

Step 1. Preparation of 2-hydroxy-6,7,8,9-tetrahydrodibenzo[b,d furan

Phenylhydrazine (5 g, 46 mmol) was dissolved in toluene, and 4-(cyclohexyl-1-en-1-yl)morpholine (8.5 g, 51 mmol) was added dropwise at 0 ° C, and stirred at 0 ° C overnight. After filtration, the residue was washed thoroughly with toluene and dried for 4 h. After adding 100 mL of water, HCl (20 mL, 15 M) was added dropwise, and the mixture was stirred at room temperature for 18 h, filtered, and the residue was washed with water, washed with dichloromethane, and then extracted with water.

Step 2, (2S)- 2- ((6,7,8,9-tetrahydrodibenzo[b,furan-2-yloxy) ((2R, 3R, 4R, 5R)- 5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl) Preparation of amino)propionic acid isopropyl ester

2-hydroxy-6, 7, 8, 9-tetrahydrodibenzo[6, ί]furan, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R The title compound was obtained by the same procedure as in Example 1 using -2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300 MHz, DMS0-c _e ) δ ppm: 11.51 (s, 1H), 7.52 (s, 1H), 7.43 (d, 1H), 7.29 (s, 1H), 7.04 (d, 1H), 6.02 (d, 1H), 5.97 (d, 1H), 5.84 (s, 1H), 5.49 (d, 1H), 4.37-4.39 (m, 1H), 4.23-4.24 (m, 1H), 4.01-4.05 ( m, 2H), 3.79-3.84 (m, 2H), 2.70 (m, 2H), 2.49 (m, 2H), 1.86-1.87 (m, 2H), 1.77-1.78 (m, 2H), 1.25 (d, 3H), 1.21 (d, 3H), 1.13 (t, 6H).

ESI-MS m/z: [M+H] ⁺ = 624.3.

Example 7 (2S) -2- ((dibenzo[b,d]thiophen-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) -3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 2-hydroxy-dibenzo[b,dthiophene

1.1 Preparation of 2-dioxaborane

In a dry reaction flask, 2-bromo-dibenzo[6,c]thiophene (2.64 g, 10.0 mmol), benzoic acid pinacol ester (6.09 g, 24.0 mmol), potassium acetate (2.94 g, 30.0) Methyl), 1,4-dioxane (50 ml) and [1,-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ , 364 mg, 0.5 mmol). Heat to 90 ° C under nitrogen protection, reaction for 24 h, TLC detection. After the reaction was completed and the reaction system was cooled to room temperature, water (100 mL) was added thereto, and the mixture was extracted with ethyl acetate (60 mL×3) three times, and the organic phase was combined and washed once with saturated brine (60 mL). The title compound was obtained as a yellow oil. 3⁄4匪R (500 MHz, MSO-de) δ ppm _: 8.61 (s, 1H), 8.25-8.23 (m, 1H) : 7.88-7.82 (m, 3H), 7.45-7.43 (m, 2H) , 1.39- 1.33 (m, 12H).

1.2 Preparation of 2-hydroxy-dibenzo[b,dthiophene

In a dry reaction flask, add the compound 2-(dibenzo[6, ί]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3, 2 obtained in the above step 1.1. - dioxoboron (2.0 g, 6.44 mmol), ethanol (20 ml), hydroxylamine hydrochloride (1.34 g, 19.32 mmol) and sodium hydroxide solid (1.03 g, 25.76 mmol). After stirring at room temperature for 10 minutes under nitrogen atmosphere, the mixture was heated to 60 ° C for 24 h, and detected by TLC. After the reaction system was cooled to room temperature, water (100 mL) was added thereto, and extracted with ethyl acetate (60 mL) three times, and the organic phase was combined, and then washed once with saturated brine (60 mL). The title compound was obtained as a yellow oil.

3⁄4匪R (500 MHz, DMS0-c _e ) δ ppm: 8.06-8.05 (m, 1H), 7.83-7.81 (m, 1H), 7.69-7.37 (m, 1H), 7.59-7.57 (m, 1H) , 7.45-7.41 (m, 2H), 7.01-6.99 (m, 1H), 4.79 (brs, 1H).

Step 2, (2S) -2- ((dibenzo[b, d]thiophen-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl Preparation

Prepared 2-hydroxy-dibenzo[6, ί]thiophene, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2 Using the title of '-fluoro-2'-methyluridine as the starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4 wake up (500 MHz, DMS0) δ ppm: 11.47 (s, 1H), 8.29 (d, 1H), 8.19 (s, 1H), 8.02 (m, 2H), 7.58-7.56 (m, 1H), 7.54- 7.50 (m, 2H), 7.41-7.40 (d, 1H), 6.13-6.03 (m, 2H), 5.85 (d, 1H), 5.55 (d, 1H), 4.87-4.82 (m, 1H), 4.44- 4.38 (m, 1H), 4.30-4.28 (m, 1H), 4.05—4.01 (m, 1H), 3.90—3.86 (m, 2H), 1.28-1.23 (m, 6H), 1.18-1.12 (m, 6H) ).

ESI-MS m/z: [M+H] ⁺ = 636.0.

Example 8 (2S)-2-(((9-Oxo-^"thiazepine-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) 3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 2-hydroxy-9-oxo-^"thiazepine

Thiosalicylic acid (9 g), phenol (24.7 g), was placed in a reaction flask, then concentrated sulfuric acid (85 mL) was slowly added, and the reaction was heated at 75 ° C for 2 h, and the reaction was stopped by TLC. The reaction mixture was poured into a solution of 60 ° C under stirring, and solid was precipitated.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 10.24 (s, 1H), 8.49-8.52 (m, 1H),

7.80-7.92 (m, 4H), 7.53-7.63 (m, 1H), 7.31-7.34 (m, 1H).

Step 2, (2S) -2- ((9-oxothiazepine-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3 , 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

2-hydroxy-9-oxo-9 /-thiazepine, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2 Using the title of '-fluoro-2'-methyluridine as the starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 11.49 (s, 1H), 8.41-8.44 (d, 1H),

8.24 (s, 1H), 7.83-7.91 (m, 3H), 7.56-7.76 (m, 3H), 6.19-6.22 (t, 1H), 5.94-5.99 (m, 2H), 5.86 (s, 1H), 4.75-4.82 (m, 1H), 4.23-4.29 (m, 2H), 3.78-3.82 (m, 3H), 1.11-1.24 (m, 6H), 1.05-1.11 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 664.

Example 9 (2S)-2-(((9-Oxo-^"oxaindole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) 3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 3-hydroxy-9-oxo-^"oxaxan

1.1

In a reaction flask, 2-hydroxy-4-methoxybenzaldehyde (1.5 g) was dissolved in DMF (40 mL), and 1,2-dibromobenzene (4.6 g) and potassium carbonate (2.76 g) were slowly added at room temperature. Then, it was heated to 120 ° C, stirred under nitrogen for 12 h, TLC showed the reaction was completed, cooled to room temperature, diluted with ethyl acetate (150 mL), and the organic phase was washed sequentially with water, 10% LiCl aqueous solution and saturated brine. The organic phase was purified by EtOAc (EtOAc:EtOAc)

3⁄4匪R (400 MHz, MSO-de) δ ppm: 8.16-8.19 (q, 1H), 8.09-8.12 (d, 1H), 7.83-7.88 (m, 1H), 7.62-7.65 (m, 1H), 7.45-7.50 (m, 1H), 7.17-7.20 (d, 1H), 7.05-7.08 (dd, 1H), 3.94 (s, 3H ).

1.2 Preparation of 3-hydroxy-9-oxo-^"oxaxan

In the reaction flask, the compound 3-methoxy-9-oxo-9/-oxaxan (300 mg) obtained in the above step 1.1 was dissolved in dichloromethane (5 mL) in dry ice acetone bath Under nitrogen protection, add BBr ₃ (983 mg), stir until the end of the reaction, quench with 1 mL of water, add 10 mL of dichloromethane, wash the organic phase with water, saturated brine, dry dichloromethane, reduce The organic phase was evaporated to give the title compound, m.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.00 (s, 1H), 8.15-8.17 (t, 1H),

8.04-8.06 (d, 1H), 7.29 (m, 1H), 7.60-7.63 (m, 1H), 7.45 (m, 1H), 6.88-6.93 (m, 2H).

Step 2, (2S) -2- ((9-oxooxaindole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3 , 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

3-hydroxy-9-oxo-9 /-oxaxanth, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2 Using the title of '-fluoro-2'-methyluridine as the starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.51 (s, 1H), 8.18-8.23 (m, 2H), 7.87-7.90 (m, 1H), 7.66-7· 68 (d, 1H) , 7.49-7· 55 (m, 3H), 7.33-7· 35 (m, 1H), 6.33-6.40 (m, 1H), 5.91-6.07 (m, 2H), 5.57-5.59 (d, 1H), 4.82-4.86 (m, 1H), 4.35-4.44 (m, 2H), 3.88—4.03 (m, 3H), 1.14—1.29 (m, 6H), 1.10-1.15 (m, 6H).

LC-MS m/z: [M+H] ⁺ =648.

Example 10 (2S)- 2- (((SW" carbazole-2-yloxy) (((2R, 3R, 4R, 5R)- 5- (2, 4-dioxo-3, 4- Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

2-hydroxy-9 /-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro-2' Using methyl uridine as a starting material, the title compound was obtained in the same manner as in Example 1. After purification by HPLC, isomer I, white solid and isomer II, white solid.

HPLC conditions: Instrument: Shimadzu preparation HPLC (Preparative liquid chromatography Shimadzu); ^{Column: Benetnoch TM _C18, 20x250 mm,} 10 μ m; detection wavelength: 254 nm; Mobile Phase 0: MeOH = 30: 70.

Corresponding isomer I:

3⁄4匪R (300MHz, DMS0-c _e ) δ: 11.48 (s, 1H), 11.27 (s, 1H), 8.06 (d, 2H), 7.60-7.58 (d, 1H), 7.46-7.45 (d, 1H ), 7.36-7.35 (d, 2H), 7.33-7.31 (m, 1H), 7.14-7.13 (d, 1H), 6.08-6.12 (m, 2H), 5.90 (d, 1H), 5.59 (d, 1H) ), 4.91-4.82 (m, 1H), 4.67—4.32 (m, 1H), 4.32—4.21 (m, 1H), 4.05—4.01 (m, 1H), 3.88-3.79 (m, 2H), 2.3 (s , 3H), 1.58 (d, 3H), 1.30-1.20 (m, 9H). ESI-MS m/z: [M+Na] ⁺ = 641.3.

Recombinant II:

3⁄4匪R (300 MHz, DMS0-c _e ) δ ppm: 11.48 (s, 1H), 11.26 (s, 1H), 8.01 (d, 2H), 7.61-7.59 (d, 1H), 7.47-7.45 (d , 1H), 7.36-7.34 (d, 2H), 7.33-7.31 (m, 1H), 7.14-7.13 (d, 1H), 6.08-6.12 (m, 2H), 5.91 (d, 1H), 5.59 (d , 1H), 4.91-4.82 (m, 1H), 4.67-4.32 (m, 1H), 4.32-4.21 (m, 1H), 4.05-4.01 (m, 1H), 3.88-3.79 (m, 2H), 2.3 (s, 3H), 1.30-1.20 (m, 9H), 1.58 (d, 3H).

ESI - MS m/z: [M+Na] ⁺ = 641.

Example 11(2S)- 2-(((2,3,4,9-tetrahydro-1H-carbazole-6-yloxy) (((2R, 3R, 4R, 5R)-5-(2) , 4-dioxo-3, 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)

Step - Preparation of hydroxy- 2, 3, 4, 9- ^ ^ "tetrahydrocarbazole

In the reaction flask, p-methoxyphenylhydrazine hydrochloride (5 g, 29 mmol), acetic acid (30 mL), cyclohexanone (2.8 g, 29 mmol), heated to 70 ° C, fully dissolved, continue After stirring for 5 minutes, a large amount of yellow solid precipitated, TLC was monitored until the reaction was completed, and the temperature was lowered to room temperature. 30 mL of HBr/0 solution was added, and then heated to 80 V for 4 hours. TLC was monitored until the starting material disappeared, the reaction was stopped, and the temperature was lowered to room temperature. The title compound was obtained as a yellow solid. EtOAc (EtOAc)

Step 2, (2S)- 2- (((2,3,4,9-tetrahydro-1H-carbazole-6-yloxy) ((2R, 3R, 4R, 5R)- 5- (2 , 4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino) Isopropyl propionate

6-Hydroxy-2,3,4, tetrahydrocarbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (500 MHz, DMS0-c _e ) δ ppm: 11.47 (s, 1H), 10.64 (s, 1H), 7.51 (d, 1H), 7.17-7.11 (m, 2H), 6.84 (d, 1H ), 6· 03- 5· 99 (m, 1H), 5.86-5.80 (m, 2H), 5.50-5.44 (m, 1H), 4.88-4.83 (m, 1H), 4.36-4.33 (m, 1H) , 4.22-4.19 (m, 1H), 4.05—4.00 (m, 1H), 3.84— 3.75 (m, 2H), 2.68—2.54 (m, 4H), 1.81—1.78 (m, 4H), 1.26-1.21 ( m, 6H), 1· 17- 1· 14 (m, 6H).

ESI-MS m/z: [M+H] ⁺ = 623.0. Example 12 (2S)- 2-(((SW"carbazole-3-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3, 4- Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 3-hydroxy-^ "carbazole

Preparation of 1.1-formyl-9-tert-butoxycarbonyl-^ "carbazole

In a reaction flask, N-Boc-3-bromocarbazole (3 g) was dissolved in THF (10 mL), cooled to -78 ° C under nitrogen atmosphere, and n-BuLi (6.5 mL) was added. After stirring at _78 ° C for 1 h, DMF (952 mg) was added thereto. After the addition was completed, the cooling was stopped, the reaction temperature was allowed to rise to room temperature, and quenched with saturated NH ₄ C1 (1 mL). The mixture was diluted with EtOAc (EtOAc)EtOAc.

1.2 3- - 9-tert-Butoxycarbonyl-^ "Preparation of carbazole

In the reaction flask, 3-formyl-9-tert-butoxycarbonyl-9 /-carbazole (600 mg) was dissolved in THF (10 mL), then m-chloro-benzoic acid (m-CPBA, The reaction mixture was stirred at rt EtOAc EtOAc EtOAc.

Preparation of 1.3-hydroxy- 9-tert-butoxycarbonyl-^ "carbazole

3-formyloxy-9-tert-butoxycarbonyl-9 /-carbazole (670 mg) was dissolved in Me0H/H ₂ 0 (7.5 mL (2:1 by volume)) in a reaction flask. Further, K ₂ C0 ₃ (890 mg) was added, and the reaction mixture was stirred at room temperature for 12 h, diluted with ethyl acetate (20 mL), and the organic phase was washed with water and brine, and then evaporated. Purification by silica gel column chromatography (EtOAc:EtOAc)

1.4 Preparation of 3-hydroxy-5 carbazole H

3-Hydroxy-9-tert-butoxycarbonyl-9 /-carbazole (240 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (TFA, 2 mL) was added dropwise at 0 °C. After stirring for 2 hours, the reaction is completed. Pour the reaction solution into an appropriate amount of ice water with stirring, adjust the pH to neutral with a saturated sodium hydrogencarbonate solution, and extract with dichloromethane (10 mL X2). The title compound was obtained as a pale yellow solid.

Step 2, (2S) -2- ((carbazole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidine) Preparation of -1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

3-hydroxy-9 /-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R)-2'-deoxy-2'-fluoro-2' Using methyl uridine as a starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.53 (s, 1H), 11.28 (s, 1H), 7.59-8.06 (m, 2H), 7.57-7.60 (m, 1H), 7.40-7.47 (m, 3H), 7.16-7.28 (m, 1H), 7.12-7.14 (m, 1H), 6.03-6.06 (m, 2H), 5.52-5.55 (m, 1H), 4.82-4.86 (m, 2H) , 3.86 (m, 1H), 3.85 (m, 2H), 1.21-1.27 (m, 6H), 1.11-1.14 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 619.

Example 13 (2S)-2-(((9-Methyl-^"carbazole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) -3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 3-hydroxy-9-methyl-^"carbazole

1.1

In a reaction flask, 3-hydroxy-9 /-carbazole (400 mg) was dissolved in anhydrous DMF (10 mL) at 0 ° C, and iodothymidine (0.55 mL) was added, and stirring was continued at 0 ° C for 0.5 h. . Further, sodium hydride (352 mg) was added, and after stirring for 5 minutes, it was stirred to room temperature and stirred until TLC showed the end of the reaction. The mixture was diluted with EtOAc (EtOAc) (EtOAc) solid.

3⁄4匪R (400 MHz, MSO-de) δ ppm: 8.04-8.06 (d, 1H), 7· 58- 7· 59 (d, 1H), 7.11-7.48 (m, 5H), 3.94 (m, 3H), 3.83

LC-MS m/z: [M+H] ⁺ = 212.

1.2

In the reaction flask, 3-methoxy-9-methyl-9 /-carbazole (115 mg) was dissolved in dichloromethane (5 mL), and BBr was slowly added dropwise under dry ice acetone bath and nitrogen. ₃ (0.1 mL), after completion, the mixture was stirred at room temperature until stirring until TLC showed the end of reaction. After quenching with water (1 mL), dichloromethane (10 mL) was added, and the organic phase was washed with water and brine, and then dichloromethane was evaporated. PET: EA = 5: 1) The title compound was obtained as a white solid product.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 9.01 (s, 1H), 8.01-8.03 (d, 1H), 7.37-7.51 (m, 4H), 7.09-7.13 (m, 1H), 6.94 -6.97 (m, 1H), 3.80 (s, 3H). Step 2, (2S) -2- ((9-Methylcarbazole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, Preparation of 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

3-hydroxy-9-methyl-9 /-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.53 (s, 1H), 7.95-8.13 (m, 2H), 7.46-7.60 (m, 4H), 7.18—7.37 (m, 2H), 5.92 —6.08 (m, 3H), 5.51—5.55 (m, 1H), 4.83-4.88 (m, 1H), 4.24-2.32 (m, 2H), 4.03-4.06 (m, 1H), 3.81-3.87 (m, 5H), 1.10-1.27 (m, 12H).

LC-MS m/z: [M+H] ⁺ =633 ₀

Example 14 (2S)- 2-(((10-Methyl-9-oxo-9,10-dihydroacridin-2-yloxy) (((2R, 3R, 4R, 5R)-5) - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)- 4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy

Step 1. Preparation of 2-hydroxy- 10-methyl- 9-oxo- 9, 10-dihydroacridine

1.1

In a reaction flask, 2-fluorobenzoic acid (1.68 g) and p-methoxyaniline (1.23 g) were dissolved in THF. (15 mL), lithium amide (460 mg) was slowly added at room temperature, and the mixture was heated to 50 ° C under nitrogen for 4 h, and the reaction was completed. After cooling to room temperature, the mixture was diluted with EtOAc (EtOAc)EtOAc. Alcohol (10 mL), EtOAc (EtOAc)EtOAc.

3⁄4匪R (400 MHz, MSO-de) δ ppm: 12.98 (s, 1H), 9.50 (s, 1H), 7.90-7.93 (m, 1H), 7.37—7.39 (m, 1H), 7.35 (m, 2H) , 6.97—7.02 (m, 3H), 6.71—6.74 (m, 1H), 3.81 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 244.

1.2

In the reaction flask, 2-(4-methoxyanilino)benzoic acid (8001!^) was suspended in ? In 0 (1 ₃ (10 mL), heat to reflux until the reaction is completed (LC-MS detection), P0C1 _{3 is} evaporated under reduced pressure _; ethanol is added to the concentrate: 10% hydrochloric acid = 8:1 (¥: ¥) solution ( The title compound was obtained as a yellow solid.

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 11.77 (s, 1H), 8.22-8.24 (d, 1H), 7.40-7.73 (m, 5H), 7.22-7.26 (m, 1H), 3.86 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 226.

Preparation of 1.3-hydroxy- 9-oxo- 9, 10-dihydroacridine

In a reaction flask, 2-methoxy-9-oxo-9, 10-dihydroacridine (670 mg) was added to a 40% aqueous solution of HBr (13 mL), and then heated to reflux for 24 h. The title compound was obtained as a yellow solid.

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 11.64 (s, 1H), 8.18-8.20 (m, 1H), 7.68-7.69 (m, 1H), 7.45-7.56 (m, 3H), 7.17 -7.27 (m, 2H).

LC-MS m/z: [M+H] ⁺ = 212.

1.4 Preparation

In a reaction flask, 2-hydroxy-9-oxo-9, 10-dihydroacridine (211 mg) was dissolved in DMF (3 mL) and NaH (160 mg) was added at 0 ° C, then After stirring for 30 min, additional Mel (0.18 mL) was added, and the reaction was continued at room temperature for 30 min, and the reaction was completed. The mixture was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The title compound was obtained as a yellow solid.

LC-MS m/z: [M+H] ⁺ = 240.

Preparation of 1.5 2-hydroxy- 10-methyl- 9-oxo- 9, 10-dihydroacridine

In a reaction flask, 2-methoxy-10-methyl-9-oxo-9, 10-dihydroacridine (156 mg) was dissolved in dichloromethane (3 mL), dry ice acetone bath and nitrogen Under the protection, BBr ₃ (0.125 mL) was slowly added dropwise, and the mixture was added dropwise to room temperature and stirred until TLC showed the end of the reaction. After quenching with water (1 mL), dichloromethane (10 mL) was added, and the organic phase was washed successively with water and brine, and then evaporated. :EA = 5:1) Purification afforded the title compound as a yellow solid.

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 9.69 (s, 1H), 8.29-8.31 (d, 1H),

7.67-7.79 (m, 4H), 7.26-7.34 (m, 2H), 3.91 (s, 3H).

IX-MS m/z: [M+H] ⁺ = 212.

Step 2. (2S)-2-(((10-Methyl-9-oxo-9, 10-dihydroacridin-2-yloxy) ((2R, 3R, 4R, 5R)-5 - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl Preparation of amino)propionic acid isopropyl ester

2-hydroxy-10-methyl-9-oxo-9, 10-dihydroacridine, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) The title compound (white solid) was obtained in the same manner as in Example 1 to give the title compound.

3⁄4 NMR (400 MHz, DMS0-c _e ) δ ppm: 11.53 (s, 1H), 8.32-8.34 (d, 1H),

8.13-8.14 (d, 1H), 7.92 (m, 3H), 7.85 (m, 1H), 7.71 (m, 1H), 7.35 (m, 1H), 6.16 (t, 1H), 5.86-6.04 (m, 2H) , 5.53-5.55 (d, 1H), 4.81-4.85 (m, 1H), 4.41 (m, 1H), 4.28 (m, 1H), 4.01 (m, 1H), 3.96 (s, 3H), 3.80 (m, 2H), 1.22-1.28 (m, 6H), 1.10-1.134 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 661.

Example 15 (2S)-2-(((1-Fluoro-carbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 1-fluoro-4-hydroxy-9 carbazole

1.1 -Fluoro- 2-methoxyphenyl boron

2-Bromo-4-fluoroanisole (5 g) was placed in a reaction flask, then anhydrous THF (80 mL) was added, ice bath, Under the protection of nitrogen, n-butyllithium (20 mL) was slowly added dropwise. After the dropwise addition, the reaction was carried out for 1 hour. Then, trimethyl borate (5.5 mL) was added slowly, stirred at room temperature for 3 h, and monitored by TCL to stop the reaction. The reaction mixture was adjusted to pH 1 with 18% aqueous hydrochloric acid, and then ethyl acetate (200 mL). , white solid, crude product can be directly used in the next reaction.

1. Preparation of 2-fluoro-2-methoxy-2'-nitrobiphenyl

5-Fluoro-2-methoxybenzeneboronic acid (500 mg), 1-bromo-2-nitrobenzene (591 mg), [1,-bis(diphenylphosphino)ferrocene]palladium dichloride Dichloromethane ruthenium complex (215 mg), potassium carbonate (811 mg) was placed in the reaction flask, and then added with 1,4-dioxane 20 mL and water 4 mL, heated to 90 ° C under nitrogen atmosphere. 1. 5 h, TCL monitoring, stop the reaction. The reaction mixture was added with ethyl acetate (100 mL), EtOAc (EtOAc)EtOAc. Purification by column chromatography (EtOAc:EtOAc:EtOAc:

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 7. 99-8. 01 (d, 1H), 7. 76-7. 79 (m, 1H), 7. 63-7. 65 (m , 1H), 7. 50-7. 53 (m, 1H), 7. 23-7. 28 (m, 2H), 7. 03-7. 07 (m, 1H), 3. 60 (s, 3H ).

1. Preparation of 3 1- - 4-methoxy oxazole

5-Fluoro 2-methoxy-2'-nitrobiphenyl (1 g) was placed in a reaction flask, followed by the addition of triphenylphosphine (2.1 g), 1,2-dichlorobenzene (10 mL) ), heating under a nitrogen atmosphere to 190 ° C overnight. TLC monitoring, stop the reaction. The reaction mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal

LC-MS m/z: [M+H] ⁺ = 216.

1. Preparation of 4 1- - 4-hydroxy-9 carbazole

In a reaction flask, 1-fluoro-4-methoxy-9 /-carbazole (250 mg) was dissolved in dichloromethane (5 mL), and BBr was slowly added dropwise under dry ice acetone bath and nitrogen. ₃ (0. 22 mL), after completion, the mixture was stirred at room temperature until stirring until TLC showed the end of reaction. Quenched with water (1 mL), added with dichloromethane (20 mL). The organic phase was washed successively with water and brine, and then evaporated and evaporated. : EA = 5: 1) The title compound was obtained after purification, white solid.

LC-MS m/z: [M+H] ⁺ = 202. Step 2, 2S) -2- (((1-fluoro-carbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4 -Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

1-fluoro-4-hydroxy-9 /-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'- The title compound was obtained as a white solid in the same manner as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.96-11.96 (m, 1H), 11.60 (s, 1H), 8.26-8.29 (d, 1H), 7.51-7.61 (m, 3H), 7.15 -7.33 (m, 3H), 6.32-6.38 (m, 1H), 5.96-5.98 (m, 2H), 5.34 (m, 1H), 4.90-4.93 (m, 1H), 4.38-4.54 (m, 2H) , 4.11-4.14 (m, 1H), 3.91-3.92 (m, 2H), 1.05-1.14 (m, 12H).

LC-MS m/z: [M+H] ⁺ = 637.

Example 16 (2S)-2-(((l-Fluoro-9-methyl-9H~ carbazole-4-yloxy) (((2R, 3R, 4R, 5R)-5-(2, 4) -dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid Isopropyl ester

Preparation of 1-fluoro-4-hydroxy-9-methyl-9 oxazole

Of -fluoro-4-methoxy-9-methyl-9i?"carbazole

1-Fluoro-4-methoxy-9 /-carbazole (200 mg) was added to the reaction flask, and sodium hydride (45 mg) was slowly added with stirring in an ice bath. After the addition, the reaction was continued for 30 minutes, and then Iodomethyl hydrazine (0.15 mL) was added and the mixture was reacted at room temperature for 1 h. TLC monitoring, stop the reaction. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. .

1.2 Preparation

In a reaction flask, 1-fluoro-4-methoxy-9-methyl-9 /-carbazole (190 mg) was dissolved in dichloromethane (10 mL) under dry ice acetone and nitrogen BBr ₃ (0.2 mL) was added dropwise, and the mixture was stirred at _78 ° C for 2 h, then the mixture was stirred at room temperature for 2 h, and the reaction was finished, and then dichloromethane (10 mL) was added, and the mixture was diluted with 1 mL of saturated sodium hydrogen carbonate solution. The organic phase was washed with EtOAc (EtOAc m. LC-MS m/z: [M+H] ⁺ = 216.

Step 2, (2S)-2-(((l-fluoro-9-methyl-9H~ carbazole-4-yloxy) ((2R, 3R, 4R, 5R)-5-(2, 4 -dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid Preparation of isopropyl ester

1-fluoro-4-hydroxy-9-methyl-9/-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'- The title compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

Isomer I (white solid) and isomer II (white solid) were further separated by HPLC.

HPLC conditions:

Instrument: SHIMADZU LC-6A; Column: Shim-pack PREP-ODS (H) (250*20mm, 10um); Flow rate: 12 mL/min; Detection wavelength: 220/254 nm; Mobile phase: Phase A: H ₂ 0 (0.1% FA) Phase B: CH Phoenix

Isomer I: 3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.52 (s, 1H), 8.24-8.26 (d, 1H), 7.66-7.68 (d, 1H), 7· 45- 7 · 59 (m, 2H), 7.12-7.30 (m, 3H), 6.28-6.35 (m, 1H), 5.91-6.03 (m, 2H), 5.21 (s, 1H), 4.83-4.87 (t, 1H) , 4.31-4.44 (m, 2H), 4.05 (m, 4H), 3.84-3.89 (m, 2H), 1.18-1.23 (m, 6H), 1.12-1.24 (m, 6H).

LC-MS m/z: [M+H] ⁺ =651 ₀

Isomer II: 3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.53 (s, 1H), 8.23-8.25 (d, 1H), 7.65-7.67 (d, 1H), 7.5-7.56 (m , 2H) , 7.12-7.18 (m, 3H), 6.33—6.37 (m, 1H), 5.97 -6.07 (m, 2H), 5.21 -5.27 (m, 1H), 4.73 -4.76 (t, 1H), 4.35 -4.36 (m, 2H), 4.04-4.09 (m, 4H), 3.85 -3.89 (m, 2H), 1.20-1.23 (m, 6H), 0.99 -1.14 (m, 6H).

LC-MS m/z: [M+H] ⁺ =651 ₀

Example 17(2S)- 2-(((9-oxo-9 oxazepine-2)oxy)(((2R, 3R, 4R, 5R)-5-(2,4-dioxo- 3, 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl

Step 1. Preparation of 2-hydroxy-9-oxo-9-oxaxanthene

1.1

In a reaction flask, 2-nitrobenzaldehyde (1.5 g) was dissolved in toluene (10 mL) and slowly added at room temperature. Into p-methoxyphenol (1.24 g), copper chloride (66 mg), triphenylphosphine (196 mg) and potassium phosphate (4.6 g), the reaction solution was exposed to air, heated to 110 ° C for 24 h, TLC The reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to ethyl acetate (150 mL). EtOAcjjjjjjjjjj Compound, light yellow solid product. R (400 MHz, MSO-de) δ ppm: 8.17-8.20 (m, 1H), 7.83-7.90 (m, 1H), 7.60-7.65 (m 2H), 7.53-7· 55 (d, 1H), 7.44 -7· 48 (m, 2H), 3.87 (s, 3H).

1.2 Preparation of 2-hydroxy-9-oxo-9 oxazepine

In the reaction flask, 2-methoxy-9-oxo-9 /-oxaxan (200 mg) was dissolved in dichloromethane (5 mL), dry ice acetone bath and nitrogen protection, BBr was added dropwise ₃ (437 mg), stir at _78 ° C for 2 h, then continue stirring at room temperature for 2 h, the reaction is complete, add 1 mL of saturated sodium bicarbonate solution and dichloromethane (10 mL), the organic phase sequentially with water, saturated brine The organic layer was washed with EtOAc (EtOAc).

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 10.00 (s, 1H), 8.17-8.19 (m, 1H), 7.83-7.88 (m, 1H), 7.55-7.66 (m, 2H), 7.44 -7.49 (m, 2H), 7.31-7.35 (m, 1H).

Step 2, (2S) -2- ((9-oxo-9 oxazepine-2^-oxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo- Preparation of 3, 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

2-hydroxy-9-oxo-9 /-oxaxanthene, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2 The title compound (white solid) was obtained by the same procedure as in Example 1 using <->

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.54 (s, 1H), 8.24-8.27 (d, 1H), 7.93-8.05 (m, 2H), 7.73-7.82 (m, 3H), 7.54 -7.84 (m, 2H), 6.27-6.28 (m, 1H), 5.94-6.13 (m, 2H), 5.60-5.62 (m, 1H), 4.86-4.89 (t, 1H), 4.31-4.49 (m, 2H), 4.07 (m, 1H), 3.89-3.93 (m, 2H), 1.28-1.34 (m, 6H), 1.15-1.20 (m, 6H).

LC-MS m/z: [M+H] ⁺ =648.

Example 18(2S)- 2-(((9-Methyl-2,3,4,9-tetrahydro-1H-indazole-6-yloxy) (((2R, 3R, 4R, 5R)) - 5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyl-2-yl)methoxy)phosphoryl Amino) isopropyl propionate

Step 1. Preparation of 6-hydroxy- 9-methyl-2,3,4,9-^^"tetrahydrocarbazole Preparation of 6-methoxy-9-methyl-2,3,4,9-tetrahydrocarbazole

In the reaction flask, 6-methoxy-2,3,4,9-1 /-tetrahydrocarbazole (2.5 g, 12 mmol) and THF (20 mL) were added, dissolved and cooled to _1 (TC, Slowly add NaH (1.5 g, 36 mmol), add, stir for 30 minutes, add 2.5 mL of methyl iodide, add, add to room temperature for 30 minutes, then heat to 50 ° C, reaction for 1.5 hours, reaction After completion, it was cooled to room temperature, EtOAc (EtOAc)EtOAc.

1.2 Preparation

In the reaction flask, the compound 6-methoxy-9-methyl-2,3,4,9-tetrahydrocarbazole (0.7 g, 3.2 mmol) obtained in the above step 1.1 was added, 40% aqueous solution of HBr and acetic acid. Each of 10 mL, heated to 110 ° C, and reacted for 6 hours, the starting material was completely reacted, cooled to room temperature, extracted with water and ethyl acetate, concentrated and purified by preparative chromatography, PET: EA = 10% to give the title compound as a yellow solid.

Step 2, (2S)-2-(((9-methyl-2,3,4,9-tetrahydro-1H-indazole-6-yloxy) ((2R, 3R, 4R, 5R) - 5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy) Preparation of phosphato)amino)propionic acid isopropyl ester

Taking 6-hydroxy-9-methyl-2,3,4, tetrahydrocarbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2' Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the title compound was obtained by the same procedure as in Example 1.

3⁄4 NMR (500MHz, DMS0) δ ppm: ll.48 (s, 1H), 7.49-6.90 (m, 4H), 6.04-5.97 (m, 2H), 5.90-5.81 (m, 1H), 5.49-5.41 (m , 1H), 4.88-4.83 (m, 1H), 4.38-4.33 (m, 1H), 4.22-4.20 (m, 1H), 4.02—3.99 (m, 1H), 3.82—3.79 (m, 2H), 3.57 (s, 3H), 2.69 (m, 4H), 1.84-1.77 (m, 4H), 1.27-1.22 (m, 6H), 1· 19- 1· 13 (m, 6H

ESI-MS m/z: [M+Na] ⁺ = 659.2.

Example 19 (2S)-2-(((9-Methyl-^"carbazol-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3, 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

Step 1. Preparation of 2-hydroxy- 9-methyl-^ "carbazole

1.1 2- -9-methyl - 5 ^

2-Hydroxy-g/-carbazole (915 mg, 5 mmol), THF (15 mL) was added to a reaction flask, and NaH (130 mg, 20 mmol) was added in portions at 0 °C for 30 min. Further, a solution of iodothymidine (568 mg, 20 mmol) in THF (5 ml) was added and the mixture was reacted at 30 ° C overnight (about 10 h). The reaction was quenched by EtOAc (EtOAc)EtOAc.

1.2 2- - 9-Methyl-^ "Preparation of carbazole

2-methoxy-9-methyl-9/-carbazole (730 mg) was added to the reaction flask, 40% HBr aqueous solution and glacial acetic acid were added, and the reaction was completed at 105 ° C for 24 h, and the reaction was monitored by TLC. The reaction solution was added to 20 ml of water, extracted with dichloromethane for 3 times and purified by silica gel column. The title compound was obtained.

Step 2, (2S) -2- ((9-Methylcarbazole-2-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, Preparation of 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

2-hydroxy-9-methyl-9/-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4 NMR (300MHz, DMSO-c6) δ ppm: 11.45 (s, 1H), 8.10-8.11 (d, 1H), 7.95-7.97 (d, 1H), 7.60-7.61 (m, 1H), 7.59-7.60 (m , 1H), 7.56-7.58 (m, 1H), 7.44-7.45 (m, 1H), 7.36-7.38 (m, 1H), 7.19-7.22 (m, 1H), 7.07-7.09 (m, 1H), 6.05 -6.07 (m, 2H) , 5.91 (m, 1H), 5.26 (s, 1H), 4.83—4.89 (m, 1H), 4.31—4.48 (m, 1H), 3.92—4.14 (m, 1H), 3.84 —3.93 (m, 5H), 1.25—1.26 (m, 6H), 1.11-1.14 (m, 6H).

ESI - MS m/z: [M+H] ⁺ = 633.3.

Example 20 (2S)-2-((dibenzo[b,d]furan-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) -3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid

Step 1. Preparation of 3-hydroxy-dibenzo[b,dfuran]

1.1 Preparation of 3-amino-dibenzo[b,dfuran]

3-Nitrodibenzofuran (4 g), reduced iron powder (5.26 g), ammonium chloride (5 g) were placed in a reaction flask, ethanol (150 mL) was added, and refluxed at 90 ° C until TLC Monitor the reaction of the starting material completely and stop the reaction. After cooling, suction filtration, and the filtrate was concentrated under reduced pressure.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 7.84-7.82 (m, 1H), 7.71-7.69 (d, 1H), 7.52-7.50 (m, 1H), 7.30-7.25 (m, 2H) , 6.75-6.75 (d, 1H), 6.64-6.62 (m, 1H), 5.57 (s, 2H).

IX-MS m/z: [M+H] ⁺ = 184.

Preparation of 1.23-bromo-dibenzo[b, furan

3-Amino-dibenzo[6,c]furan (1 g, 5.46 mmol) was dissolved in acetonitrile (10 mL), and butyl nitrite (731 mg, 7.10 mmol) was slowly added dropwise under ice bath, then Then slowly add copper bromide ( 1.46 g, 6.55 mmol), add the reaction solution, stir the reaction to 50 ° C for 1 hour, the reaction is finished, the reaction of the raw materials is completed, water (1 mL) is quenched, filtered, and the filtrate is added. Chloroformamide (20 mL), EtOAc (EtOAc)EtOAc.

3⁄4 NMR (400 MHz, DMS0- c _s ) δ ppm: 8.16 (m, 1H), 8.11— 8.13 (d, 1H), 8.02 (s, 1H), 7.71-7.73 (d, 1H), 7.56-7.58 ( m, 2H), 7.42-7.45 (m, 1H).

Preparation of 1.3-formyl-dibenzo[b,dfuran]

3-Bromo-dibenzo[6,c]furan (247 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and n-butyllithium (0.6 mL) was slowly added dropwise at -78 °C. Continue to cool at _78 ° C for 30 minutes, then slowly add DMF (0.1 mL), and add to the mixture. Stir to room temperature and stir for 10 minutes. The reaction is complete, and the aqueous solution of ammonium chloride (0.2 mL) is added dropwise to quench. Column purification gave the title compound as a yellow solid.

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 10.15 (s, 1H), 8.38-8.40 (d, 1H), 8.300 (m, 1H), 8.24 (s, 1H), 7.98-7· 98 (m, 1H), 7.79-7· 82 (d, 1H), 7.65-7.66 (m, 1H), 7.47-7.49 (m, 1H).

1.4 Preparation of 3-formyloxy-dibenzo[b,dfuran]

Dissolve 3-formyl-dibenzo[6,c]furan (160 mg, 0.81 mmol) in anhydrous dichloromethane (4 mL), then slowly add m-chloroperoxybenzoic acid at room temperature ( m-CPBA), after the addition, the reaction solution was stirred at room temperature overnight until the end of the reaction. Water (2 mL), EtOAc (EtOAc m.

Preparation of 1.5 3-hydroxy-dibenzo[b,d furan

3-formyloxy-dibenzo[6,c]furan (130 mg, 0.6 mmol) was dissolved in methanol (3 mL), then 5% aqueous sodium hydroxide (3 mL) After reacting at room temperature for 30 minutes, the reaction was completed, and the pH was adjusted to 2 with 2N hydrochloric acid, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl ether: ethyl acetate = 50:1) The title compound, white solid.

3⁄4 NMR (400 MHz, DMSO-c _s ) δ ppm: 9.94 (s, 1H), 7.95-7.98 (m, 1H), 7.88-7.90 (m, 1H), 7.58-7.60 (d, 1H), 7.32- 7.34 (m, 2H), 7.01-7.02 (d, 1H), 6.83-6.86 (m, 1H).

Step 2, (2S) -2- ((dibenzo[b,d]furan-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl Preparation

3-hydroxy-dibenzo-3⁄4iJ furan, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro-2' Using methyl uridine as a starting material, the title compound was obtained in the same manner as in Example 1.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.51 (s, 1H), 8.11-8.15 (m, 2H), 7.68-7.71 (d, 1H), 7.60-7.61 (m, 2H), 7.51 (m, 1H), 7.39 (m, 1H), 7.28 (m, 1H), 6.17-6.18 (m, 1H), 5.89 (m, 1H), 5.88 (m, 1H), 5.56-5.59 (d, 1H ), 4.81-4.85 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.03 (m, 1H), 3.85-3.88 (m, 2H), 1.23-1.29 (m, 6H), 1.09-1.12 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 620.

Example 21(2S)- 2-(((spiro[cyclopropane-1,9'-芴]-2'-yloxy)(((2R, 3R, 4R, 5R)- 5- (2, 4 -dioxo-3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-

Step 1. Preparation of 2'-hydroxyspiro [cyclopropane-1,9'-芴]

1.1

In a reaction flask, 2-bromoindole (2 g) was dissolved in THF (10 mL), and LiHMDS (lithium hexamethyldisilazide) (9.8 mL) was slowly added at _78 ° C, and the addition was completed. Stir for 1 h, then to 0 °C. The above mixture was slowly added to a solution of 1,2-dibromoacetone (10.5 g) in THF (10 mL). The reaction mixture was further reacted at 0 ° C for 1 h, TLC showed the end of the reaction and quenched with methanol (1 mL) The solvent was removed and the crude was purified eluting elut elut elut elut eluting

3⁄4匪R (400 MHz, MSO-de) δ ppm: 7.83-7.91 (m, 3H), 7.57-7.65 (m, 2H), 7.37-7.41 (m, 2H), 4.16 (m, 1H), 3.40-3.44 (m, 2H), 2.43-2.50 (m, 2H).

1.2

In a reaction flask, 2-bromo-9-(2-bromoethyl)-9 /-oxime (1. lg) was dissolved in DMF (5 mL), and NaH (248 mg) was slowly added at 0 °C. Then react to room temperature for 12 h. TLC showed the end of the reaction, was quenched with saturated NH ₄ C1 (1 mL) solution, diluted with EA (20 mL), and washed sequentially with 10% LiCl solution (5 mL X3) and saturated brine (5 mL). The organic phase was dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 7.87-7.95 (m, 2H), 7.51-7.53 (m, 1H), 7.46 (s, 1H), 7.31-7.38 (m, 2H), 7.19 -7.21 (m, 1H), 1.80-1.86 (m, 2H), 1.74-1.79 (m, 2H).

Preparation of 1.3 '-formyl snail [cyclopropane - 1,9' - fluorene]

In the reaction flask, 2'-bromospiro[cyclopropene-1,9'-芴] (500 mg) was dissolved in THF (5 mL) and slowly added to n-butyl at -78 °C under nitrogen. Base lithium (0.86 mL), maintain the reaction at this temperature for 1 h _; then add DMF (0.5 mL), stop cooling, naturally warm to room temperature, and TLC showed the end of the reaction, quenched with saturated NH ₄ C1 (1 mL) Add EA (20 mL) and dilute with 10% LiCl solution (5 mL X 2), brine (5 mL), EtOAc. Purify by silica gel column chromatography (EtOAc EtOAc EtOAc

3⁄4 匪R (400 MHz, DMS0-c _e ) δ ppm: 10.03 (s, 1H), 8.16-8.18 (d, 1H), 8.06-8.09 (m, 1H), 7.92-7.94 (m, 1H), 7.766 (s, 1H), 7.41-7.43 (m, 2H), 7.27-7.30 (m, 1H), 1.90-1.94 (m, 2H), 1.81-1.84 (m, 2H).

Preparation of 1.4 '-formyloxyspiro[cyclopropane-1,9'-芴]

In the reaction flask, 2'-formyl spiro[cyclopropane-1,9'-芴] (210 mg) was dissolved in DCM (dichloromethane) (10 mL), and m-CPBA was slowly added at room temperature. (328 mg) (m-chloroperoxybenzoic acid), then reacted at 25 ° C for 3 h until TLC showed the end of the reaction. Was added DCM (20 mL) was diluted and washed sequentially with saturated NaHC0 ₃ solution (5 mL X 2), saturated brine (5 mL), dried combined organic phase was dried over anhydrous sodium sulfate, filtered and the DCM was removed under reduced pressure, The title compound was obtained as a yellow solid.

Preparation of 1.5 2'-hydroxyspiro[cyclopropane-1,9'-芴]

In the reaction flask, 2'-formyloxyspiro[cyclopropene-1,9'-芴] (260 mg) was dissolved in MeOH/0 (3 mL/1 mL), and K ₂ was slowly added at room temperature. C0 ₃ (303 mg) was then reacted at 50 ° C for 1.5 h until TLC showed the end of reaction. Methanol was removed under reduced pressure, EtOAc (EtOAc) (EtOAc)EtOAc. Purify by silica gel column chromatography (EtOAc EtOAc EtOAc

3⁄4 NMR (400 MHz, DMS0-c _e ) δ ppm: 9.48 (s, 1H), 7.67-7.74 (m, 2H), 7.08-7.29 (m, 3H), 6.74—6.77 (m, 1H), 6.52— 6.53 (m, 1H), 1.67-1.71 (m, 2H), 1.60-1.63 (m, 2H).

Step 2, (2S)-2-(((spiro[cyclopropane-1,9'-芴]-2'-yloxy) (((2R, 3R, 4R, 5R)- 5- (2, 4 -dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid Preparation of isopropyl ester

2'-hydroxyspiro[cyclopropene-1,9'-芴], phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxygenation The title compound was obtained by the same procedure as in Example 1 using -2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.44 (s, 1H), 7.88-7.91 (s, 2H), 7.57-7.59 (m, 1H), 7.17-7.36 (m, 4H), 7.07 (s, 1H), 6.07-6.13 (m, 2H), 5.93 (br, 1H), 5.56—5.58 (m, 1H), 4.83—4.87 (m, 1H), 4.37—4.41 (m, 1H), 4.25 -4.27 (m, 1H), 4.0—4.04 (m, 1H), 3.80—3.87 (m, 2H), 1.69—1.78 (m, 4H), 1.23-1.28 (m, 6H), 1.13-1.15 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 644.

Example 22 (2S)-2-(((pyrido[1,2-a]benzimidazole-7-yloxy)(((2R, 3R, 4R, 5R)-5-(2, 4- Dioxo-3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy

4-Methoxy-2-nitroaniline (1.68 g) was dissolved in acetonitrile (30 mL), then t-butyl nitrite (1.34 g) was slowly added dropwise at ice bath temperature, followed by copper bromide ( 2.67 g) slowly added to the reaction flask, the reaction solution was heated to 80 ° C under nitrogen for 2 hours, the reaction was completed, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA = 20:1) , yellow solid.

1.2 Preparation of 2-bromo-5-methoxyaniline

o'

1-Bromo 4-methoxy-2-nitrobenzene (2.1 g) was dissolved in methanol (10 mL), then iron powder (1.5 g) was added, and concentrated hydrochloric acid (2 mL) was added to the reaction mixture. After refluxing for 2 h, it was cooled to room temperature, solid sodium carbonate was added until no bubbles appeared, and extracted with EA. The EA layer was washed with saturated brine, dried, filtered, and the solvent was removed under reduced pressure. The crude product was separated by silica gel column chromatography (PE: EA Purification of the title compound as a pale yellow oil.

LC-MS m/z: [M+H] ⁺ = 202.

Preparation of N-N- 2-bromo-5-methoxyphenyl)pyridin-2-amine

2-Bromo-5-methoxyaniline (1.2 g) was dissolved in anhydrous dioxane (6 mL), 2-bromopyridine (0.68 mL), tris(dibenzylideneacetone) dipalladium (Pd2) (dba) 3, 100 mg), 4, 5-bisdiphenylphosphino-9, 9-dimethyloxaxime (Xant-phos, 50 mg) and cesium carbonate (2.87 g), added, reaction solution The mixture was heated to 100 ° C under a nitrogen atmosphere, and the mixture was stirred for 3 hours. The reaction mixture was evaporated.

LC-MS m/z: [M+H] + = 280.

Preparation of 1.4 7--pyrido[1,2a]benzimidazole

Dissolve N-(2-bromo-5-methoxyphenyl)pyridin-2-amine (lg) in anhydrous acetonitrile (10 mL), then add potassium carbonate (590 mg), hydrazine, Ν'-dimethyl Ethylenediamine (315 mg) and cuprous iodide (68 mg), the reaction solution is heated to 80 ° C under nitrogen atmosphere to react overnight, the reaction is completed, filtered, and the filtrate is concentrated under reduced pressure, and the concentrate is directly separated by silica gel column chromatography. Title compound, yellow solid.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 9.06-9.08 (d, 1H), 8.23-8.25 (d, 1H), 7.66-7.68 (d, 1H), 7.56-7.58 (m, 1H) , 7.31-7.32 (d, 1H), 7.01-7.05 (m, 1H), 3.91 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 199.

Preparation of 1.5-Hydroxy-pyrido[1,2a]benzimidazole

Dissolve 7-methoxy-pyrido[1,2a]benzimidazole (210 mg) in dichloromethane (10 mL), cool to -78 ° C, then slowly add boron tribromide (550 mg) After the addition, the reaction was carried out for 1 hour at room temperature. After the reaction was completed, it was quenched with ice water, then methanol (5 mL) was evaporated, washed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (30mL×3) Dry over sodium sulfate and 3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 9.55 (br, 1H), 8.95-8.97 (d, 1H), 8.07-8.09 (d, 1H), 7.45-7.57 (m, 2H) , 7.05 -7.06 (d, 1H), 6.91-6.94 (m, 1H), 6.84-6.86 (m, 1H).

LC-MS m/z: [M+H] ⁺ = 185.

Step 2, (2S)-2-(((pyrido[1,2- a]benzimidazole-7-yloxy)(((2R, 3R, 4R, 5R)-5-(2, 4- Dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid Preparation of propyl ester

Taking 7-hydroxy-pyrido[1,2a]benzimidazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.51 (br, 1H), 9.07-9.09 (d, 1H), 8.30-8.32 (d, 1H), 7.55-7.68 (m, 4H), 7.22 -7.25 (m, 1H), 7.01-7.04 (m, 1H), 5.92-6.14 (m, 3H), 5.51—5.57 (m, 1H), 4.82—4.85 (m, 1H), 4.28—4.38 (m, 2H), 4.02-4.04 (m, 1H), 3.80-3.89 (m, 2H), 1.19-1.28 (m, 6H), 1.12-1.15 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 620.

Example 23 (2S)-2-(((pyrido[1,2-a]benzimidazole-8-yloxy)(((2R, 3R, 4R, 5R)-5-(2, 4- Dioxo-3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyl)propanoic acid isopropyl ester

Step 1. Preparation of 8-hydroxy-pyrido[1,2a]benzimidazole

Preparation of 1-bromo 4-methoxy-1-nitrobenzene

5-methoxy-2-nitroaniline (3 g) was dissolved in acetonitrile (30 mL), then t-butyl nitrite (2.78 mL) was slowly added dropwise at ice bath temperature, and then copper bromide ( 4.7 g) Slowly added to the reaction flask, and the reaction mixture was heated to 65 ° C for 2 hours under nitrogen atmosphere. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by column chromatography.

Preparation of 1.2-bromo-4-methoxyaniline

2-Bromo 4-methoxy-1-nitrobenzene (4.3 g) was dissolved in ethanol (15 mL), then iron powder (4 g) and ammonium chloride (7.8 g) were added, and finally water (15 mL) was added. The reaction solution was reacted at 90 ° C for 3 hours, the reaction was completed, the reaction solution was cooled to room temperature, the solid was filtered off, and the filter cake was washed with dichloromethane, and the filtrate was used. The mixture was extracted with chloroformamide, washed with EtOAc (EtOAc)

¾ bandit R (400 MHz, DMS0-c e) δ ppm: 6.69-6.96 (m, 1H), 6.67-6.74 (m, 2H), 4.08 (s, 2H), 3.64 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 202.

Preparation

2-Bromo-4-methoxyaniline (1.2 g) was dissolved in anhydrous dioxane (6 mL), 2-bromopyridine (0.68 mL), tris(dibenzylideneacetone) dipalladium (100 mg) , 4, 5-bisdiphenylphosphino-9, 9-dimethyloxaxanthene (50 mg) and cesium carbonate (2.87 g), after completion, the reaction solution is heated to 10 under nitrogen protection (TC stirring reaction 3 After the reaction was completed, the residue was evaporated.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 8.13 (s, 1H), 7.99-8.00 (m, 1H), 7.46-7.54 (m, 1H), 7.22 (m, 1H), 6.93-6.94 (m, 1H), 6.63-6.66 (m, 2H), 3.76 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 280.

1.4

Dissolve N-(2-bromo-4-methoxyphenyl)pyridin-2-amine (lg) in anhydrous acetonitrile (10 mL), then add potassium carbonate (590 mg), hydrazine, Ν'-dimethyl Ethylenediamine (315 mg) and cuprous iodide (68 mg), the reaction solution is heated to 80 ° C under nitrogen for reaction overnight, the reaction is completed, the solid is filtered off, the filtrate is concentrated under reduced pressure, and the concentrate is directly separated by silica gel column. The title compound was obtained as a yellow solid.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 8.98-9.00 (d, 1H), 7.90 (s, 1H), 7.68-7.71 (d, 1H), 7.58-7.60 (m, 1H), 7.42 -7.44 (m, 1H), 7· 11- 7· 14 (m, 1H), 6.92-6.95 (m, 1H), 3.88 (s, 3H).

LC-MS m/z: [M+H] ⁺ = 199.

Preparation of 1.5-Hydroxy-pyrido[1,2a]benzimidazole

Dissolve 8-methoxy-pyrido[1,2a]benzimidazole (100 mg) in dichloromethane (3 mL), cool to -78 ° C, then slowly add boron tribromide (0.096) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The extract was dried over anhydrous sodium

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 9.54 (s, 1H), 8.84-8.86 (d, 1H), 7.60-7.62 (d, 1H), 7.54-7.55 (m, 2H), 7.38-7.40 (m, 1H), 7.01-7.04 (d, 1H), 6.85-6.88 (m, 1H).

LC-MS m/z: [M+H] ⁺ = 185.

Taking 8-hydroxy-pyrido[1,2a]benzimidazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2' The title compound was obtained by the same procedure as in Example 1 using fluoro-2'-methyluridine as a starting material.

3⁄4匪R (400 MHz, DMS0-c _e ) δ ppm: 11.50 (s, 1H), 8.98-8.99 (d, 1H),

8.19 (s, 1H), 7.77-7.80 (m, 1H), 7.64 (m, 1H), 7.54 (m, 2H),

7.40-7.43 (m, 1H), 6.97-6.99 (m, 1H), 6.07-6.13 (m, 2H), 5.91 (m, 1H), 5.51—5.55 (m, 1H), 4.80—4.84 (m, 1H) ), 4.41—4.44 (m, 1H), 4.31 (m, 1H), 3.88-4.02 (m, 1H), 3.82-3.86 (m, 2H), 1.21-1.26 (m, 6H), 1.08-1.11 (m , 6H).

LC-MS m/z: [M+H] ⁺ = 620.

Example 24 (2S) -2- ((9-Methylcarbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid ethyl ester

4-Hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2' R) -2' prepared by the first step of Example 2. The desired compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMS0-c _e ) δ ppm: 11.46 (s, 1H), 8.20-8.23 (d, 1H), 7.61-7.63 (m, 1H), 7.40-7.50 (m, 4H), 7.17- 7.24 (m, 2H) , 6.24-6.32 (m, 1H), 5.90-6.05 (m, 2H), 5.15 (s, 1H), 4.83-4.89 (m, 1H), 4.32 (m, 1H), 4.04 ( m, 1H), 3.92-3.93 (m, 2H), 3.84-3.92 (m, 5H), 1.05-1.22 (m, 6H), 1.01-1.02

(m, 3H).

LC-MS m/z: [M+H] ⁺ = 619.

Example 25 (2S) -2- ((9-Methylcarbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanate cyclopentyl ester

Step 1. Synthesis of L-alanine cyclopentyl ester hydrochloride

L-alanine (8.9 g, 100 mmol) was weighed into a 250 mL round bottom flask, and 20 ml of cyclopentanol was added. Under ice bath, thionyl chloride (11.9 g, 100 mmol) was slowly added, and the temperature was slowly raised to room temperature. The reaction was carried out at room temperature overnight, concentrated, EtOAc EtOAc (EtOAc)

Step 2, (2S) -2- ((9-Methyl-^"carbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3, 4-Dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid benzyl ester

4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine cyclopentyl ester hydrochloride, pentafluorophenol and (2' R) -2 prepared in the first step of Example 2. The target compound was obtained by the same procedure as in Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMS0-c _e ) δ ppm: 11.15 (s, 1H), 8.21-8.24 (d, 1H), 7.59-7.62

(m, 1H), 7.41-7.50 (m, 4H), 7.16-7.21 (m, 2H), 6.22-6.26 (m, 1H),

6.04-6.18 (m, 2H) , 5.19 (s, 1H), 5.02-5.17 (m, 1H), 4.44-4.45 (m, 1H),

4.42 (m, 1H), 4.01—4.02 (m, 1H), 3.88—3.92 (m, 5H), 1.25— 1.28 (m, 6H),

1.21-122 (m, 8H).

LC-MS m/z: [M+H] ⁺ = 659.

Example 26 (2S)-2-(((9-Methyl-^"carbazole-4-yloxy)((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) -3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid benzyl ester

4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine benzyl ester hydrochloride, pentafluorophenol and (2' R) -2' prepared in the first step of Example 2. The desired compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4 NMR (300MHz, DMS0-c _e ) δ ppm: 11.508 (s, 1H), 8.22-8.25 (d, 1H), 7.59-7.62 (m, 1H), 7.47-7.50 (m, 3H), 7.38-7.41 (m, 4H), 7.13-7.18 (m, 3H), 6.36-6.40 (m, 1H), 5.90-6.04 (m, 2H), 4.83-5.15 (m, 3H), 4.33-4.44 (m, 2H) , 4.04 (m, 2H), 3.88 (m, 3H), 3.55 (m, 2H), 1.24-1.26 (m, 6H). LC-MS m/z: [M+H] ⁺ = 681.

Example 27 (2S)-2-(((9-Methyl-^"carbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-di) Oxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid

Step 1. Synthesis of L-alanine neopentyl ester hydrochloride

Starting from L-alanine and neopentyl alcohol, the title compound was obtained in the same manner as in Example 25 Step 1. Step 2, (2S) -2- ((9-Methyl-^"carbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3,4-Dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid neopentyl ester

4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine neopentyl ester hydrochloride, pentafluorophenol and (2' R) -2 prepared in the first step of Example 2. The target compound was obtained by the same procedure as in Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMS0-c _e ) δ ppm: 11.48 (s, 1H), 8.22-8.24 (d, 1H), 7.59-7.62 (m, 1H), 7.45-7.48 (m, 4H), 7.15- 7.22 (m, 2H), 6.29-6.33 (m, 1H), 5.91-5.98 (m, 1H), 5.20-5.22 (s, 1H), 4.46-4.47 (m, 1H), 4.32 (m, 1H), 4.29-4.31 (m, 1H), 4.06-4.12 (m, 1H), 3.96-3.99 (m, 1H), 3.84-3.92 (m, 4H), 3.80-3.87 (m, 2H), 1.24-1.28 (m , 6H), 1.22-1.23 (m, 9H).

LC-MS m/z: [M+H] ⁺ = 661.

Example 28 (2S)-2-(((9, 9-Dimethyl-5^ 芴-4-yloxy) (((2R, 3R, 4R, 5R)-5-(2, 4-) Oxo-3, 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methylpropyl ester

Step 1, 2'-methylbiphenyl- 2-

Weigh 2-methylbenzeneboronic acid (lg, 7.35 mmol), methyl iodobenzoate (1.75 g, 6.7 mmol), Pd(dppf)Cl ₂ (0.47 g, 0.67 mmol), cesium carbonate (2.8 g, 20 mmol) In a 250 mL eggplant-shaped flask, 50 mL of 1,4-dioxane and 5 mL of water were added, and the reaction was carried out at 90 ° C for 1.5 h under nitrogen atmosphere. After the reaction was completed, ethyl acetate (100 mL) was added. Saturated aqueous sodium chloride solution (50 mL), extracted with a sep. funnel, washed three times, then the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography The title compound was purified.

LC-MS m/z: [M+H] ⁺ = 227

Step 2 Synthesis of 4-methyl-9-fluorenone

Weigh the 2'-methylbiphenyl-2-carboxylic acid methyl ester (lg 4.42mmol) from step 1 and put it into a 100mL eggplant-shaped bottle, then add 2ml of concentrated sulfuric acid, stir at room temperature for 1.5h, stop the reaction, The reaction solution was poured into ice water, a saturated sodium carbonate solution was added, and the mixture was adjusted to neutral, and ethyl acetate (100 mL) was added, and the mixture was extracted with a separating funnel, washed with water three times, and then the organic phase was collected. Drying, filtration, concentration and purification by column chromatography gave the title compound.

LC-MS m/z: [M+H] ⁺ =195

Step 3 4 9 9-Trimethyl-9-anthracene synthesis

In a 50 ml single-mouth bottle, replace with argon three times, and take a solution of dimethylzinc toluene (30 ml of 30 mmol -50 ° C with titanium tetrachloride (3.5 ml 60 mmol) and stir for 1 hour, then take step 2 4-methyl-9-fluorenone (1.94 g lOmmol) was added to 2 ml of dichloromethane, and slowly dropped into a single-mouth bottle. After the reaction was completed, it was poured into ice water and quenched, and ethyl acetate (500 mL) was added. The mixture was extracted with a sep. funnel, washed with water, and then filtered, and then evaporated.

LC-MS m/z: [M+H] ⁺ =209

Step 4 9,9-Dimethyl-4-hydroxymethyl-9

In a 100 mL single-mouth bottle, add the step 4 9 49-trimethyl-9-oxime (1. lg 5 1) carbon tetrachloride 5 ml NBS (lg 5.6 mmol) and azobisisobutyronitrile (ΑΙΒΝ The mixture was heated to reflux with EtOAc (EtOAc)EtOAc. The obtained crude product was placed in a 250 mL single-mouth bottle, and potassium carbonate (910 mg 6.6 mmol), water 20 ml, and P 1 4-dioxane 50 ml were added, and the mixture was heated to 90 ° C for 3 hours, and the reaction was completed. 500 mL), extracted with a sep. funnel, washed with water over 3 EtOAc.

LC-MS m/z: [M+H] ⁺ =225

Step 5 9,9-Dimethyl-4-formyl-9H-indole

The product of step 4, 9,9-dimethyl-4-hydroxymethyl-9H-indole (400 mg, 1.7 mmol) was placed in a 50 mL single-mouth bottle, 15 ml of dichloromethane was added, and pyridine chromium chloride was added under ice bath. The acid salt (PCC, 1.2 g, 6 mmol) was evaporated. EtOAc (EtOAc) (EtOAc) Purification by column chromatography gave the title compound.

LC-MS m/z: [M+H] ⁺ = 223.

Step 6, 4-hydroxy- 9,9-dimethyl-9-

The product of step 5, 9,9-dimethyl-4-formyl-911-oxime (20011^, 0.95 mmol) was placed in a 50 mL single-mouth bottle, and 15 ml of dichloromethane was added thereto. Oxybenzoic acid (mCPBA, 500 mg, 3 mmol), warmed to room temperature and stirred at room temperature overnight. After the reaction was completed, ethyl acetate (200 mL) was added and extracted with a sep. funnel. After 3 times, it was dried over anhydrous sodium sulfate, filtered, and concentrated, dried, then 15 ml of methanol, K0H (56 mg, lmmol), and reacted at room temperature. After completion of the reaction, ethyl acetate (200 mL) was added and extracted with a separating funnel. The organic phase was collected, washed with anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography.

LC-MS m/z: [M+H] ⁺ = 211.

Step 7, (2S) -2- ((9, 9-Dimethylindole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo- 3, 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester

The product obtained in step 6 is 4-hydroxy-9,9-dimethyl-9-indole, phosphorus oxychloride, isopropyl isopropylate hydrochloride, pentafluorophenol and (2' R) -2' Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in Example 1 was carried out to obtain the target compound.

3⁄4匪R (300MHz, DMS0-c _e ) δ ppm: 11.46 (s, 1H), 8.20-8.23 (d, 1H), 7.66-7.69 (m, 1H), 7.38-7.47 (m, 4H), 7.19- 7.21 (m, 2H), 6.23-6.27 (m, 1H), 6.02-6.19 (m, 1H), 5.86-5.95 (m, 1H), 5.08 (s, 1H), 4.88-4.90 (m, 1H), 4.45-47 (m, 1H), 4.30-41 (m, 1H), 4.28-4.31 (m, 1H), 3.92-3.94 (m, 2H), 1.05-1.22 (m, 18H).

LC-MS m/z: [M+H] ⁺ = 659.

Example 29 (2S)-2-(((9-Cyclopropylcarbazol-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3) , 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester Step 1, 4-methoxy-9H-oxime

Weigh 4-hydroxycarbazole (9. lg, 50 excitation 1), potassium carbonate (6.9 g, 50 excitation 1) into a 500 ml three-necked flask, add 250 ml of acetone, and slowly add sulfuric acid in an ice bath. The methyl ester (4.8 ml, 50 mmol) was reacted at room temperature for 2 h. After the reaction was completed, ethyl acetate (100 mL) was added and the organic phase was washed with water, brine, dried, filtered, Compound.

LC-MS m/z: [M+H] ⁺ = 198.

Step 2. 9-Cyclopropyl-4-methoxy-9H-

The obtained step 1 was weighed 4-methoxy-9H-carbazole (3. 96 g, 20 mmol), copper acetate (4.0 g, 20 mmol), cyclopropylboronic acid (3.44 g, 40 mmol) and DMAP (7. 32 g, 60 mmol) was placed in a 500 ml eggplant-shaped flask, 200 ml of toluene and 20 ml of sodium bis(trimethylsilyl)amide (NaHMDS) were added, and reacted at 95 ° C for 4 h. After completion of the reaction, it was diluted with ethyl acetate (500 mL). The organic phase was washed with water, brine, dried, filtered,

LC-MS m/z: [M+H] ⁺ = 238.

Step 3, 9-cyclopropyl-4-hydroxy- 9H-

The step 9 was weighed and the 9-cyclopropyl-4-methoxy-9H-carbazole (1. 19 g, 5 mmol) was placed in a 250 ml eggplant-shaped flask, and 100 ml of dichloromethane was added thereto at -50 °C. Next, slowly add BBr ₃ (7ml, 7. 5 excitation 1), add, and react at -20 °C for 4h. After the reaction is completed, slowly add 200ml of water, extract with ethyl acetate (500mL), and then wash the organic phase with water. Washed with brine, dried, filtered, evaporated LC-MS m/z: [M+H] ⁺ = 224.

Step 4, (2S) -2- ((9-Cyclopropyl-^ "carbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) 3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester Preparation

The product obtained in step 3 is 9-cyclopropyl-4-hydroxy-9H-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'- The target compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMS0-c _e ) δ ppm: 11.45 (s, 1H), 7.97-7.98 (d, 1H), 7.53-7.56 (m, 2H), 7.36-7.38 (m, 2H), 7.27- 7.30 (m, 3H), 6.20-6.22 (m, 1H), 6.18-6.20 (m, 1H), 6.00-6.05 (m, 1H), 5.31 (s, 1H), 4.86-4.89 (m, 1H), 4.45-4.47 (m, 1H), 4.32- 4.33 (m, 1H), 4.29-4.31 (m, 1H), 3.87- 3.89 (m, 2H), 2.42 (m, 1H), 1.42-1.43 (m, 6H ), 1.32 (m, 2H), 1.28 (m, 2H), 1.23-1.24 (m, 6H).

LC-MS m/z: [M+H] ⁺ = 659.

Example 30 (2S)-2-((dibenzo[b,d]furan-1-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) -3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid

Preparation of step 1, 3, 4, 6, 7, 8, 9-hexahydrodiphenyl-1(2H)-one

In a 250 mL three-necked flask, 1,3-cyclohexanedione (llg, 0.1 mol), cyclohexanone (10 g, 0.1 mol), xylene 100 ml, p-toluenesulfonic acid 0.45 g (0. Olmol) , adding a water trap, refluxing at 170 ° C for 5 h, after completion of the reaction, cooling to room temperature, concentration and purification by column chromatography to give the title compound.

Step 2, 1-hydroxydibenzo[b, d]fur

In a 250 mL single-mouth bottle, add the step 3, 3, 4, 6, 7, 8, 9-hexahydrodibenzo[b,d]furan-1(2H)-one 5.2 g (0.027 mmol), pair Isopropyltoluene 80 mL, 10%Pa/C3g, was refluxed at 170 ° C for 18 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled, filtered, concentrated and purified by column chromatography. Step 3, (2S) -2- ((dibenzo[b,d]furan-1-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3,4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl Preparation

The product obtained in the step 2 is 1-hydroxydibenzo[b,d]furan, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride The target compound was obtained by the same procedure as in Example 1 using salt, pentafluorophenol and (2'R) -2'-deoxy-2'-fluoro-2'-methyluridine as starting materials.

3⁄4 NMR ((300MHz, DMSO-d ₆ ) δ ppm: 11.49 (s, 1H), 8.43 (m, 1H), 8.16 (d, 1H), 7.74 (d, 1H), 7.53-7.38 (m, 5H), 6.34 (m, 1H), 6.05 (m, 1H), 5.89 (m, 1H), 5.37 (m, 1H), 5.19 (m, 1H), 4, 84 (m, 1H), 4.45 (m, 1H) , 4.04 (m, 1H), 3.91 (m, 2H), 1, 26-1· 10 (m, 12H).

LC-MS m/z: [M+H] ⁺ = 620.

Example 31 (2S)- 2-(((5-Methyl-6-oxo-5,6-dihydrophenanthrin-4-yloxy) (((2R, 3R, 4R, 5R)-5) - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-

Step 1. 3-Hydroxy-N- (2-

The m-hydroxybenzoic acid (lg, 7.25 mmol) was dissolved in 20 ML N, N-dimethylacetamide, and thionyl chloride (1.3 g, 10.9 mmol) was added dropwise at 0-4 ° C, and the reaction was carried out at room temperature for 0.5 h. After that, the o-iodoaniline (1.6 g, 7.25 mmol) was added dropwise, and the reaction was completed, and the mixture was evaporated.

Step 2. Preparation of 3-methoxy-N- (2-formamide)

In a 100 mL single-mouth bottle, the 3-hydroxy-N-(2-iodophenyl)benzamide (0.5 g, 1.47 mmol) obtained in Step 1 was dissolved in DMF under ice bath, force B NaH (0.2 g, 4·42mmol), after stirring for 0.5h, add 1.33g (10.5mml) of dimethyl sulfate, add the mixture, react at room temperature for 2h, complete the reaction, quench with water and ice, extract with ethyl acetate and water, and dry. Filtration, concentration and purification by column chromatography gave the title compound.

Step 3. Preparation of 10-methoxy-5-methylphenanthridine-6 5H)-one

In a 100 mL single-mouth bottle, add the step 2-derived 3-methoxy-N(2-iodophenyl)methylbenzamide (0.5 g 1.36 1), dissolve in DMF 20 ml, add Pd (OAc) ₂ (50 mg). , 0.22mmol), PPh ₃ (70mg 0.267mmol), K ₂ C0 ₃ (0.4g, 2.9mmol), replaced with nitrogen three times, refluxed at 160 ° C for 3h, the reaction was cooled, added with water and ethyl acetate, dried, filtered, Concentrated, purified by column chromatography to give the title compound

Step 4, Preparation of 10-hydroxy-5-methylphenanthridine-6 (-ketone)

In a 100 mL single-mouth bottle, add the product of step 3 to 10-methoxy-5-methylphenanthridine-6(5H)-one (0.15 g 0.6 mmol), HBr/H ₂ 0 (40%, 5 ml). The reaction of the reaction mixture was carried out, and the mixture was evaporated.

Step 5 (2S)-2-(((5-Methyl-6-oxo-5,6-dihydrophenanthryl-10-yloxy) (((2R, 3R, 4R, 5R)- 5- (2,4-dioxo-3 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino Isopropyl propionate

The product obtained in the step 4 is 10-hydroxy-5-methylphenanthridine-6(5H)-one, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)- The target compound was obtained by the same procedure as in Example 1 using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4 匪R (500MHz, DMS0-d ₆ ) δ ppm: 11.47 (s, 1H) 9· 04 (d 1H 8.30 (d, 1H) , 7.8-7.3 (m, 6H) 6.39-6.30 (m, 1H) 5.80 -6.06 (m, 2H) 5.20 (m, 1H) 4.80 (m 2H), 4.40 - 4.25 (m, 2H) , 3.91 (m, 2H) , 3.78 (s, 3H) , 1.05-1.25 (m 12H) LC -MS m/z: [M+H] + = 661

Example 32 (2S)-2-(((9-Methylcarbazole-4-yloxy)(((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3 4 -dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoate

The product obtained in the first step of Example 2, 4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2' R) -2' The desired compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4 匪R (300MHz, DMS0-d ₆ ) δ ppm: 11.47 (s, 1H) 8.23 (d, 1H) 7.61-7.63 (d, 1H 7.40-7.50 (m, 4H) 7.17-7.24 (m, 2H) , 6.24-6.32 (m, 1H) 5.90-6.05 (m, 2H) , 5.15 (s 1H) 4.83-4.89 (m, 1H) 4.32 (m, 1H) 4.04 (m 1H 3.92-3.93 (m 5H) 3.60 (s 3H) 1.05-1.25 (m 6H)

LC-MS m/z: [M+H] ⁺ = 605

Example 33 (2S) -2- ((9H-芴- 4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3 4-dihydrol) Pyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester Step 1, 4-hydroxy- 9H-

The title compound was obtained by the same procedure as in Example 28 Steps 3, 4, 5 and

Step 2, 4-hydroxy- 9H-芴 system

In a 100 mL single-mouth bottle, add the 4-hydroxy-9H-purin-9-one (200 mg, 1.02 mmol) from the step 1, dissolve in methanol 20 ml, force B 10% palladium carbon 20 mg, and dilute hydrogen at room temperature. After the reaction was completed overnight, filtered and concentrated to give the title compound.

Step 3, (2S) -2- ((9H-芴- 4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-di Hydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)methyl propionate

The product obtained in step 2 is 4-hydroxy-9H-indole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro- The target compound was obtained by the same procedure as in Example 1 using 2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMSO—d ₆ ) δ ppm: 11. 46 (s, 1H), 8. 23 (d, 1H), 7. 61-7. 20 (m, 7H), 6. 24-6 . 32 (m, 1H), 5. 85-6. 05 (m, 2H), 5. 20 (s, 1H), 4. 83 (m, 1H), 4. 30 (m, 1H), 4. 14 (m, 1H), 3. 90 (m, 1H) , 3. 80 (d, 2H) , 3. 62 (m, 2H) , 1. 05-1. 25

(m, 12H).

LC-MS m/z: [M+H] + = 618.

Example 34 (2S)-2-(((9-Oxo-9H-indol-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo- 3, 4-dihydropyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl

The product obtained in the first step of Example 33, 4-hydroxy-9H-indol-9-one, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'- The target compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMSO—d ₆ ) δ ppm: 11.46 (s, 1H), 8.23 (d, 1H), 7.61-7.20 (m, 7H), 6.24-6.32 (m, 1H), 5.85-6.05 ( m, 2H), 5.20 (s, 1H), 4.83 (m, 1H), 4.30 (m, 1H), 4.14 (m, 1H), 3.90 (m, 1H), 3.80 (d, 2H), 1.05-1.25 (m, 12H). LC-MS m/z: [M+H] ⁺ = 632.

Example 35 (2S)-2-(((5-Methyl-6-oxo-5,6-dihydrophenanthridine-1-yloxy) (((2R, 3R, 4R, 5R)-5) - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl

Step 1, N-(3-hydroxybenzene

5 g (45.9 mmol) of m-aminophenol was added to a 500 ml single-mouth bottle, dissolved in 80 ml of THF, 14 g (56.5 mmol) of o-iodobenzoic acid, 13 g (67.8 mmol) of EDCI and 1.3 g (10.6 mmol) of DMAP were stirred at room temperature. After the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated

Step 2. Preparation of 1-hydroxy-5-methylphenanthridine-6-one

Using the N-(3-hydroxyphenyl) 2-iodobenzylamine as the starting material, the title compound was obtained according to the procedure of Steps 2, 3 and 4 of Example 31.

Step 3, (2S)-2-(((5-Methyl-6-oxo-5,6-dihydrophenanthr-1-yloxy) (((2R, 3R, 4R, 5R)-5) - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl Amino) isopropyl propionate

The product obtained in the step 2 is 1-hydroxy-5-methylphenanthridine-6(5H)-one, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)- The target compound was obtained by the same procedure as in Example 1 using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.

3⁄4匪R (300MHz, DMSO—d ₆ ) δ ppm: 11.50 (s, 1H) , 9.0 (d, 1H) 8.23 (d, 1H), 7.8-7.20 (m, 5H), 6.40-6.30 (m, 1H) ), 5.82-6.06 (m, 2H), 5.20 (m, 1H), 4.80 (m, 2H), 4.40 - 4.25 (m, 2H), 4.12 (m, 1H), 3.91 (m, 1H), 3.80 ( m, 1H), 3.65 (s, 3H), 1.05-1.25 (m, 12H). LC-MS m/z: [M+H] + = 661. Experimental Example 1 Pharmacological activity study:

Experimental material

1. 1 Reagents:

Table 1. Reagent list

Reagent name for.,Ί

DMEM Cell Culture Medium Invitrogen Fetal Bovine Serum (FBS) Gibco

L-Glutamine Invitrogen Penicillin - Streptomycin Solution Invitrogen

DPBS/Modified Hyclone

Trypsin / EDTA Invitrogen Dimethyl Sulfoxide (DMS0) Sigma

Bright - Glo Promega

Cell growth fluorescence titration test

Promega

Agent

1. 2 Huh7 lb cell line:

The Huh7 lb cell line was supplied by Shanghai WuXi PharmaTech Development Co., Ltd. as a Huh7 cell line containing the HCV lb replicon with a stable luciferase (Luc) reporter. It cloned the HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector by gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance screening, the HCV replicon was stably replicated and the related protein and luciferase were stably expressed in huh7 cells. This cell model is used for in vitro screening of anti-HCV compounds. The anti-HCV activity of the compounds was determined by examining the expression level of luciferase. See Lohmann V, et al. 1999. Repl ication of subgenomic hepatitis C virus RNAs in a hepatoma cel l l ine. Science. 285 (5424): 110-113.

1. 3 positive control drugs:

The structure of the reference drug used in the experimental example of the present invention is:

It is W0 2008/121634 (PCT/US2008/058183) The compound of Example 25, ie (S) -2- { [(2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3) , 4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} Isopropyl propionate ((S) -2- { [ (2R, 3R, 4R, 5R) -5- (2, 4- dioxo- 3, 4- dihydro-2H- pyrimidin- 1- yl) - 4- f luoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosp horylamino} -propionic acid isopropyl ester).

This compound was prepared by the method described in J. Org. Chem, 2011, 76, 8311-8319 and identified by hydrogen spectroscopy and mass spectrometry.

2. Experimental steps: 2.1 Compound Preparation: The compound of the present invention prepared in the above examples was added to the well plate using a POD 810 fully automated microplate pretreatment system (LabCyte, Inc., USA), and the compound was always at a concentration of 10 μM per compound. 5%; DMS0 final concentration of 0. 5%;

2.2 Cell preparation: Huh7 lb cells were separately seeded into 96-well plates, 125 μl system, 8×10 ³ cells/well, and cultured at 37 ° C, 5% C0 ₂ incubator for 72 hours;

2.3 Cell viability assay: Add 30 μl cell growth fluorescent titration detection reagent per well, incubate the cells for 1 hour at 37 °C, 5% C0 ₂ incubator, and measure the fluorescence signal value on a spectrophotometer. The data were used for the calculation of compound cytotoxicity. ;

2.4 Bright-Glo assay: Add 100 μl of luciferase luminescent substrate Bright-Glo per well, and use a chemiluminescence detection system EnVision (PerkinElmer, USA) to detect fluorescence signal values within 5 minutes. The data obtained were used for compound potency calculation.

2.5 Data Processing: Convert the resulting data to a percentage of cell viability (Viabi lity%) using the following formula:

CPD

Viability % 100

ZPE

CPD: Fluorescence signal value of compound pore

ZPE (Zero percent effect) invalid effect control fluorescence signal value

Use the following formula A to process the raw data as an inhibition percentage (Inhibition):

CPD - HPE

Inhibition % 100

ZPE - HPE

CPD: Fluorescence signal value of compound pore

HPE (Hundred percent effect): 100% effective control fluorescence signal value

ZPE (Zero percent effect): Ineffective effect control fluorescence signal value

The percent inhibition is further introduced into the processing results corresponding to GraphPad Prism and the curves EC _5. value. The data is shown in Table 2.

Table 2

Detection of antiviral activity of compounds of the invention against HCV infection model (HCVcc) 2a 1 Experimental materials

1. 1 compound

The compound of the present invention and the control compound prepared in the above Examples 2, 7 and 25 were formulated into 10 mM mother liquor with DMS0, diluted to 10 μM with DMEM complete culture medium containing 0.5% DMS0, and then diluted 3 times in sequence. , a total of 10 concentrations.

1. 2 cells

Huh 7. 5. 1 cells, supplied by WuXi PharmaTech (Shanghai) New Drug Development Co., Ltd.

1. 3 virus

The HCVcc reporter virus, a full-length HCV mutant transfected with luciferase and GFP, produces a virus with the same infectious ability as JFH-1 wild type, provided by WuXi PharmaTech (Shanghai) New Drug Development Co., Ltd.

1. 4 reagents

DMEM medium (DMEM medium), purchased from Invitrogen, USA;

Fetal bovine serum (FBS), purchased from Sigma, USA;

L-Glutamine (L(+)-Glutamine), purchased from Invitrogen, USA;

Penicillin-streptomycin (Pen-Str), purchased from Invitrogen, USA;

Phosphate buffered sal ine (PBS), purchased from Hyclone, USA;

Trypsin, purchased from Invitrogen, USA;

Dimethyl sulfoxide (DMS0), purchased from Sigma, USA; cell lysis buffer, purchased from Promega, USA;

Renillaluciferase test reagent, purchased from Promega, USA;

Alamar Blue test reagent, purchased from Invitrogen, USA.

1. 4 instruments

EnVision multi-function microplate reader, purchased from Perkin-Elmer, USA.

2 Experimental methods

1) Huh7. 5. 1 Cell preparation: Collect log phase Huh 7.5.1 cells, resuspend in DMEM complete medium, inoculate in 96-well plates (7 X 10 ³ cells/well), set Incubate overnight at 37 ° C in a 5% C0 ₂ incubator;

2) Viral infection: HCVcc report virus was resuspended in DMEM complete medium, and 100 μl virus supernatant (M0I = 0.2) was added to the above 96-well plate;

3) Compound preparation: The compound of Example 2, Example 7, Example 25 and the above control compound were added to the HCVcc-reported virus-infected Huh7.5.1 cells, and each compound was provided with double duplicated pores at each concentration; Zero percent effect (ZPE) and 100% effective control group (Hundred percent effect, HPE): The ZPE group replaced the compound with a complete medium containing 0.5% DMSO, and the HPE group was virus-free. Cell

4) Cell culture: 96-well plate was placed at 37 ° C, incubated in a 5% C0 ₂ incubator for 72 hr;

5) Detection of anti-HCV virus activity: After the culture is completed, discard the supernatant of each well, add 20 μ ΐ cell lysate and luciferase detection reagent to each well, and read the relative luminescence intensity (RLU) with the EnVision multi-function microplate reader. The data were used to calculate the anti-HCV activity of the compound, and the calculation formula is:

Inhibit ion% = (RLU _ZPE - RLU _CPD ) / (RLU _ZPE - RLU _HPE ) X 100 where RLU. _PD is the fluorescence signal value of the test compound well, which is the fluorescence signal value of the ineffective control well, and RLU _HPE is the fluorescence signal value of the 100% effective control well.

6) Cell viability assay: The same amount of Huh 7.5.1 cells were seeded in 96-well plates and added to the above-mentioned thick The gradient of the compound of the invention was treated for 72 hr; a DMS0 vehicle control group was also established. After the completion of the culture, 10% Alamar Blue detection reagent was added to each well, and cultured at 37 ° C, 5% C0 ₂ incubator for 2 hr, and the relative fluorescence intensity (RFU) was read using an EnVision multi-function microplate reader. For the calculation of compound cytotoxicity, the formula is:

Viabili ty% = RFU _CPD / RFU X 100

7) Data processing: Inhibition%, Viabiity ^Q /c^ are imported into GraphPad Prism software for data processing, and the half effective concentration EC _{5 of the} compound to HCVcc is obtained. And half the cytotoxic concentration CC ₅ . The experimental results are shown in Table 3.

table 3

As can be seen from Table 3, the compounds of Examples 2, 7 and 25 of the present invention have excellent antiviral activity and are less cytotoxic to the HCV in vitro cell infection model.

In addition, experiments have also shown that other compounds prepared by the examples of the present invention are as in Examples 1, 5, 6, 8, 9, 10-1, 10-11, 11, 12, 13, 14 using the HCV in vitro cell infection model. , 15, 16-1, 16-11, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 30, 31, 32, 33, 34, 35, etc. have compounds for HCVcc GT2a virus Low half effective concentration EC ₅ . And a high half cytotoxic concentration CC ₅ . , showing good inhibitory activity and small cytotoxicity.

The above experimental results indicate that the compound of the present invention has an efficient ability to inhibit HCV virus, EC ₅ compared with the positive control drug. It has a comparable or superior effect and has good prospects for the treatment of HCV infection.

While the invention has been described hereinabove, it will be understood by those skilled in the art The scope of the present invention is not limited to the detailed description set forth above, but rather the claims.

Claims

Rights request

A tricyclic fused heterocyclic nucleoside phosphoramidate compound, a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, as shown in the formula (I),

P* represents a chiral phosphorus atom,

among them,

(5) D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0_, -S0 ₂ -, -CO-, -N(R _d ) -, - (CH) „-, wherein R _d is absent, hydrogen, Indenyl or halogenated fluorenyl, said n is 0, 1 or 2, said _(CH) „ - optionally decyloxy, hydrazino, 3⁄4, hydroxy, amino, nitro, cyano , mercaptoacyl, aminoacyl, guanidino An acyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl group;

(6) G and G ¹ are each -N- or -CH-;

(7) "―" is a single key or a double key, two of which are "^" are single keys, or one "^" is a single key and the other is a double key;

(8) Ring T is selected from:

2. A compound according to claim 1, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein

3⁄4 is selected from the group consisting of 11 and ( ₆ fluorenyl), optionally substituted by one or more d- ₆ fluorenyl, d- ₆ decyloxy, d- ₆ fluorenylamino, halogen, hydroxy, amino, nitro, a cyano group, a ( _-6- ylhydryl acyl group, an aminoacyl group, a d- ₆ hydrazinoyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;

Or absent, or selected from d- ₆ fluorenyl, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, d- ₆ methoxy, fluoro, chloro, bromo, halogenated d- ₆ fluorenyl, d- ₆ alkyl with an amino group, sulfonyl group embankment ₆ D-, D- embankment ₆ sulfonylamino group, sulfamoyl group D- embankment _6, halo (- embankment ₆ alkoxy, hydroxy, nitro, amino, mono (^ ₆垸 amino, bis ₆垸 amino, -CN, acylamino, ester, C _3S cyclodecyl, C ₃ - _s heterocycloalkyl, aryl and heteroaryl.

3. A compound according to claim 1 or 2, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein D is selected from the group consisting of _ (CR _al R _a 0-, - (CR _al R _a2 ) „S -, _S0_, - S0 ₂ _, -CO-, - N (RJ -, -N0 -C0- and -C (R _cl R _c2 ) -, said R _al , Each of R _a2 is hydrogen, fluorenyl, halogen, halogenated fluorenyl, C ₂ _-6 alkenyl or halogenated C ₂ _-6 alkenyl, or R _al , R _a2 are attached _thereto C together constitutes a C ₃ — _s cyclodecyl group, said m is 0 or 1, said R _b being absent, hydrogen, d- ₆ fluorenyl, decylsulfonyl or fluorenylcarbonyl, said, each Is hydrogen, halogen, fluorenyl, C ₂ _-6 alkenyl or halogenated C ₂ _-6 alkenyl, or when R _cl , R. ₂ is selected from ( ₃ ), C and R. C ₃ _ ₇ cyclodecyl; preferably D is selected from _ (CR _al R _a 0-, - (CR _al R _a2 ) „S -, - S0_, -S0 ₂ _, -CO-, - N (R _b ) - , -NO -CO^PC O -, each of R _al and R _a2 is hydrogen, methyl or ethyl, said m Is 0 or 1, said R _b is absent, hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, methylsulfonyl or methylcarbonyl, said R. ₂ is hydrogen, fluoro, methyl, ethyl, C ₂ _ ₄ alkenyl group or a halogenated C ₂ _ ₄ alkenyl group, or when, while R. ₂ are both methyl, C may be, constitute a cyclopropyl.

The compound according to any one of claims 1 to 3, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein D ^{1 is} selected from the group consisting of oxygen, sulfur, -S0-, -S0 ₂ -, -C0-, -N (R _d ) ^P- (CH) „-, said R _d is absent, hydrogen, ( _-6 mercapto or halogenated d _ ₆垸Further, the n is 0, 1 or 2, and the _ (CH) „- is optionally d_ ₆ methoxy, d ₆垸 amino, halogen, hydroxy, amino, nitro, cyano, ₆垸Substituted by a acyl group, an aminoacyl group, a d- ₆ acylamino acyl group, a sulfonyl group, a sulfinyl group, a fluorenyl group, an aryl group or a heteroaryl group.

The compound according to any one of claims 1 to 3, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein the ring T is selected from at least one impurity a five-membered aromatic heterocyclic ring and a six-membered aromatic heterocyclic ring, a benzene ring, a c ₃ _{s s} fluorene hydrocarbon and a C ₃ _{s s} heterocyclic fluorene hydrocarbon, preferably the ring T is selected from at least one N, 0 or S hetero atom. Five-membered heteroaryl ring and six-membered aromatic heterocyclic ring, benzene ring, cyclopentamidine, cyclohexanyl, and cycloglycan.

The compound according to any one of claims 1 to 5, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein D ¹ is absent, then D , G, G ¹ and the benzene ring to which they are attached constitute a benzo five- or six-membered ring, as shown by the formula (Π),

(11).

7. A compound according to claim 1, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein the compound is a compound of the following specific structure and its non-correspondence Structure:

S9T6.0/M0ZN3/X3d £9

S9T6.0/M0ZN3/X3d 9Z8t6I/ 0Z OAV

A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystallization thereof, and a pharmaceutically acceptable Carrier.

A compound according to any one of claims 1 to 7, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof or a pharmaceutical composition according to claim 8 For the treatment of Flaviviridae viruses, especially hepatitis C virus infection.

10. A method for the treatment and/or prevention of a Flaviviridae virus, in particular a hepatitis C virus infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7 A construct, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal or a pharmaceutical composition according to claim 8.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment and/or prophylaxis of Flaviviridae viruses, in particular hepatitis C virus infections.

International application No.

INTERNATIONAL SEARCH REPORT

PCT/CN2014/079165

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons:

1. Kl Claims Nos.: 10

Because they relate to subject matter not required to be searched by this Authority, ie:

[1] Claim 10 relates to a method for treatment of the human or animal body, and falls within the range of methods for the treatment of diseases, and does not meet the requirements of PCT Rule 39.

2. □ Claims Nos.:

Because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no express international search can be carried out, specifically:

3. □ Claims Nos.:

Because they are belongs claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Form PCT/IS A/210 (continuation of first sheet (2)) (July 2009)