CN105315319B

CN105315319B - Hepatitis C virus inhibitor and application thereof

Info

Publication number: CN105315319B
Application number: CN201510453910.XA
Authority: CN
Inventors: 王勇; 赵立文; 张先; 毕胜; 高毅平; 陈宏雁; 王德忠; 南阳; 张仓; 李玉秀; 张迪
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2014-07-30
Filing date: 2015-07-29
Publication date: 2020-11-20
Anticipated expiration: 2035-07-29
Also published as: CN105315319A; WO2016015638A1

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound with a good hepatitis C virus inhibition effect, a preparation method thereof, a composition containing the compound, and application of the compound or the composition as a medicament for treating hepatitis C virus infectious diseases. The compound of the invention has excellent antiviral activity, small cytotoxicity, good safety and good plasma protein binding rate, is suitable for patent medicine and has good clinical application prospect.

Description

Hepatitis C virus inhibitor and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound with a good hepatitis C virus inhibition effect, a preparation method thereof, a composition containing the compound, and application of the compound or the composition as a medicament for treating hepatitis C virus infectious diseases.

Background

Hepatitis C Virus (HCV) infection is a worldwide epidemic with more than 2 billion of chronic infected people worldwide, with a 3.2% rate of infection in china, and the top three worldwide. The clinical manifestations of hepatitis c virus infection are diverse, mild to inflammation and severe to cirrhosis and liver cancer. Chronic hepatitis c may also be associated with certain extrahepatic manifestations, including rheumatoid arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed porphyria cutanea dermalis, which may be the result of an abnormal immune response in the body. When the hepatitis C cirrhosis is in the decompensation stage, various complications can appear, such as ascites abdominal infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatic failure and the like.

HCV belongs to the flaviviridae family of viruses of the hepacivirus genus, which has a gene structure similar to that of the other two genera in the flaviviridae family, namely pestivirus and flavivirus. Currently, standard methods of treating HCV infection are interferon and ribavirin combination therapy. However, only 50% of the patients respond to this method, and interferons have significant side effects such as influenza-like symptoms, weight loss, and fatigue weakness, while interferon and ribavirin combination therapy produces considerable side effects including hemolysis, anemia, and fatigue.

In addition, drugs that have been developed for the treatment of HCV infection include protease inhibitors, thiazolidine derivatives, thiazolidine and benzanilide, phenanthrenequinone, helicase inhibitors, nucleoside polymerase inhibitors and gliotoxin, antisense phosphorothioate oligonucleotides, inhibitors of IRES-dependent translation, ribozymes, and nucleoside analogs, and the like.

Nucleoside phosphate esters are currently an important development direction in the field for the treatment of flaviviridae, especially HCV, infections. WO 2006/065335 discloses a fluorinated pyrrolo [2,3, d ] pyrimidine nucleoside compound that inhibits the HCV virus. US 2006/0241064 discloses nucleoside compounds for use in the treatment of viral infections caused by viruses of the flaviviridae family, such as HCV. WO 2008/121634 discloses nucleoside phosphoramidate compounds for use in the treatment of viral infections in mammals.

Despite the above disclosures, there is still a great need for effective compounds for the treatment and/or prevention of HCV infection.

Disclosure of Invention

An object of the present invention is to provide a compound represented by the general formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof for use in the treatment and/or prevention of hepatitis c virus infection:

it is another object of the present invention to provide a process for preparing the compound of formula I of the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof.

It is a further object of the present invention to provide a composition comprising a compound of formula I of the present invention or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof and a pharmaceutically acceptable carrier, and a composition comprising a compound of formula I of the present invention or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof and another antiviral agent.

Still another object of the present invention is to provide a method for treating and/or preventing hepatitis c virus infection by using the compound of formula I or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal, and the use of the compound of formula I or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal in preparing a medicament for treating and/or preventing virus infection.

Aiming at the above purpose, the invention provides the following technical scheme:

in a first aspect, the present invention provides a compound represented by the general formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof:

wherein:

R₁selected from the group consisting of H, alkyl, and haloalkyl;

R₂selected from H and halogen;

R₃selected from H, OH and alkoxy;

R₄selected from H and alkyl, wherein said alkyl is optionally substituted with one or more groups selected from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, and heteroaryl;

R₅selected from the group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl and heteroaryl;

Cy₁selected from aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro, cyano;

Cy₂selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein said aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl are optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, nitro, cyano;

conditionIs Cy₁When it is aryl, Cy₂Is not hydrogen or aryl, and the compounds of formula I of the present invention are not the following:

(2S) -isopropyl 2- (((4- (1,2, 3-thiadiazol-4-yl) phen-1-yl) 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) amino) propionate;

(2S) -isopropyl 2- (((2- (quinoxalin-5-yl) phen-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) propionate;

(2S) -isopropyl 2- (((4- (thiazol-2-yl) phen-1-yl) 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) amino) propionate;

(2S) -isopropyl 2- (((4- (thiazol-5-yl) phen-1-yl) 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) amino) propionate;

(2S) -isopropyl 2- (((1H-indol-5-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) propionate;

(2S) -isopropyl 2- (((4-fluoro-2-methyl-1H-indol-5-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) propionate;

(2S) -isopropyl 2- (((3-methoxycarbonylmethyl-benzofuran-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) propionate;

(2S) -isopropyl 2- (((4-oxo-2-phenyl-4H-chromen-6-yl) 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) amino) propionate;

(2S) -isopropyl 2- (((quinoxalin-5-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) propionate;

(2S) -isopropyl 2- (((4-oxo-2-phenylbenzodihydropyran-7-yl) 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) amino) propionate;

(2S) -isopropyl 2- ((((4- (1H-1,2, 4-triazol-1-yl) phenyloxy) (((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) propionate;

(2S) -isopropyl 2- (((4- (pyrimidin-2-yl) phenoxy) ((((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) propionate;

(2S) -2- (((S) - ((4-fluoro-1, 2-dimethyl-1H-indol-5-yl) 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) amino) isopropyl propionate;

(2S) -isopropyl 2- ((((6-fluoro-3-methylbenzo [ d ] isoxazol-5-yl) 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) amino) propionate;

(2S) -isopropyl 2- ((((6-fluorobenzo [ c ] [1,2,5] thiadiazol-5-yl) 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) amino) propionate; and

(2S) -isopropyl 2- (((4- (thiazol-4-yl) phenoxy) (((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) propionate.

In some preferred embodiments, R₁Selected from H, C_1-6Alkyl, halo C_1-6Alkyl radical, R₂Selected from H, fluorine, chlorine, bromine, R₃Selected from H, OH.

In othersIn a preferred embodiment, R₁Selected from H, C_1-3Alkyl radical, R₂Selected from fluorine, chlorine, R₃Selected from H, OH.

In some preferred embodiments, R₄Selected from H, C_1-6Alkyl radical, R₅Is selected from C_1-6Alkyl and C_3-8Cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more groups selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, and heteroaryl.

In other preferred embodiments, R₄Selected from H, C_1-3Alkyl radical, R₅Is selected from C_1-6Alkyl and C_3-6Cycloalkyl, wherein said alkyl and cycloalkyl may be selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, and heteroaryl.

In other preferred embodiments, R₄Selected from H, C_1-3Alkyl radical, R₅Is selected from C_1-3Alkyl and C_3-6Cycloalkyl, wherein said alkyl and cycloalkyl may be selected from C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, phenyl, and heteroaryl.

In some preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said phenyl ring, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally substituted with a halogen selected from the group consisting of halogen,Hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from heteroaryl, C_3-8Heterocycloalkyl and C_3-8Heterocycloalkenyl, wherein the phenyl ring, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from halogen, hydroxy, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, amino, C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from heteroaryl, C_3-6Heterocycloalkyl and C_3-6Heterocycloalkenyl, wherein the phenyl ring, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from halogen, hydroxy, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, amino, C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing at least one N atom, wherein said benzene ring, five-or six-membered heteroaryl, heterocycloalkylOptionally substituted or unsubstituted with one or more substituents selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1 to 3N atoms, wherein said phenyl ring, five-or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by a group selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing only 1S atom, wherein said phenyl ring, five-or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In some specific embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from six-membered heteroaryl, heterocycloalkyl and heterocycle containing 1N atomAlkenyl, wherein said phenyl ring, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other specific embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl groups containing only 1S atom, wherein said phenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other specific embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 2N atoms, wherein said phenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other specific embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-membered heteroaryl containing 1N atom and 1 sulfur atom,Heterocycloalkyl and heterocycloalkenyl, wherein said phenyl ring, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other specific embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1N atom and 1 oxygen atom, wherein said phenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazole ring, benzothiophene ring, benzodiazepine ring, benzodioxole ring, benzoxazole ring, benzothiophene ring, wherein said furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazoie ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazole ring, benzothiophene ring, benzodiazepine ring, benzodioxoleBenzoxazepines or benzothiazepines, optionally substituted by a group selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from the benzene ring, Cy₂Selected from the group consisting of furan, pyrrole, thiophene, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazoxide, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, benzazepine, benzoxazole, benzothiophene, benzodiazepine, benzoxazepine, benzothiophene, benzodiazepine, pyrimidine, isothiazole, oxazole, isoxazole, triazoxide, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, benzodiazepine, benzoxazole, benzothiophene, benzodiazepine, benzoxazepine, benzoxazole, pyridine, pyrimidine, triazine, benzoxazole, benzothiophene, benzodiazepine, benzoxazepine, benzothiazepine, and benzothiazepine, which are optionally selected from the group consisting of halogen, triazine, benzoxazole, triazine, benzoxazepine, and benzothiophenazepine, Hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂At Cy₁Para or meta.

In some preferred embodiments, the compound of general formula I according to the invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein Cy is₂At Cy₁Para or meta. The inventors of the present invention have unexpectedly found that Cy in the general formula I₂At Cy₁The compound of the present invention has very excellent antiviral activity at the para or meta position.

In other preferred embodiments, Cy₁Selected from naphthalene ring, heteroaryl, Cy₂Selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally substituted with a group selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from naphthalene ring, heteroaryl, Cy₂Selected from hydrogen, aryl, heteroaryl, C_3-8Heterocycloalkyl and C_3-8Heterocycloalkenyl, wherein the naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano. In other preferred embodiments, Cy₁Selected from naphthalene ring, heteroaryl, Cy₂Selected from hydrogen, aryl, heteroaryl, C_3-6Heterocycloalkyl and C_3-6Heterocycloalkenyl, wherein the naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, amino, C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from five-membered or six-membered heterocyclic rings containing at least one N atom, wherein the five-membered or six-membered heterocyclic ring containing at least one N atom is optionally selected from halogen, hydroxyl, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen. In other preferred embodiments, Cy₁Selected from five-membered or six-membered heterocyclic rings containing only one S atom in the benzo group, wherein the five-membered or six-membered heterocyclic ring containing only one S atom in the benzo group is optionally selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen.

In some specific embodiments, Cy₁Is selected from a benzo five-or six-membered heteroaromatic ring containing 1,2 or 3 nitrogen atoms, wherein the benzo five-or six-membered heteroaromatic ring containing 1,2 or 3 nitrogen atoms is optionally substituted by a substituent selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen.

In other specific embodiments, Cy₁Is selected from a heteroaromatic ring containing 1 or 2 nitrogen atoms in the benzo five-membered ring, wherein the heteroaromatic ring containing 1 or 2 nitrogen atoms in the benzo five-membered ring is optionally selected from halogen, hydroxyl, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen.

In other specific embodiments, Cy₁A heteroaromatic ring containing 1 nitrogen atom and 1 oxygen atom selected from benzo five-membered rings, wherein said heteroaromatic ring containing 1 nitrogen atom and 1 oxygen atom of benzo five-membered rings is optionally substituted with one or more substituents selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen.

In other specific embodiments, Cy₁Selected from five-membered heteroaromatic rings containing only 1S atom in the benzene, wherein the five-membered heteroaromatic rings containing only 1S atom in the benzene are optionally selected from halogen, hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, nitro, cyano, and Cy₂Is hydrogen.

In addition toIn some preferred embodiments, Cy₁Selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazole ring, benzothiophene ring, benzodiazepine ring, benzoxazole ring, benzothiophene ring, Cy₂Selected from the group consisting of hydrogen, benzene ring, furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazole ring, benzothiophene ring, benzodiazepine ring, benzodithiol ring, benzoxazepine ring, benzothiophene ring, wherein said benzene ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazepine ring, benzothiophene ring, benzodiazepine ring, benzoxazepine ring, benzothiophene ring optionally selected from the group consisting of halogen, a, Hydroxy, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In other preferred embodiments, Cy₁Selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzofuran ring, benzopyrrole ring, benzothiophene ring, benzimidazole ring, benzopyrazole ring, benzothiazole ring, benzisothiazole ring, benzoxazole ring, benzisoxazole ringA ring, a benzotriazole ring, a benzothiadiazole ring, a benzoxadiazole ring, a benzopyridine ring, a benzopyrimidine ring, a benzopyrazine ring, a benzopyridazine ring, Cy₂Is hydrogen, wherein Cy is₁Optionally selected from halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof:

wherein:

R_a1selected from the group consisting of heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl, and heterocycloalkenyl are optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkanoyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano;

R_a2selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkanoyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro and cyano; or

R_a1、R_a2Together with the carbon atom to which they are attached form a heteroaryl, heterocycloalkyl, or heterocycloalkenyl group;

R_a3、R_a4、R_a5independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloAlkoxy, alkylamino, alkanoyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano;

R₁、R₂、R₃、R₄、R₅have the definition in the general formula I.

In some embodiments, a compound according to general formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, according to the invention, wherein R is₁Selected from H, C_1-6Alkyl and halo C_1-6Alkyl, preferably selected from H and C_1-3An alkyl group; r₂Selected from H, fluorine, chlorine and bromine, preferably from fluorine and chlorine; r₃Selected from H and OH; r₄Selected from H and C_1-6Alkyl, wherein said alkyl is optionally selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl and heteroaryl, preferably, R₄Selected from H and C_1-3Alkyl, wherein said alkyl is optionally selected from C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, and heteroaryl; and R₅Selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are optionally selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl and heteroarylR is preferably₅Selected from H, C_1-3Alkyl radical, C_3-6Cycloalkyl and aryl, wherein said alkyl is optionally selected from C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino, halogen, hydroxy, amino, nitro, cyano, C_1-3Alkyl acyl, amino acyl, C_1-3One or more of alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, and heteroaryl.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Is selected from C_4-8Heteroaryl group, C_4-8Heterocycloalkyl and C_4-8Heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a2selected from hydrogen, halogen, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro and cyano; or

R_a1、R_a2Together with the carbon atom to which they are attached form C_4-8Heteroaryl group, C_4-8Heterocycloalkyl or C_4-8A heterocycloalkenyl group.

In other preferred embodiments, the present invention provides compounds of formula Ia or a stereoisomeric form thereofA structure, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein R is_a1Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl groups containing at least one N atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl groups are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a1、R_a2Together with the carbon atoms to which they are attached form a five or six membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing at least one N atom. In other preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1 to 3N atoms, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6In alkylamino acyl, sulfonyl, sulfinyl, mercapto, nitro or cyano groupsSubstituted with one or more groups of (a);

R_a1、R_a2Together with the carbon atoms to which they are attached form a five-or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing 1-3N atoms.

In other preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl groups containing only one S atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl groups are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a1、R_a2Together with the carbon atom to which they are attached form a five-or six-membered heteroaryl, heterocyclic ring containing only one S atomAlkyl or heterocycloalkenyl.

In some particular embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of six membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1N atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted; and

R_a2selected from hydrogen, halogen, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro and cyano.

In other specific embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1、R_a2Together with the carbon atom to which they are attached form a five-or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing 1N atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl group are optionally selected from halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylamino acyl, sulfonyl, sulfinyl, mercapto,And one or more of nitro and cyano are substituted.

In other specific embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl groups containing 2N atoms, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl groups are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a1、R_a2Together with the carbon atom to which they are attached, form a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing 2N atoms.

In other specific embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1N atom and 1 sulfur atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a1、R_a2Together with the carbon atoms to which they are attached form a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing 1N atom and 1 sulfur atom.

In other specific embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl containing 1N atom and 1 oxygen atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a2selected from hydrogen, halogen, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercaptoNitro and cyano; or

R_a1、R_a2Together with the carbon atom to which they are attached form a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing 1N atom and 1 oxygen atom.

In other specific embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is_a1Selected from the group consisting of five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl groups containing only 1S atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl groups are optionally selected from the group consisting of halogen, hydroxy, amino, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6One or more of alkyl amino acyl, sulfonyl, sulfinyl, sulfydryl, nitro and cyano is substituted;

R_a1、R_a2Together with the carbon atoms to which they are attached form a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing only 1S atom.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is₁Is H, methyl, ethyl, n-propyl or isopropyl, R₂Is F, R₃Is OH, R₄Selected from H, methyl, ethyl, n-propyl or isopropyl, R₅Selected from methyl, ethyl, n-propyl, isopropyl,Cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R_a1Selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzazepine ring, benzoxazole ring, benzothiophene ring, benzodiazepine ring, benzoxazole ring, benzothiophene ring, wherein R is as defined above_a1Optionally selected from halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano; r_a2、R_a3、R_a4、R_a5Independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is₁Is H or methyl, R₂Is F, R₃Is OH, R₄Selected from H, methyl, ethyl, n-propyl or isopropyl, R₅Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R_a1Selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzofuran ringA benzopyrrole ring, a benzothiophene ring, a benzimidazole ring, a benzopyrazole ring, a benzothiazole ring, a benzisothiazole ring, a benzoxazole ring, a benzisoxazole ring, a benzotriazol ring, a benzothiadiazole ring, a benzoxadiazole ring, a benzopyridine ring, a benzopyrimidine ring, a benzopyrazine ring, a pyridazine ring, wherein R is as defined above_a1Optionally selected from halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano; r_a2、R_a3、R_a4、R_a5Independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is₁Is H, methyl, ethyl, n-propyl or isopropyl, R₂Is F, R₃Is OH, R₄Selected from H, methyl, ethyl, n-propyl or isopropyl, R₅Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R_a1、R_a2Together with the carbon atom to which they are attached form a benzoazacycle, benzoxaheterocycle, benzothiacycle, benzodiazepinecycle, benzodiazepine, benzodisulfur cycle, benzoxazepine, benzodiazepine, benzodisulfur cycle, benzoxazepine, benzothiepine, benzodiazepine, optionally selected from halogen, hydroxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano; r_a3、R_a4、R_a5Independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano.

In some preferred embodiments, the present invention provides a compound of formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R is₁Is H, methyl, ethyl, n-propyl or isopropyl, R₂Is F, R₃Is OH, R₄Selected from H, methyl, ethyl, n-propyl or isopropyl, R₅Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R_a1、R_a2Together with the carbon atom to which they are attached form a benzofuran ring, a benzopyrrole ring, a benzothiophene ring, a benzimidazole ring, a benzopyrazole ring, a benzothiazole ring, a benzisothiazole ring, a benzoxazole ring, a benzisoxazole ring, a benzotriazol ring, a benzothiadiazole ring, a benzoxadiazole ring, a benzopyridine ring, a benzopyrimidine ring, a benzopyrazidine ring, a benzopyrazine ring, wherein said benzofuran ring, benzopyrrole ring, benzothiophene ring, benzimidazole ring, benzopyrazolyl ring, benzothiazazole ring, benzoxazole ring, benzisoxazole ring, benzotriazol ring, benzothiadiazole ring, benzoxadiazole ring, benzopyridine ring, benzopyrimidine ring, benzopyrazidine ring, and benzopyrazidine ring are optionally selected from halogen, hydroxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radicalAmino group, C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6One or more of alkyl amino acyl, nitro and cyano; r_a3、R_a4、R_a5Independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, C_3-8Cycloalkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkyl acyl radical, C_1-6Alkoxyacyl, aminoacyl, C_1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, nitro, cyano.

In the preferred embodiments described above, the compounds of formula Ia according to the invention are not the following compounds:

The present invention provides the following specific compounds:

in another aspect, the present invention provides a process for the preparation of a compound of formula I according to the invention, comprising the steps of:

a) reacting the compound of the formula (1) with phosphorus oxychloride under alkaline conditions to obtain a compound of a formula (2);

b) reacting the compound of formula (2) with the compound of formula (3) to obtain a compound of formula (4);

c) reacting the compound shown in the formula (4) with pentafluorophenol to obtain a compound shown in a formula (5);

d) reacting the compound of formula (5) with the compound of formula (6) to produce the compound of general formula (I).

Wherein R is₁、R₂、R₃、R₄、R₅、Cy₁、Cy₂As defined in formula I above.

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

In some embodiments, the present invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the present invention and a pharmaceutical composition comprising the same for use in the treatment and/or prevention of liver disease caused by hepatitis c virus.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formula I or Ia, further comprising one or more additional anti-HCV therapeutic agents selected from the group consisting of: HCV NS3 protease inhibitors, HCV NS5B RNA-dependent RNA polymerase inhibitors, nucleoside analogs, interferon alpha, pegylated interferon, ribavirin, levovirin, viramidine, TLR7 agonists, TLR9 agonists, cyclophilin inhibitors, alpha glucosidase inhibitors, NS5A inhibitors, and NS3 helicase inhibitors.

The compounds represented by the general formulae I and Ia, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or crystals of the present invention may be mixed with pharmaceutically acceptable carriers, diluents or excipients to prepare pharmaceutical preparations 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 formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration 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 include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.

In a fourth aspect, the present invention provides a method of treating a subject infected with a flaviviridae virus with a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formulae I and Ia of the present invention or a pharmaceutical composition of the present invention, comprising administering to the subject a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formulae I and Ia or a pharmaceutical composition comprising a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formulae I and Ia in an amount effective to reduce the viral load of the virus in the subject. In one embodiment, the present invention provides a method for the treatment and/or prevention of an infection by an RNA virus, such as a virus of the flaviviridae family, comprising administering to a subject in need of such treatment a compound of the present invention, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, or a pharmaceutical composition thereof. In another embodiment, the present invention provides a method of inhibiting infection by an RNA virus, such as a virus of the flaviviridae family, comprising contacting said virus with a therapeutically effective amount of a compound of the present invention, a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, or a pharmaceutical composition thereof.

By "flaviviridae virus" is meant any virus of the flaviviridae family, including those that infect humans and non-human animals, such as flaviviruses, plague viruses, and hepatitis c viruses. The compounds and compositions of the present invention are particularly useful in the therapeutic and/or prophylactic treatment of HCV.

In another aspect, the present invention provides the use of the compounds represented by the general formulae I and Ia, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or crystals of the present invention for preventing or treating viral infections, especially flavivirus infections, and for preparing a medicament for preventing and/or treating viral infections, especially HCV viral hepatitis. Examples of such diseases are acute hepatitis c, chronic hepatitis c and mixed infections of hepatitis c and hepatitis b or hepatitis d.

In some embodiments, the present invention provides a method for the treatment and/or prevention of a viral infection, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the present invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or crystal thereof, or a pharmaceutical composition of the present invention. A compound of the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, or a pharmaceutical composition of the present invention may be administered to a mammal in need thereof to inhibit viruses and prevent the progression of the disease.

In other embodiments, the methods or uses for treating and/or preventing a viral infection further comprise administering to the subject a compound of formula I of the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof or a pharmaceutical composition comprising the same, and administering at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of formula I of the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof or a pharmaceutical composition comprising the same.

In some embodiments, at least one of the additional compounds is an interferon or a ribavirin. In some specific embodiments, the interferon is selected from interferon alpha 2B, PEG, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau. In other embodiments, at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, interfering RNA, antisense RNA, imiquimod, ribavirin, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, and rimantadine. In other embodiments, at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV egress, HCV NS3/4A protein, and IMPDH for the treatment of an HCV infection.

Definition of terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "stereoisomer" refers to an isomer resulting from the different arrangement of atoms in a molecule. Including cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present invention. Individual stereoisomers of the compounds of the invention may be substantially free of other isomers or may be mixed, for example, as racemates or with all other stereoisomers.

The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be selected, for example, 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, methanesulfonic acid, or the like.

The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.

The term "crystalline" refers to the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group, preferably a hydrocarbon group of 6 carbon atoms or less. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-methylbutyl and 2, 3-dimethylbutyl. The term "C_1-6Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms. The term "C_1-4Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing 1 to 4 carbon atoms.

The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.

The term "cycloalkyl" refers to a cyclic saturated hydrocarbon group, preferably a hydrocarbon group of 8 or less carbon atoms. The term "C_3-8Cycloalkyl "refers to a cyclic saturated hydrocarbon group containing 3 to 8 carbon atoms. The term "C_3-6Cycloalkyl "means a straight or branched chain saturated hydrocarbon group containing 3 to 6 carbon atoms.

The term "alkoxy" refers to-O-alkyl.

The term "halogen" refers to fluorine, chlorine, bromine, iodine.

The term "alkylamino" refers to-NH-alkyl or-N- (alkyl).

The term "alkanoyl" refers to-c (o) -alkyl.

The term "aminoacyl" refers to-C (O) -NH₂The term "alkylaminoacyl" refers to-C (O) -NH-alkyl or-C (O) -N- (alkyl).

The term "sulfonyl" refers to-S (O)₂-alkyl, the term "sulfinyl" refers to-s (o) -alkyl.

The term "aryl" refers to an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.

The term "heteroaryl" refers to an aromatic group in which at least one carbon atom of the aryl group is replaced with a heteroatom. The heteroatom is O, S, N. For example, heteroaryl groups described herein include, but are not limited to, pyridyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl.

The term "heterocycloalkyl" refers to a saturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.

The term "heterocycloalkenyl" refers to an unsaturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.

Detailed Description

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

Example 1(2S) -2- (((4- (pyridin-2-yl) phenyloxy) ((((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 14 preparation of- (pyridin-2-yl) phenol

1.38g of 4-hydroxyphenylboronic acid (10mmol), 1.58g of 2-bromopyridine (10mmol) and 0.4g of [1,1' -bis (diphenylphosphino) ferrocene are weighed out]Palladium dichloride (Pd (dppf) Cl₂0.5mmol) and 9g cesium carbonate (30mmol) in a 250mL eggplant-shaped bottle, 50mL 1, 4-dioxane and 5mL water are added, reaction is carried out at 90 ℃ for 1.5h under the protection of argon, after the reaction is finished, 100mL ethyl acetate and 50mL saturated aqueous sodium chloride solution are added for extraction, an organic phase is collected, washing is carried out with saturated aqueous sodium chloride solution (3X 50mL), anhydrous sodium sulfate is dried, filtration, reduced pressure concentration and column chromatography purification are carried out, thus obtaining the title compound.

LC-MS m/z:[M+H]⁺＝172。

Step 22 preparation of isopropyl- (((pentafluorophenoxy) (4- (pyridin-2-yl) phenoxy) phosphoryl) amino) propionate

Measuring 0.32mL of phosphorus oxychloride into a reaction bottle, adding 5mL of anhydrous tetrahydrofuran, dropwise adding 10mL of anhydrous tetrahydrofuran solution in which 342mg of 4- (pyridine-2-yl) phenol obtained in the step 1 and 0.42mL of triethylamine are dissolved at 60 ℃, heating to 25 ℃ for reaction for 2 hours after dropwise adding, then adding 334mg of alanine isopropyl hydrochloride at-60 ℃, stirring for 10 minutes, dropwise adding 5mL of anhydrous tetrahydrofuran in which 1.05mL of triethylamine is dissolved, after dropwise adding, slowly heating to-5 ℃, adding 5mL of anhydrous tetrahydrofuran liquid in which 0.385g of pentafluorophenol and 0.42mL of triethylamine are dissolved, after dropwise adding, reacting at room temperature for 30 minutes, and after the reaction is finished, purifying by column chromatography to obtain the title compound.

Step 3 preparation of isopropyl (2S) -2- (((4- (pyridin-2-yl) phenoxy) (((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) propionate

Weighing 260mg of (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine (1mmol) into a reaction bottle, sealing, injecting 10mL of anhydrous Tetrahydrofuran (THF) under the protection of argon, injecting 10mLt-BuMgCl solution (1M in THF) at 0 ℃, after reacting for 3h at room temperature, injecting 10mL of tetrahydrofuran solution in which 600mg of isopropyl 2- (((pentafluorophenoxy) (4- (pyridin-2-yl) phenoxy) phosphoryl) amino) propionate obtained in the step 2 is dissolved, reacting for 16h at 25 ℃, after finishing the reaction, adding 15mL of 2N HCl solution to quench the reaction, extracting with ethyl acetate, washing an organic phase with saturated sodium bicarbonate solution, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain a title compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.64-8.65(m,1H),8.08-8.11(m,2H),7.93-7.95(m,2H),7.56-7.59(m,1H),7.32-7.35(m,3H),6.12-6.16(m,2H),5.84-5.87(m,1H),5.58(m,1H),4.87-4.89(m,1H),4.36-4.38(m,1H),4.26-4.28(m,1H),4.01(m,1H),3.82-3.84(m,2H),1.26-1.29(m,6H),1.13-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝607。

Example 2 isopropyl (2S) -2- (((4- (3-fluoropyridin-2-yl) phenyloxy) (((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) propionate

Step 14 preparation of (3-fluoropyridin-2-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 2-bromo-3-fluoropyridine as starting materials.

LC-MS m/z:[M+H]⁺＝190。

Step 2 preparation of isopropyl (2S) -2- (((4- (3-fluoropyridin-2-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (3-fluoropyridin-2-yl) phenol obtained in step 1, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.53-8.54(m,1H),7.92-7.95(m,2H),7.83-7.86(m,1H),7.54-7.57(m,1H),7.45-7.47(m,1H),7.33-7.35(m,2H),6.19-6.23(m,1H),6.07-6.15(m,1H),5.91-5.93(m,1H),5.57-5.60(m,1H),4.87-4.90(m,1H),4.41-4.46(m,1H),4.30-4.30(m,1H),4.05(m,1H),3.79-3.82(m,2H),1.20-1.27(m,6H),1.13-1.17(m,6H)。

LC-MS m/z:[M+H]⁺＝625。

Example 3 isopropyl (2S) -2- (((4- (2-fluoropyridin-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (2-fluoropyridin-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 2-fluoro-4-bromopyridine as starting materials.

LC-MS m/z:[M+H]⁺＝190。

Step 2 preparation of isopropyl (2S) -2- (((4- (2-fluoropyridin-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (2-fluoropyridin-4-yl) phenol obtained in step 1, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.28-8.30(m,1H),7.89-7.92(m,2H),7.68-7.70(m,1H),7.55-7.58(m,1H),7.52(m,1H),7.36-7.39(m,2H),6.11-6.19(m,1H),5.98-6.05(m,1H),5.84-5.86(m,1H),5.54-5.56(m,1H),4.81-4.90(m,1H),4.37-4.39(m,1H),4.26-4.28(m,1H),3.89-4.01(m,1H),3.83-3.85(m,2H),1.22-1.29(m,6H),1.14-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝625。

Example 4 isopropyl (2S) -2- (((4- (pyridin-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (pyridin-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 4-bromopyridine as starting materials. LC-MS M/z [ M + H ]]⁺＝172。

Step 2 preparation of isopropyl (2S) -2- (((4- (pyridin-4-yl) phenoxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (pyridin-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.52(s,1H),8.61-8.62(m,2H),7.82-7.84(m,2H),7.67-7.68(m,2H),7.36-7.37(m,1H),7.32-7.34(m,2H),6.19-6.21(m,1H),6.13-6.16(m,1H),5.90-5.91(m,1H),5.56-5.58(m,1H),4.83-4.86(m,1H),4.30-4.31(m,1H),4.26-4.29(m,1H),4.01-4.05(m,1H),3.82-3.84(m,2H),1.26-1.28(m,6H),1.13-1.15(m,6H)。

LC-MS m/z:[M+H]⁺＝607。

Example 5 isopropyl (2S) -2- (((4- (1-methyl-1H-pyrazol-4-yl) phenyloxy) (((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) propionate

Step 14- (1-methyl-1H-pyrazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 1-methyl-4-bromo-1H-pyrazole as starting materials.

LC-MS m/z:[M+H]⁺＝175。

Step 2 preparation of isopropyl (2S) -2- (((4- (1-methyl-1H-pyrazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (1-methyl-1H-pyrazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),8.06(s,1H),7.79(m,1H),7.52-7.58(m,3H),7.15-7.17(m,2H),6.00-6.06(m,2H),5.86-5.88(m,1H),5.55-5.60(m,1H),4.83-4.90(m,1H),4.38-4.42(m,1H),4.27-4.29(m,1H),4.03-4.06(m,1H),3.81-3.83(m,3H),3.78-3.81(m,2H),1.20-1.28(m,6H),1.14-1.17(m,6H)。

LC-MS m/z:[M+H]⁺＝610。

Example 6 isopropyl (2S) -2- (((4- (1-methyl-1H-pyrazol-3-yl) phenyloxy) (((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) propionate

Step 14- (1-methyl-1H-pyrazol-3-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 3-bromo-1-methyl-1H-pyrazole as starting materials.

LC-MS m/z:[M+H]⁺＝175。

Step 2 preparation of isopropyl (2S) -2- (((4- (1-methyl-1H-pyrazol-3-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (1-methyl-1H-pyrazol-3-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

LC-MS m/z:[M+H]⁺＝610。

Example 7 isopropyl (2S) -2- (((4- (1-methyl-3-methylaminocarbonyl-1H-pyrazol-4-yl) phenoxy) (((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) propionate

Step 14-bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester

Weighing 4.10g of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (20mmol) into a 250mL eggplant-shaped bottle, adding 100mL of methanol, slowly adding 5mL of thionyl chloride at 0-4 ℃, after the reaction is finished at normal temperature, adding 500mL of ethyl acetate and 250mL of saturated sodium chloride aqueous solution for extraction, collecting an organic phase, washing for 3 times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝219。

Step 24- (1-methyl-3-methoxycarbonyl-1H-pyrazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 and step 1 of example 1, using methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate obtained in step 1 and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝233。

Step 34- (1-methyl-3-methylaminocarbonyl-1H-pyrazol-4-yl) phenol

Weighing 2.33g of 4- (1-methyl-3-methoxycarbonyl-1H-pyrazol-4-yl) phenol (10mmol) obtained in the step 2 into a 250mL eggplant-shaped bottle, adding 100mL of a methylamine water solution and 10mL of methanol, reacting at normal temperature, adding 500mL of ethyl acetate and 250mL of a saturated sodium chloride water solution after the reaction is finished, extracting, collecting an organic phase, washing for 3 times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝232。

Step 4(2S) -isopropyl 2- (((4- (1-methyl-3-methylaminocarbonyl-1H-pyrazol-4-yl) phenoxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (1-methyl-3-methylaminocarbonyl-1H-pyrazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 3 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.45(s,1H),8.03-8.04(m,1H),7.95(m,1H),7.53-7.56(m,3H),7.11-7.14(m,2H),6.06-6.10(m,2H),5.88-5.98(m,1H),5.56-5.59(m,1H),4.85-4.87(m,1H),4.38-4.39(m,1H),4.25-4.29(m,1H),4.02-4.04(m,1H),3.81-3.87(m,3H),3.72-3.78(m,2H),2.86-2.70(m,3H),1.21-1.26(m,6H),1.13-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝667。

Example 8 isopropyl (2S) -2- (((4- (1-methyl-3-cyano-1H-pyrazol-4-yl) phenoxy) ((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) propionate

Step preparation of 11-methyl-3-aminoacyl-4-bromo-1H-pyrazole

4.10g of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (20mmol), 2.14g of ammonium chloride (40mmol), 15.2g of HATU (40mmol) and 6.98mL of DIPEA (40mmol) are put in a 250mL eggplant-shaped bottle, 100mL of DMF is added for reaction at normal temperature for 12 hours, after the reaction is finished, 500mL of ethyl acetate and 250mL of saturated sodium chloride aqueous solution are added for extraction, an organic phase is collected and washed for 3 times by water, and the obtained product is dried by anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝204。

Step 21 preparation of methyl-3-cyano-4-bromo-1H-pyrazole

Weighing 2.03g of 1-methyl-3-aminoacyl-4-bromo-1H-pyrazole (10mmol) obtained in the step 1 into a 250mL eggplant-shaped bottle, adding 100mL of pyridine, slowly adding 30mL of phosphorus oxychloride at 0-4 ℃, reacting for 12H at normal temperature, after the reaction is finished, adding a saturated sodium carbonate aqueous solution for neutralization, then adding 500mL of ethyl acetate and 250mL of a saturated sodium chloride aqueous solution for extraction, collecting an organic phase, washing for 3 times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝186。

Step 34- (1-methyl-3-cyano-1H-pyrazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-hydroxyphenylboronic acid and 1-methyl-3-cyano-4-bromo-1H-pyrazole obtained in step 2 as starting materials.

LC-MS m/z:[M+H]⁺＝200。

Step 4(2S) -isopropyl 2- (((4- (1-methyl-3-cyano-1H-pyrazol-4-yl) phenoxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 4- (1-methyl-3-cyano-1H-pyrazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 3 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),8.03-8.09(m,1H),7.61-7.62(m,2H),7.55-7.57(m,1H),7.33-7.34(m,2H),6.09-6.11(m,1H),6.04-6.07(m,1H),5.98-6.00(m,1H),5.54-5.56(m,1H),4.83-4.88(m,1H),4.38-4.40(m,1H),4.24-4.27(m,1H),4.01-4.03(m,1H),3.82-3.84(m,3H),3.81(m,2H),1.23-1.27(m,6H),1.15-1.15(m,6H)。

LC-MS m/z:[M+H]⁺＝635。

Example 9 isopropyl (2S) -2- (((4- (pyridin-3-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (pyridin-3-yl) phenol

In a 100mL single-necked flask were charged 1g of 3-bromopyridine (6.4mmol), 0.96g of p-hydroxyphenylboronic acid (7.0mmol), 2.6g of potassium carbonate (21mmol), and 0.45g of PdCl₂(PPh₃)₂(0.65mmol), 15mL of water and 30mL of 1, 4-dioxane, reacting for 2h at 80 ℃ under the protection of nitrogen, cooling to room temperature after the reaction is finished, filtering, concentrating, adding ethyl acetateAnd extracting with ethyl acetate and water, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

¹HNMR((300MHz,DMSO-d6)ppm:9.67(s,1H),8.82(s,1H),8.49(d,1H),7.99(d,1H),7.65-7.54(m,2H),7.46-7.42(m,1H),6.88(d,2H)。

LC-MS m/z:[M+H]⁺＝172。

Step 2(2S) -isopropyl 2- (((4- (pyridin-3-yl) phenoxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (pyridin-3-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.50(s,1H),8.87(s,1H),8.56(d,1H),8.05(d,1H),7.74(d,2H),7.59-7.46(m,2H),7.35(d,2H),6.20-6.00(m,2H),5.90(d,1H),5.58(d,1H),4.90-4.82(m,1H),4.43(m,1H),4.31(m,1H),4.05(m,1H),3.84-3.78(m,2H),1.28-1.20(m,6H)，1.17-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝607。

Example 10 isopropyl (2S) -2- (((4- (5-fluoropyridin-2-yl) phenyloxy) (((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) propionate

Step 14 preparation of (5-fluoropyridin-2-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 9 using 2-bromo-5-fluoropyridine and 4-hydroxyphenylboronic acid as starting materials.

¹HNMR((300MHz,CDCl3-d₆)ppm:8.50(s,1H),7.82(d,2H),7.64(m,1H),7.46(m,1H),6.90(d,2H),7.53(s,1H)。

Step 2(2S) -isopropyl 2- (((4- (5-fluoropyridin-2-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-fluoropyridin-2-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.50(s,1H),8.64(d,1H),8.04(d,3H),7.80(m,1H),7.56(d,1H),7.33(d,2H),6.15-6.07(m,2H),5.84(d,1H),5.56(d,1H),4.90-4.83(m,1H),4.43(m,1H),4.27(m,1H),4.01(m,1H),3.88-3.78(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝625。

Example 11 isopropyl (2S) -2- (((4- (2-chloropyridin-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (2-chloropyridin-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 9 using 2-chloro-4-bromopyridine and p-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝206。

Step 2(2S) -isopropyl 2- (((4- (2-chloropyridin-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (2-chloropyridin-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.46(d,1H),7.92(m,3H),7.42(d,1H),7.62-7.56(m,1H),7.37(d,2H),6.20-5.99(m,2H),5.86(d,1H),5.54(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.89-3.81(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝641。

Example 12 isopropyl (2S) -2- (((4- (5-methylthiazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of bromo-5 methylthiazole

1g of 5-methylthiazole (10mmol),1.8g N-bromosuccinimide (10mmol) and 30mL of dichloromethane are added into a 100mL single-neck flask, and the mixture reacts for 12h at room temperature, and after the reaction is finished, the mixture is concentrated and purified by column chromatography to obtain the title compound.

Step 24- (5-methylthiazol-4-yl) phenol preparation

The title compound was obtained in the same manner as in step 1 of example 9 using 4-bromo-5-methylthiazole obtained in step 1 and p-hydroxyphenylboronic acid as starting materials.

¹HNMR((300MHz,CDCl₃-d6)ppm:8.65(s,1H),7.52(d,2H),6.88(d,2H),2.57(s,3H)。

Step 3(2S) -isopropyl 2- (((4- (5-methylthiazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-methylthiazol-4-yl) phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),7.89(d,2H),7.58(m,2H),7.33(d,2H),6.18-5.98(m,2H),5.86(d,1H),5.57(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.89-3.81(m,2H),2.50(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝627。

Example 13 isopropyl (2S) -2- (((1-methyl-1H-indazol-5-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) propionate

The title compound was prepared in the same manner as in steps 2 and 3 of example 1, using 5-hydroxy-1-methyl-1H-indazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

1H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),7.99(s,1H),7.63(d,1H),7.54(d,2H),7.26(d,1H),6.18-5.98(m,2H),5.86(d,1H),5.57(d,1H),4.88-4.81(m,1H),4.39(m,1H),4.27(m,1H),4.04(m,1H),3.99(s,3H),3.89-3.81(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝584。

Example 14 isopropyl (2S) -2- (((1-methyl-1H-indol-5-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) propionate

Step 15-methoxy-1-methyl-1H-indole preparation

Weighing 5g of 5-methoxy-1H-indole (0.034mol) into a 500mL single-neck bottle, adding 200mL of DMF to dissolve the 5g of 5-methoxy-1H-indole, adding 2.7g of sodium hydride (0.068mol) at 0-4 ℃, stirring for 0.5H after the addition is finished, dropwise adding 4.4g of dimethyl sulfate (0.035mol), reacting for 0.5H at room temperature after the addition is finished, adding water under ice bath to quench after the reaction is finished, filtering and drying to obtain the title compound.

Step 25 preparation of hydroxy-1-methyl-1H-indole

Weighing 0.7g of 5-methoxy-1-methyl-1H-indole (4.34mmol) obtained in the step 1 into a 100mL single-neck bottle, adding 20mL of dichloromethane for dissolving, dropwise adding 0.52g of boron tribromide (21mmol) at-30 ℃, stirring at room temperature for 12H after the addition is finished, after the reaction is finished, adding dichloromethane for dilution under ice bath, adding water for quenching, extracting, drying, concentrating, and purifying by column chromatography to obtain the title compound.

Step 3(2S) -isopropyl 2- (((1-methyl-1H-indol-5-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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 5-hydroxy-1-methyl-1H-indole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),8.37(d,1H),7.55-7.34(m,3H),7.02(d,1H),6.36(d,1H),6.04-5.85(m,3H),5.48(d,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,5H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝583。

Example 15 isopropyl (2S) -2- (((2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenoxy) (((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) propionate

Step 14 preparation of (1-methyl-1H-pyrazol-3-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 1-methyl-3-bromo-1H-pyrazole and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝175。

Step 22 preparation of fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenol

Weighing 1.71g of 4- (1-methyl-1H-pyrazol-3-yl) phenol obtained in the step 1, 3.54g of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (fluoroborate) (selective fluoride) in a 100mL eggplant-shaped bottle, adding 50mL of trifluoroacetic acid, reacting at 60 ℃ for 12 hours, adjusting the pH value of a reaction solution to about 7 after the reaction is finished, adding 100mL of ethyl acetate and 50mL of saturated sodium chloride aqueous solution for extraction, washing for 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝193。

Step 3 preparation of isopropyl (2S) -2- (((2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenoxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.50(s,1H),7.70-7.73(m,2H),7.60-7.66(m,2H),7.44-7.47(m,1H),6.67(s,1H),6.21-6.24(m,1H),6.19-6.20(m,1H),5.86-5.89(m,1H),5.56-5.59(m,1H),4.81-4.90(m,1H),4.38-4.42(m,1H),4.27-4.28(m,1H),4.01-4.06(m,1H),3.81-3.84(m,3H),3.78-3.80(m,2H),1.27-1.29(m,6H),1.14-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝628。

Example 16 isopropyl (2S) -2- (((4- (5-cyanothiazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of bromo-5-methylthiazole

Weighing 15g of 5-methylthiazole into a 500mL single-mouth bottle, adding 250mL of dichloromethane for dissolving, adding 27g of NBS in batches, reacting at room temperature for 12h after the addition is finished, concentrating after the reaction is finished, and purifying by column chromatography to obtain the title compound.

Step 24 preparation of bromo-5-bromomethylthiazole

And (2) weighing 5g of the 4-bromo-5-methylthiazole obtained in the step 1 and 5g of NBS in a 250mL single-neck bottle, adding 80mL of carbon tetrachloride to dissolve, carrying out reflux reaction for 2h, cooling to room temperature after the reaction is finished, concentrating, and carrying out column chromatography purification to obtain the title compound.

Step 34 preparation of bromo-5-hydroxymethylthiazole

Weighing 2g of 4-bromo-5-bromomethylthiazole obtained in the step 2 and 3.2g of potassium carbonate in a 100mL single-neck bottle, adding 50mL of 1, 4-dioxane and 20mL of water to dissolve, reacting for 1h at 90 ℃, concentrating after the reaction is finished, and purifying by column chromatography to obtain the title compound.

Step 44 preparation of bromo-5-formylthiazole

Weighing 1g of the 4-bromo-5-hydroxymethylthiazole obtained in the step 3 into a 100mL single-neck bottle, adding 30mL of dichloromethane for dissolving, adding 1.5g of pyridinium chlorochromate (PCC) in batches, reacting at room temperature for 3 hours after the addition is finished, concentrating after the reaction is finished, and purifying by column chromatography to obtain the title compound.

Step 54- (5-Formylthiazol-4-yl) phenol preparation

The title compound was obtained in the same manner as in step 1 of example 9 using 4-bromo-5-formylthiazole and 4-hydroxyphenylboronic acid obtained in step 4 as starting materials.

Step 64- (Thiazol-5-Formaldehyde Oxime-4-yl) phenol

And weighing 1g of 4- (5-formylthiazole-4-yl) phenol obtained in the step 5, 0.51g of hydroxylamine hydrochloride and 0.6g of sodium acetate in a 100mL single-neck bottle, adding 30mL of ethanol and 5mL of water for dissolving, carrying out reflux reaction for 1h, cooling to room temperature after the reaction is finished, concentrating, and carrying out column chromatography purification to obtain the title compound.

Step 74- (5-Cyanothiazol-4-yl) phenol preparation

Weighing 1g of 4- (thiazole-5-formaldoxime-4-yl) phenol obtained in the step 6 into a 100mL single-neck bottle, adding 10mL of THF (tetrahydrofuran) for dissolving, adding 8mL of pyridine and 8mL of trifluoroacetic anhydride, reacting at room temperature for 12h, cooling to room temperature after the reaction is finished, concentrating, and purifying by column chromatography to obtain the title compound.

Step 8 preparation of isopropyl (2S) -2- (((4- (5-cyanothiazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-cyanothiazol-4-yl) phenol obtained in step 7, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),8.74(d,1H),8.05(d,2H),7.02(d,1H),7.54(d,1H),7.41(d,2H),6.22(m,1H),6.17(m,1H),5.85(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝638。

Example 17 isopropyl (2S) -2- (((3-methylbenzo [ d ] isoxazol-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) phosphoryl) amino) propionate

Step 1 preparation of (Z) -1- (2, 4-dihydroxyphenyl) ethanone oxime

Weighing 5g of 1- (2, 4-dihydroxyphenyl) ethanone into a 100mL single-mouth bottle, adding 50mL of ethanol for dissolving, adding 2.3g of hydroxylamine hydrochloride, 2.7g of sodium acetate and 5mL of water, carrying out reflux reaction for 2h, concentrating after the reaction is finished, and carrying out column chromatography purification to obtain the title compound.

Step preparation of 26-hydroxy-3-methylbenzo [ d ] isoxazoles

1g of dichlorodicyanobenzoquinone (DDQ) and 1.2g of PPh were weighed₃After 30mL of methylene chloride was added to a 100mL single-neck flask and stirred to dissolve, 30mL of a methylene chloride solution in which 0.5g of (Z) -1- (2, 4-dihydroxyphenyl) ethanone oxime obtained in step 1 was dissolved was added dropwise, and the mixture was reacted at room temperature for 0.5 hour, followed by concentration and column chromatography purification after the reaction was completed to obtain the title compound.

Step 3 preparation of isopropyl (2S) -2- (((3-methylbenzo [ d ] isoxazol-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) phosphoryl) amino) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 6-hydroxy-3-methylbenzo [ d ] isoxazole obtained in step 2, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.49(s,1H),7.63(d,1H),7.53(d,2H),7.19(d,1H),6.10-6.07(m,2H),5.84(m,1H),5.54(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),2.56(s,3H),1.29-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝585。

Example 18 isopropyl (2S) -2- (((4- (5-chlorothiazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (Thiazol-4-Yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 4-bromothiazole and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝178。

Step 24- (5-chlorothiazol-4-yl) phenol preparation

Weighing 1g of the 4- (thiazol-4-yl) phenol obtained in the step 1 into a 100mL single-neck bottle, adding 50mL of dichloromethane to dissolve the phenol, adding 0.75g of NCS, reacting at room temperature for 12h, concentrating after the reaction is finished, and purifying by column chromatography to obtain the title compound.

Step 3 preparation of isopropyl (2S) -2- (((4- (5-chlorothiazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-chlorothiazol-4-yl) phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),9.13(s,1H),7.92(d,2H),7.57(d,1H),7.35(d,2H),6.17-6.07(m,2H),5.85(m,1H),5.56(m,1H)4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝647。

Example 19 isopropyl (2S) -2- (((4- (3, 5-dimethylisoxazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of (3, 5-dimethylisoxazol-4-yl) phenol

The title compound was prepared in the same manner as in example 1, step 1, starting from 4-bromo-3, 5-dimethylisoxazole and p-hydroxyphenylboronic acid.

Step 2(2S) -isopropyl 2- (((4- (3, 5-dimethylisoxazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (3, 5-dimethylisoxazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.49(s,1H),7.57(s,1H),7.39(d,2H),7.31(d,2H),6.00-6.11(m,2H),5.85(s,1H),5.51(m,1H),4.83-4.89(m,1H),4.39(m,1H),4.27(m,1H),4.02(m,1H),3.83-3.87(m,2H),2.38(s,3H),2.21(s,3H),1.23-1.28(m,6H),1.14-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝625。

EXAMPLE 20 isopropyl (2S) -2- (((4- (4-chloro-1-methyl-1H-pyrazol-3-yl) phenoxy) ((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) propionate

Step 14- (4-chloro-1-methyl-1H-pyrazol-3-yl) phenol

0.5g of 4- (1-methyl-1H-pyrazol-3-yl) phenol (2.9mmol) prepared in step 1 of example 15 and 0.385g of NCS (2.9mmol) were weighed in a 50mL eggplant-shaped bottle, and 5mL of THF and 5mL of CH were added₃CN, reacting at 50 ℃ for 3h, after the reaction is finished, adding 100mL ethyl acetate and 50mL saturated sodium chloride aqueous solution for extraction, washing for 3 times, then collecting an organic phase, drying by anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝209。

Step 2 preparation of isopropyl (2S) -2- (((4- (4-chloro-1-methyl-1H-pyrazol-3-yl) phenoxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 4- (4-chloro-1-methyl-1H-pyrazol-3-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),8.02(s,1H),7.78-7.80(m,2H),7.56-7.57(m,1H),7.29-7.31(m,2H),6.00-6.09(m,2H),5.82-5.84(m,1H),5.57-5.58(m,1H),4.83-4.88(m,1H),4.37-4.40(m,1H),4.24-4.26(m,1H),4.00-4.03(m,1H),3.80-3.86(m,5H),1.23-1.29(m,6H),1.14-1.15(m,6H)。

LC-MS m/z:[M+H]⁺＝644。

Example 21 isopropyl (2S) -2- (((4- (5-methyloxazol-4-yl) phenyloxy) (((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) propionate

Step 12 preparation of bromo-1- (4-methoxyphenyl) -1-propanone

1g of 1- (4-methoxyphenyl) -1-acetone (6.1mmol), 1.2g of p-toluenesulfonic acid monohydrate (6.1mmol) and 1.1g of NBS (6.1mmol) are weighed into a 100mL single-neck bottle, 30mL of acetonitrile is added for dissolution, reflux reaction is carried out for 4h, and after the reaction is finished, the mixture is concentrated and purified by column chromatography to obtain the title compound.

Step 24- (4-methoxyphenyl) -5-methyloxazole preparation

1g of 2-bromo-1- (4-methoxyphenyl) -1-propanone (4.4mmol) obtained in step 1 was weighed into a 100mL single-necked flask, and 2mL of formamide and 20mL of DMF were added and reacted under reflux for 2 hours. After the reaction is finished, concentrating, pouring the concentrated solution into ice water, extracting by ethyl acetate, drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

Step 34- (5-Methyloxazol-4-yl) phenol preparation

Weighing 0.4g of 4- (4-methoxyphenyl) -5-methyloxazole (1.7mmol) obtained in the step 2 into a 100mL single-neck bottle, adding 20mL of dichloromethane for dissolving, dropwise adding 8mL of dichloromethane solution dissolved with 8mmol of boron tribromide under ice bath, reacting at room temperature for 12h, after the raw material is finished, adding water under ice bath for quenching, extracting with dichloromethane, drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

Step 4 preparation of isopropyl (2S) -2- (((4- (5-methyloxazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-methyloxazol-4-yl) phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 3 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.28(s,1H),7.68(d,2H),7.56(d,1H),7.31(d,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),2.50(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝611。

Example 22 isopropyl (2S) -2- (((1-methyl-1H-indol-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) propionate

Step 1N-methyl-4-methoxyindole

Weighing 1.47g of 4-methoxyindole (10mmol) and 1.38g of potassium carbonate (10mmol) in a 250mL eggplant-shaped bottle, adding 100mL of acetone to dissolve the 4-methoxyindole, slowly adding 2.84g of methyl iodide (20mmol), reacting at room temperature, adding 100mL of ethyl acetate and 50mL of saturated sodium chloride aqueous solution to the reaction solution after the reaction is finished, extracting, washing for 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝162。

Step 2N-methyl-4-hydroxyindole

The title compound was obtained in the same manner as in step 2 of example 14 using N-methyl-4-methoxyindole obtained in step 1 as a starting material.

LC-MS m/z:[M+H]⁺＝148。

Step 3 preparation of isopropyl (2S) -2- (((1-methyl-1H-indol-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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using N-methyl-4-hydroxyindole obtained in step 2, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.47(s,1H),7.46-7.48(m,1H),7.31-7.32(m,1H),7.25-7.27(m,1H),7.05-7.11(m,1H),6.95-6.97(m,1H),6.49-6.50(m,1H),5.96-6.04(m,2H),5.83-5.85(m,1H),5.33-5.35(m,1H),4.82-4.90(m,1H),4.35-4.41(m,1H),4.20-4.28(m,1H),3.88-4.00(m,1H),3.84-3.87(m,2H),3.78-3.82(m,3H),1.20-1.27(m,6H),1.14-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝583。

Example 23 isopropyl (2S) -2- (((4- (oxazol-4-yl) phenyloxy) (((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) propionate

Step 12-bromo-1- (4-methoxyphenyl) ethanone preparation

1g of 1- (4-methoxyphenyl) ethanone (6.7mmol), 1.5g of p-toluenesulfonic acid monohydrate (6.7mmol) and 1.2g of NBS (6.7mmol) are weighed into a 100mL single-neck flask, 30mL of acetonitrile is added for dissolution, reflux reaction is carried out for 4 hours, and after the reaction is finished, concentration and column chromatography purification are carried out to obtain the title compound.

Step 24 preparation of (4-methoxyphenyl) oxazole

Weighing 1g of the 2-bromo-1- (4-methoxyphenyl) ethanone (4.4mmol) obtained in the step 1 into a 100mL single-neck bottle, adding 2mL of formamide and 20mL of DMF, carrying out reflux reaction for 2h, concentrating after the raw materials are finished, pouring the reaction liquid into ice water, extracting with ethyl acetate, drying, filtering, concentrating, and carrying out column chromatography purification to obtain the title compound.

Step 34 preparation of (oxazol-4-yl) phenol

Weighing 0.4g of 4- (4-methoxyphenyl) oxazole (2.3mmol) obtained in the step 2 into a 100mL single-neck bottle, adding 20mL of dichloromethane for dissolving, adding 8mL of a boron tribromide dichloromethane solution (1.0mol/L,8mL) under ice bath, reacting at room temperature for 24h after the addition is finished, adding water under ice bath for quenching after the reaction is finished, extracting with dichloromethane, drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

Step 4 preparation of isopropyl (2S) -2- (((4- (oxazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (oxazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 3 as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.51(s,1H),8.59(s,1H),8.45(s,1H),7.78(d,2H),7.56(d,1H),7.31(d,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝597。

Example 24 isopropyl (2S) -2- (((4- (5-fluorothiazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of (5-fluoro-thiazol-4-yl) phenol

3g of 4- (thiazol-4-yl) phenol (16mmol) obtained in step 1 of example 18 and 6.0g of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (16mmol) were weighed out and dissolved in 50mL of 1, 4-dioxane in a 100mL single-neck flask, and after the reaction was completed, the mixture was concentrated and purified by column chromatography to obtain the title compound.

Step 2 preparation of isopropyl (2S) -2- (((4- (5-fluorothiazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-fluoro-thiazol-4-yl) phenol obtained in step 1, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.51(s,1H),8.75(s,1H),7.84(d,2H),7.56(d,1H),7.35(d,2H),6.17-6.05(m,2H),5.86(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.31(m,2H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝631。

Example 25 isopropyl (2S) -2- (((2-fluoro-4- (thiazol-4-yl) phenyloxy) ((((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) propionate

Step preparation of 12-fluoro-4- (thiazol-4-yl) phenol

Weighing 3g of 4- (thiazole-4-yl) phenol (0.017mol), 6.0g of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor,0.017mol) in a 250mL single-neck bottle, adding 30mL of trifluoroacetic acid, reacting at 95 ℃ for 3h, concentrating after complete reaction, adding water and ethyl acetate for extraction, drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

Step 2 preparation of isopropyl (2S) -2- (((2-fluoro-4- (thiazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 2-fluoro-4- (thiazol-4-yl) phenol obtained in step 1, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.50(s,1H),9.21(s,1H),8.25(s,1H),7.96-7.81(m,2H),7.66-7.56(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),1.29-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝631。

Example 26 isopropyl (2S) -2- (((4- (thiophen-2-yl) phenoxy) (((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) propionate

Step 14 preparation of (thien-2-yl) phenol

3g of 4-hydroxyphenylboronic acid (22mmol), 3g of 2-bromo-thiophene (18mmol), 7.5g of potassium carbonate (55mmol),1.2g of PdCl₂(PPh₃)₂(1.7mmol) in a 250mL single-neck flask, adding 50mL of 1, 4-dioxane and 10mL of water, reacting at 95 ℃ for 3h under the protection of nitrogen, concentrating after the reaction is finished, adding water and ethyl acetate for extraction, drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

Step 2 preparation of isopropyl (2S) -2- (((4- (thiophen-2-yl) phenoxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (thien-2-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.50(s,1H),7.66-7.56(m,3H),7.42-7.22(m,2H),7.26(d,2H),7.12(m,1H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),,1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝612。

Example 27 isopropyl (2S) -2- (((3-fluoro-4- (thiazol-4-yl) phenyloxy) ((((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) propionate

Step 13 preparation of fluoro-4- (thiazol-4-yl) phenol

The title compound was obtained in the same manner as in example 26, step 1 using 4-hydroxy-2-fluorobenzeneboronic acid and 4-bromo-thiazole as starting materials.

Step 2 preparation of isopropyl (2S) -2- (((3-fluoro-4- (thiazol-4-yl) phenyloxy) ((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) propionate

The target compound was prepared in the same manner as in steps 2 and 3 of example 1, using 3-fluoro-4- (thiazol-4-yl) phenol obtained in step 1, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.49(s,1H),9.23(s,1H),8.17(m,1H),8.13(s,1H),7.55(d,1H),7.30-7.19(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),1.29-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝631。

Example 28 isopropyl (2S) -2- (((3-methyl-4- (thiazol-4-yl) phenyloxy) ((((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) propionate

Step 13 preparation of methyl-4- (thiazol-4-yl) phenol

The title compound was obtained in the same manner as in example 26, step 1, starting from 4-hydroxy-2-methylphenylboronic acid and 4-bromothiazole.

Step 2(2S) -isopropyl 2- (((3-methyl-4- (thiazol-4-yl) phenyloxy) (((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) propionate

The target compound was prepared in the same manner as in steps 2 and 3 of example 1, using 3-methyl-4- (thiazol-4-yl) phenol obtained in step 1, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.51(s,1H),9.19(s,1H),7.80(s,1H),7.60(d,2H),7.17(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),2.39(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝627。

Example 29 isopropyl (2S) -2- (((3-methyl-4- (1-methyl-1H-imidazol-4-yl) phenyloxy) (((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) propionate

Step 13 preparation of methyl-4- (1-methyl-1H-imidazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 26 using 4-hydroxy-2-methylphenylboronic acid and 4-bromo-N-methylimidazole as starting materials.

Step 2(2S) -isopropyl 2- (((3-methyl-4- (1-methyl-1H-imidazol-4-yl) phenyloxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 3-methyl-4- (1-methyl-1H-imidazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),7.80-7.31(m,4H),7.07(m,2H),6.13-6.05(m,2H),5.87(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.04-3.78(m,1H),3.89-3.75(m,2H),3.71(s.3H),3.54(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝624。

Example 30 isopropyl (2S) -2- (((4- (1-methyl-1H-imidazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of (1-methyl-1H-imidazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 26 using 4-hydroxyphenylboronic acid and 4-bromo-N-methylimidazole as starting materials.

Step 2 preparation of isopropyl (2S) -2- (((4- (1-methyl-1H-imidazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (1-methyl-1H-imidazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(500MHz,DMSO-d₆)ppm:11.510(s,1H),7.72-7.58(m,5H),7.20(m,2H),6.04-6.00(m,2H),5.89(m,1H),5.58(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),3.68(s,3H),1.28-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝610。

Example 31 isopropyl (2S) -2- (((4- (3-chloropyridin-2-yl) phenyloxy) (((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) propionate

Step 13 preparation of chloro-2- (4-hydroxyphenyl) pyridine

Weighing 1.38g of 4-hydroxyphenylboronic acid (10mmol), 1.91g of 2-bromo-3-chloropyridine (10mmol), 0.4g of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.5mmol) and 9g of cesium carbonate (30mmol) in a 250mL eggplant-shaped bottle, adding 50mL of 1, 4-dioxane and 5mL of water, reacting for 1.5h at 90 ℃ under the protection of nitrogen, adding 100mL of ethyl acetate and 50mL of saturated aqueous sodium chloride solution after the reaction is finished, extracting, washing with water for 3 times, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝206。

Step 2 preparation of isopropyl (2S) -2- (((4- (3-chloropyridin-2-yl) phenyloxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 3-chloro-2- (4-hydroxyphenyl) pyridine obtained in step 1, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d₆)ppm:11.47(s,1H),8.61-8.62(m,1H),8.02-8.05(m,1H),7.69-7.72(m,2H),7.56-7.59(m,1H),7.41-7.45(m,1H),7.32-7.35(m,2H),6.14-6.17(m,1H),6.05-6.09(m,1H),5.84-5.98(m,1H),5.57-5.60(m,1H),4.83-4.91(m,1H),4.38-4.43(m,1H),4.25-4.29(m,1H),4.01-4.05(m,1H),3.80-3.89(m,2H),1.22-1.29(m,6H),1.15-1.17(m,6H)。

LC-MS m/z:[M+H]⁺＝641。

Example 32 isopropyl (2S) -2- (((4- (5-chloropyridin-2-yl) phenyloxy) (((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) propionate

Step 14 preparation of (5-chloropyridin-2-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 31 using 4-hydroxyphenylboronic acid and 2-bromo-5-chloropyridine as starting materials.

LC-MS m/z:[M+H]⁺＝206。

Step 2 preparation of isopropyl (2S) -2- (((4- (5-chloropyridin-2-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-chloropyridin-2-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.47(s,1H),8.68(m,1H),8.08-8.11(m,1H),7.82-7.85(m,1H),7.55-7.59(m,1H),7.48-7.53(m,1H),7.31-7.35(m,2H),7.15-7.20(m,1H),6.07-6.14(m,2H),5.99(m,1H),5.57-5.60(m,1H),4.85-4.89(m,1H),4.37-4.41(m,1H),4.26-4.28(m,1H),4.01(m,1H),3.80-3.87(m,2H),1.22-1.29(m,6H),1.13-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝641。

Example 33 isopropyl (2S) -2- (((4- (5-chloropyridin-2-yl) -3-methylphenyloxy) ((((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) propionate

Step 14 preparation of (5-chloropyridin-2-yl) -3-methylphenol

The title compound was obtained in the same manner as in step 1 of example 31 using 2-methyl-4-hydroxyphenylboronic acid and 2-bromo-5-chloropyridine as starting materials.

LC-MS m/z:[M+H]⁺＝220。

Step 2(2S) -isopropyl 2- (((4- (5-chloropyridin-2-yl) -3-methylphenyloxy) ((((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-chloropyridin-2-yl) -3-methylphenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.69(m,1H),7.54-7.57(m,2H),7.39-7.42(m,1H),7.14-7.17(m,2H),6.05-6.12(m,2H),5.85(m,1H),5.54-5.57(m,1H),4.82-4.91(m,1H),4.36-4.42(m,1H),4.21-4.27(m,2H),3.90-4.01(m,1H),3.82-3.88(m,2H),2.30(m,3H),1.21-1.29(m,6H),1.14-1.16(m,6H)。

LC-MS m/z:[M+H]⁺＝655。

Example 34 isopropyl (2S) -2- (((4- (3-fluoropyridin-2-yl) -3-methylphenyloxy) ((((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) propionate

Step 14 preparation of 3- (3-Fluoropyridin-2-yl) -3-methylphenol

The title compound was obtained in the same manner as in step 1 of example 31 using 2-methyl-4-hydroxyphenylboronic acid and 2-bromo-3-fluoropyridine as starting materials.

LC-MS m/z:[M+H]⁺＝204。

Step 2(2S) -isopropyl 2- (((4- (3-fluoropyridin-2-yl) -3-methylphenyloxy) ((((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (3-fluoropyridin-2-yl) -3-methylphenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.51(s,1H),8.53(m,1H),8.13(m,1H),7.79-7.86(m,1H),7.50-7.57(m,1H),7.31-7.34(m,1H),7.15-7.20(m,2H),6.06-6.13(m,2H),5.84(m,1H),5.58-5.60(m,1H),4.85-4.89(m,1H),4.39(m,1H),4.28(m,1H),4.03(m,1H),3.83-3.85(m,2H),2.15(m,3H),1.22-1.29(m,6H),1.15-1.17(m,6H)。

LC-MS m/z:[M+H]⁺＝639。

Example 35 isopropyl (2S) -2- (((4- (5-chlorooxazol-4-yl) phenyloxy) (((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) propionate

Step 12-bromo-1- (4-methoxyphenyl) ethanone preparation

The title compound was obtained in the same manner as in step 1 of example 21 using 1- (4-methoxyphenyl) ethanone as a starting material.

Step 24 preparation of (4-methoxyphenyl) oxazole

The title compound was obtained in the same manner as in step 2 of example 21 using 2-bromo-1- (4-methoxyphenyl) ethanone obtained in step 1 and formamide as starting materials.

LC-MS m/z:[M+H]⁺＝176。

Step 35 preparation of chloro-4- (4-methoxyphenyl) oxazole

3.0g of 4- (4-methoxyphenyl) oxazole (0.0171mol) obtained in step 2 was weighed out into a 100mL single-necked flask, dissolved in 30mL of acetonitrile, added with 2.29g of NCS (0.0171mol) and reacted at room temperature for 2 hours, and after the reaction was completed, the mixture was concentrated and purified by column chromatography to obtain the title compound.

LC-MS m/z:[M+H]⁺＝210。

Step 44- (5-Chlorooxazol-4-yl) phenol preparation

Weighing 1.3g of 5-chloro-4- (4-methoxyphenyl) oxazole (6.22mmol) obtained in the step 3 into a 50mL single-neck bottle, adding 15mL of methanesulfonic acid to dissolve the oxazole, adding 3.71g of DL-Met (24.8mmol), reacting at 60 ℃ for 24h, cooling after the reaction is finished, pouring ice water, extracting with ethyl acetate (50mL x 6), drying, filtering, concentrating, and purifying by column chromatography to obtain the title compound.

¹H NMR(300MHz,DMSO-d₆)ppm:9.76(s,1H),8.48(s,1H),7.69(d,2H),6.88(d,2H)。

LC-MS m/z:[M+H]⁺＝196。

Step 5 preparation of isopropyl (2S) -2- (((4- (5-chlorooxazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-chlorooxazol-4-yl) phenol obtained in step 4, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(300MHz,DMSO-d₆)ppm:11.50(s,1H),8.55(s,1H),7.87(d,2H),7.56(d,1H),7.37(d,2H),5.90-6.20(m,2H),5.85(d,1H),5.57(d,1H),4.77-4.92(m,1H),4.20-4.45(m,2H),3.95-4.10(m,1H),3.70-3.95(m,2H),1.18-1.40(m,6H),1.15(d,6H)。

LC-MS m/z:[M+H]⁺＝631。

Example 36 isopropyl (2S) -2- (((4- (3-chloropyridin-2-yl) -3-methylphenyloxy) ((((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) propionate

Step 14 preparation of 3- (3-Chloropyridin-2-yl) -3-methylphenol

The title compound was obtained in the same manner as in step 1 of example 1 using 2-bromo-3-chloropyridine and 4-hydroxy-2-methylphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝220。

Step 2 preparation of isopropyl (2S) -2- (((4- (3-chloropyridin-2-yl) -3-methylphenyloxy) (((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) propionate

The title compound was obtained in the same manner as in steps 2 and 3 of example 1 using 4- (3-chloropyridin-2-yl) -3-methylphenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹HNMR(300MHz,DMSO-d6)ppm:11.48(s,1H),8.61(d,1H),8.01(d,1H),7.58(d,1H),7.46(d,1H),7.23-7.02(m,3H),6.20-5.90(m,3H),5.58(m,1H),4.88-4.83(m,1H),4.39-4.26(m,2H),4.01-3.98(m,1H),3.90-3.78(m,2H),2.04(s,3H),1.29-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝655。.

Example 37 isopropyl (2S) -2- (((4- (5-chloro-1-methyl-1H-imidazol-4-yl) phenyloxy) (((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) propionate

Step 14- (5-chloro-1-methyl-1H-imidazol-4-yl) phenol preparation

0.81g of 4- (1-methyl-1H-imidazol-4-yl) phenol (5.14mmol) obtained in step 1 of example 30 and 0.62g of NCS (5.14mmol) were weighed into a 100mL single-necked flask, dissolved in 20mL of acetonitrile, and subjected to reflux reaction for 1 hour, followed by concentration and column chromatography purification to obtain the title compound.

Step 2 preparation of isopropyl (2S) -2- (((4- (5-chloro-1-methyl-1H-imidazol-4-yl) phenyloxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 4- (5-chloro-1-methyl-1H-imidazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials to obtain the objective compound.

¹H NMR(500MHz,DMSO-d₆)ppm:11.51(s,1H),8.40(s,1H),7.84(d,2H),7.56(d,1H),7.35(d,2H),6.17-6.05(m,2H),5.86(m,1H),5.56(m,1H),4.88-4.81(m,1H),4.35(m,1H),4.22(m,1H),4.043.78(m,1H),3.89-3.31(m,2H),3.62(s,3H),1.29-1.22(m,6H)，1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝644。

Example 38 isopropyl (2S) -2- (((3-fluoro-4- (1-methyl-1H-imidazol-4-yl) phenyloxy) (((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) propionate

Step 13-fluoro-4- (1-methyl-1H-imidazol-4-yl) phenol

The title compound was obtained in the same manner as in example 26, step 1, starting from 4-bromo-1-methyl-1H-imidazole and 2-fluoro-4-hydroxyphenylboronic acid.

Step 2 preparation of isopropyl (2S) -2- (((3-fluoro-4- (1-methyl-1H-imidazol-4-yl) phenyloxy) ((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 3-fluoro-4- (1-methyl-1H-imidazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials to obtain the objective compound.

LC-MS m/z:[M+H]⁺＝628。

Example 39 isopropyl (2S) -2- (((4- (2-methylthiazol-4-yl) phenyloxy) (((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) propionate

Step 14 preparation of- (2-methylthiazol-4-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 2-methyl-4-bromothiazole and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝192。

Step 2 preparation of isopropyl (2S) -2- (((4- (2-methylthiazol-4-yl) phenyloxy) ((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (2-methylthiazol-4-yl) phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

LC-MS m/z:[M+H]⁺＝627。

Example 40 isopropyl (2S) -2- (((4- (5-chloro-2-methylthiazol-4-yl) phenyloxy) (((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) propionate

Step 14- (5-chloro-2-methylthiazol-4-yl) phenol preparation

The title compound was obtained in the same manner as in step 1 of example 37 using 4- (2-methylthiazol-4-yl) phenol obtained in step 1 of example 39 as a starting material.

LC-MS m/z:[M+H]⁺＝226。

Step 2 preparation of isopropyl (2S) -2- (((4- (5-chloro-2-methylthiazol-4-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 4- (5-chloro-2-methylthiazol-4-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

LC-MS m/z:[M+H]⁺＝661。

EXAMPLE 41 methyl (2S) -2- (((4- (5-chloro-2-methylthiazol-4-yl) phenyloxy) (((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated except for using 4- (5-chloro-2-methylthiazol-4-yl) phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 40 as starting materials to obtain the objective compound.

LC-MS m/z:[M+H]⁺＝633。

EXAMPLE 42 methyl (2S) -2- (((4- (5-chloro-thiazol-4-yl) phenyloxy) ((((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated except for using 4- (5-chlorothiazol-4-yl) phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 of example 18 as starting materials to obtain the objective compound.

¹H NMR(300MHz,DMSO-d6)ppm:11.50(s,1H),9.13(s,1H),7.92(d,2H),7.56(d,1H),7.35(d,2H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.58(s,3H),1.28-1.22(m,6H)。

LC-MS m/z:[M+H]⁺＝619。

EXAMPLE 43 Ethyl (2S) -2- (((4- (5-chlorothiazol-4-yl) phenyloxy) (((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated except for using 4- (5-chlorothiazol-4-yl) phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 2 of example 18 as starting materials to obtain the objective compound.

LC-MS m/z:[M+H]⁺＝633。

EXAMPLE 44 methyl (2S) -2- (((4- (3-fluoropyridin-2-yl) phenyloxy) (((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated except that 4- (3-fluoropyridin-2-yl) phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 2 were used as starting materials to obtain the objective compound.

LC-MS m/z:[M+H]⁺＝597。

EXAMPLE 45 Ethyl (2S) -2- (((4- (3-fluoropyridin-2-yl) phenyloxy) (((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated except that 4- (3-fluoropyridin-2-yl) phenol, phosphorus oxychloride, ethyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 2 were used as starting materials to obtain the objective compound.

LC-MS m/z:[M+H]⁺＝611。

EXAMPLE 46 isopropyl (2S) -2- (((benzo [ b ] thiophen-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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1 using 4-hydroxybenzothiophene, phosphorus oxychloride, L-alanine isopropyl hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

¹H NMR(500MHz,DMSO-d6)ppm:11.49(s,1H),7.84-7.78(m,2H),7.51(d,2H),7.37-7.30(m,2H),6.20-6.02(m,2H),5.88(m,1H),5.43(m,1H),4.86(m,1H),4.43-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),1.28-1.22(m,6H),1.14-1.12(m,6H)。

LC-MS m/z:[M+H]⁺＝586。

EXAMPLE 47 methyl (2S) -2- (((benzo [ b ] thiophen-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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1 using 4-hydroxybenzothiophene, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

LC-MS m/z:[M+H]⁺＝558。

EXAMPLE 48 isopropyl (2S) -2- (((3-methylbenzo [ b ] thiophen-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) propionate

The objective compound was obtained in the same manner as in steps 2 and 3 of example 1, using 3-methyl-4-hydroxybenzothiophene, phosphorus oxychloride, L-alanine isopropyl hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials.

LC-MS m/z:[M+H]⁺＝600。

EXAMPLE 49 methyl (2S) -2- (((4- (3-methylthiophen-2-yl) phenyloxy) (((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) propionate

Step 14 preparation of (3-methylthiophen-2-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 2-bromo-3-methylthiophene and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝191。

Step 2 methyl (2S) -2- (((4- (3-methylthiophen-2-yl) phenyloxy) (((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) propionate

The procedure of steps 2 and 3 of example 1 was repeated using 4- (3-methylthiophen-2-yl) phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials to obtain the objective compound.

¹H NMR(500MHz,DMSO-d6)ppm:11.50(s,1H),7.57(s,1H),7.46-7.43(m,3H),7.30(d,2H),7.00(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.60(s,3H),2.24(s,3H),1.28-1.22(m,6H)。LC-MS m/z:[M+H]⁺＝598。

Example 50 isopropyl (2S) -2- (((4- (3-methylthiophen-2-yl) phenyloxy) (((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) propionate

The same procedures used in steps 2 and 3 of example 1 were repeated except for using 4- (3-methylthiophen-2-yl) phenol, phosphorus oxychloride, isopropyl L-alanine hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 49 as starting materials to obtain the objective compound.

¹H NMR(500MHz,DMSO-d6)ppm:11.50(s,1H),7.57(s,1H),7.46-7.43(m,3H),7.30(d,2H),7.00(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.88-4.83(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),2.26(s,3H),1.28-1.22(m,6H),1.17-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝626。

EXAMPLE 51 methyl (2S) -2- (((4- (5-methylthiophen-2-yl) phenyloxy) (((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) propionate

Step 14 preparation of (5-methylthiophen-2-yl) phenol

The title compound was obtained in the same manner as in step 1 of example 1 using 2-bromo-5-methylthiophene and 4-hydroxyphenylboronic acid as starting materials.

LC-MS m/z:[M+H]⁺＝191。

Step 2 methyl (2S) -2- (((4- (5-methylthiophen-2-yl) phenyloxy) (((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) propionate

The objective compound was obtained in the same manner as in example 1 using 4- (5-methylthiophen-2-yl) phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 as starting materials.

¹H NMR(300MHz,DMSO-d6)ppm:11.51(s,1H),7.59-7.55(m,3H),7.25-7.21(m,3H),6.81(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),3.30(s,3H),2.46(s,3H),1.29-1.22(m,6H)。

LC-MS m/z:[M+H]⁺＝598。

Example 52 isopropyl (2S) -2- (((4- (5-methylthiophen-2-yl) phenyloxy) (((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) propionate

Using 4- (5-methylthiophen-2-yl) phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 51 as starting materials, the objective compounds were obtained in the same manner as in steps 2 and 3 of example 1.

¹H NMR(300MHz,DMSO-d6)ppm:11.50(s,1H),7.59-7.55(m,3H),7.25-7.22(m,3H),6.80(d,1H),6.20-6.02(m,2H),5.87(m,1H),5.58(m,1H),4.88-4.83(m,1H),4.39-4.03(m,2H),4.01-3.98(m,1H),3.93-3.85(m,2H),2.46(s,3H),1.28-1.22(m,6H),1.16-1.14(m,6H)。

LC-MS m/z:[M+H]⁺＝626。

EXAMPLE 53 Ethyl (2S) -2- (((4- (5-methylthiophen-2-yl) phenyloxy) (((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) propionate

Using 4- (5-methylthiophen-2-yl) phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 51 as starting materials, the objective compounds were obtained in the same manner as in steps 2 and 3 of example 1.

¹H NMR(300MHz,DMSO-d6)ppm:11.50(s,1H),7.55-7.57(m,3H),7.21-7.25(m,3H),6.80-6.81(m,1H),6.60-6.61(m,1H),5.98-6.04(m,1H),5.83-5.86(m,1H),5.55-5.58(m,1H),4.34-4.40(m,1H),4.20-4.26(m,1H),3.90-3.93(m,1H),3.85-3.88(m,2H),3.58(m,2H),2.45-2.49(m,3H),1.21-1.29(m,9H)。

LC-MS m/z:[M+H]⁺＝612。

EXAMPLE 54 Ethyl (2S) -2- (((4- (thiophen-2-yl) phenyloxy) ((((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) propionate

The same procedures used in steps 2 and 3 of example 1 were repeated except for using 4- (thiophen-2-yl) phenol obtained in step 1 of example 26, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials to obtain the objective compounds.

¹H NMR(300MHz,DMSO-d6)ppm:11.50(s,1H),7.65(d,2H),7.58-7.52(m,2H),7.45(d,1H),7.25(d,2H),7.13-7.10(m,1H),6.14-6.06(m,2H),5.85-5.82(m,1H),5.58-5.55(m,1H),4.40-4.36(m,1H),4.26-4.22(m,1H),4.07-4.00(m,3H),3.89-3.81(m,2H),1.29-1.23(m,6H),1.16-1.11(t,3H)。

LC-MS m/z:[M+H]⁺＝598。

Example 55 methyl (2S) -2- (((4- (thiophen-2-yl) phenoxy) ((((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) propionate

The same procedures used in steps 2 and 3 of example 1 were repeated except for using 4- (thiophen-2-yl) phenol obtained in step 1 of example 26, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine as starting materials to obtain the objective compounds.

¹H NMR(500MHz,DMSO-d6)ppm:11.48(s,1H),7.66(d,2H),7.58-7.51(m,2H),7.46(d,1H),7.26(d,2H),7.13(m,1H),6.15-6.00(m,2H),5.87(m,1H),5.56(m,1H),4.41-4.37(m,1H),4.28-4.21(m,1H),4.05(m,1H),4.01-3.80(m,2H),3.60(s,3H),1.29-1.17(m,6H)。

LC-MS m/z:[M+H]⁺＝584。

EXAMPLE 56 neopentyl (2S) -2- (((4- (thien-2-yl) phenyloxy) ((((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) propionate

Using 4- (thien-2-yl) phenol, phosphorus oxychloride, L-alanine neopentyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 26 as starting materials, the objective compounds were obtained in the same manner as in steps 2 and 3 of example 1.

¹H NMR(500MHz,DMSO-d6)ppm:11.51(s,1H),7.65(d,2H),7.58-7.51(m,2H),7.45(d,1H),7.26(d,2H),7.14-7.11(m,1H),6.17-6.00(m,2H),5.86(d,1H),5.58(d,1H),4.40-4.21(m,2H),4.05-3.98(m,1H),3.93-3.85(m,3H),3.64(m,1H),1.31-1.21(m,6H)，0.86(s,9H)。

LC-MS m/z:[M+H]⁺＝640。

EXAMPLE 57 neopentyl (2S) -2- (((4- (3-methylthion-2-yl) phenyloxy) (((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) propionate

The same procedures used in steps 2 and 3 of example 1 were repeated except for using 4- (3-methylthiophen-2-yl) phenol, phosphorus oxychloride, L-alanine neopentyl ester hydrochloride, pentafluorophenol and (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine obtained in step 1 of example 49 as starting materials to obtain the objective compound.

¹H NMR(500MHz,DMSO-d6)ppm:11.50(s,1H),7.58(d,1H),7.45(m,3H),7.30(d,2H),7.00(d,1H),6.17-6.02(m,2H),5.87(m,1H),5.56(m,1H),4.40-4.21(m,2H),4.05-3.98(m,1H),3.93-3.85(m,3H),3.64(m,1H),2.26(s,3H),1.31-1.23(m,6H)，0.87(s,9H)。

LC-MS m/z:[M+H]⁺＝654。

Evaluation of pharmacological Activity

Experimental example 1 detection of antiviral Activity of Compounds of the present invention in HCV replicon System

1. Experimental Material

1.1 reagent:

TABLE 1 list of reagents

1.2Huh71b cell line:

the Huh71b cell line was provided by shanghai drug mingkude new drug development ltd and is a Huh7 cell line containing an HCV 1b replicon carrying a stable luciferase (Luc) reporter. It clones HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector through gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance selection, the HCV replicon stably replicated and the relevant protein and luciferase were stably expressed in huh7 cells. The cell model is used for in vitro screening of anti-HCV compounds. The anti-HCV activity of the compounds was determined by examining the chemiluminescence levels of luciferase luminogenic substrates. See Lohmann V, et al 1999 reproduction of pathogenic hepatitis C viruses RNAs in a hepatoma cell line, science 285(5424):110-113.

2. The experimental method comprises the following steps:

1) preparation of compound: using the compounds prepared in the above examples of the present invention, each compound was prepared as a mother solution with DMSO, then diluted to 10 μ M as a concentration of the compound all the time with DMEM complete culture solution containing 0.5% DMSO, 3-fold dilution, total 10 concentrations, and the compounds were added to 96-well plates, respectively, using POD 810 full-automatic microplate pretreatment system (LabCyte corporation, usa); a null-effect control group (complete culture solution containing 0.5% DMSO instead of the compound) and a 100% active-effect control group (complete culture solution containing 0.5% DMSO only is added) are set simultaneously;

2.1 cell preparation: the log phase of Huh71b cells were collected, resuspended in DMEM complete medium, and plated into 96-well plates at 125. mu.l/well at 8X 10³Cells/well, 5% CO at 37 ℃₂Culturing the cells in an incubator for 72 hours;

2.2 cell viability assay: adding 30 mul cell growth fluorescent titration detection reagent into each hole, at 37 deg.C and 5% CO₂Culturing cells in an incubator for 1 hour, detecting a fluorescence signal value on a spectrophotometer, and using the obtained data for calculating the cytotoxicity of the compound;

2.3Bright-Glo assay: mu.l luciferase luminescent substrate Bright-Glo was added to each well, and the fluorescence signal value was measured within 5 minutes using a chemiluminescence detection system EnVision (Perkinelmer, USA), and the data obtained was used for compound viability calculation.

2.4 data processing: the data obtained were converted to percent cell Viability (viatility%) using the following formula:

CPD (CPD): fluorescence signal values of compound wells

HPE (Hundred percent effect) 100% Effect control fluorescence Signal value

ZPE (zero percent effect) null effects control fluorescence signal values

Raw data were processed as percent Inhibition (% Inhibition) using the following equation:

CPD (CPD): chemiluminescence signal value of compound pore

HPE (Hundred percent effect) 100% effective chemiluminescent signal value

ZPE (zero percent effect) invalid effect chemiluminescent signal value

The percentage inhibition was introduced into GraphPad Prism for further processing to obtain the corresponding curve and EC₅₀The value is obtained.

The experimental results show that the EC of the compound of the invention₅₀Between about 0.05. mu.M and 1. mu.M, has a very good ability to inhibit the HCV virus. Some data are shown in table 2.

TABLE 2

Example numbering	EC₅₀(μM)	Example numbering	EC₅₀(μM)
				Example 1	0.3266	Example 2	0.1312
Example 3	0.3912	Example 4	1.188

Example 5	0.4984	Example 6	0.4834
				Example 9	0.665	Example 10	0.1498
Example 11	0.695	Example 12	0.240
				Example 13	0.772	Example 14	0.380
Example 15	0.523	Example 17	0.443
				Example 18	0.062	Example 19	0.557
Example 20	0.0783	Example 21	0.173
				Example 22	0.104	Example 23	0.265
Example 24	0.055	Example 25	0.204
				Example 26	0.019	Example 27	0.169
Example 28	0.142	Example 31	0.103
				Example 32	0.174	Example 33	0.130
Example 34	0.196	Example 35	0.051
				Example 36	0.146	Example 42	0.065
Example 46	0.055	Example 49	0.049
				Example 50	0.063	Example 51	0.018
Example 52	0.021	Example 53	0.097
				Example 54	0.020	Example 55	0.032
Example 56	0.028	Example 57	0.030

As published on the official website of Gilead corporationBest-before-drug for HCV sofosbuvir (GS7977) EC for Gene type 1b in HCV replicon assay₅₀The value is 0.102. mu.M, see in particular http:// www.gilead.com// media/Files/pdfs/media/servers-disease/solvadi _ pi. pdf. The compounds of the present invention have anti-HCV viral activity equivalent to or superior to sofosbuvir.

Experimental example 2 detection of antiviral Activity of the Compound of the present invention against HCV Cell infection model (Cell-culture-derived infection HCV, HCVcc)

1 materials of the experiment

1.1 Compounds

This experimental example used the compound of the present invention prepared in the above example, which was prepared as a 10mM stock solution in DMSO, diluted to 1000nM in DMEM complete medium containing 0.5% DMSO, and then sequentially diluted 3-fold for 8 concentrations.

1.2 cells

Huh 7.5.1 cells, provided by Shanghai Mingkude New drug development, Inc.

1.3 viruses

The J399EM (HCV genotype 2a) virus, namely HCV full-length mutant strain transfected with EGFP (enhanced green fluorescent protein), has the same infection capacity as the JFH-1 wild type, and meanwhile, by inserting the EGFP coding sequence into the NS5A region, the fluorescence of the NS5A-EGFP fusion protein can be directly observed in infected cells, which is provided by Shanghai Yao Ming kang Deg medicine development limited company.

1.4 reagents

Name of reagent	Suppliers of goods
		DMEM cell culture solution	Invitrogen
Fetal bovine serum	Sigma
		Penicillin-streptomycin	Invitrogen
Phosphate buffer	Hyclone
		Pancreatin	Invitrogen
Dimethyl sulfoxide (DMSO)	Sigma
		Fluorescence detection reagent (Renilla luciferase substrate)	Promega
Cell activity detection reagent (Alamar Blue)	Invitrogen

2 method of experiment

2) Huh 7.5.1 cell preparation: the log phase Huh 7.5.1 cells were collected, resuspended in DMEM complete medium, and plated in 96-well plates (7X 10)³Individual cells/well) at 37 ℃ in 5% CO₂Culturing in an incubator overnight;

3) and (3) drug treatment: the compound is added into a 96-well plate respectively, the concentration of the compound is 1000nM all the time, each compound is made into double-well, 3 times of dilution is carried out, the total concentration is 8, and the final concentration of DMSO is 0.5%; a null-effect control group (complete culture medium containing 0.5% DMSO instead of compound) and a 100% null-effect control group (cells without virus infection added) were set up at the same time;

4) viral infection: the J399EM virus supernatant was added to 96-well plates at a concentration of 0.2 MOI per wellIn (1). Then placed at 37 ℃ in 5% CO₂Culturing in an incubator for 3 days.

5) And (3) antiviral activity determination: after the culture is finished, adding a luciferase luminescent substrate into each hole, detecting a Luminescence signal value by using a chemiluminescence detection system Envision, and calculating the activity of the compound for inhibiting HCV according to the following calculation formula:

Inhibition％＝(RLU_s-RLU_c)/(RLU_V-RLU_c)×100

wherein, RLU_VShows the chemiluminescence intensity, RLU, of a virus control (complete medium containing 0.5% DMSO instead of compound)_SShows the chemiluminescence intensity of the corresponding compound treatment group, RLU_CThe chemiluminescence intensity of a cell control group (cells without virus infection);

6) cytotoxicity assay: the cells and compounds were treated as above, but media was added to the plates instead of virus. The same conditions were 37 ℃ and 5% CO₂After 3 days of culture in the incubator, cell viability detection reagent Alamar Blue was added, and the Fluorescence signal value was detected by a spectrophotometer. The data obtained were used for compound cytotoxicity calculations, which were calculated as:

Viability％＝RFU_S/RFU_M×100

wherein, RFU_MFluorescence intensity, RFU, of a vehicle control (complete culture medium containing 0.5% DMSO instead of compound)_SRepresents the fluorescence intensity of the corresponding compound-treated group;

7) data processing: the inhibition percentage and the cell viability percentage are respectively led into GraphPad Prism software for data processing to obtain a curve corresponding to the compound and the inhibition activity (EC) of the compound on HCV₅₀) And Cytotoxicity (CC)₅₀) Numerical values.

The results of the experiments show that the EC of the compounds of the invention₅₀Values substantially between 40nM and 150nM, CC₅₀All greater than 1000nM, e.g. EC of the compound of example 20₅₀53.4nM, CC₅₀>1000 nM. EC of part of the Compounds of the invention₅₀Smaller values, e.g. EC of example 26₅₀Is 9.3nM, CC₅₀>1000 nM. Therefore, the compound has excellent antiviral activity, small cytotoxicity and high safety.

In addition, the inventor finds that the compound has good plasma protein binding rate, is suitable for being used as a medicament and has good clinical application prospect. Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims

1. A compound represented by the general formula I:

wherein:

R₁is methyl;

R₂is fluorine;

R₃is OH;

R₄is methyl;

R₅is selected from C_1-6An alkyl group;

Cy₁is phenyl, optionally substituted with one or more groups selected from fluoro and methyl;

Cy₂selected from pyridine ring, pyrazole ring, thiazole ring, pyrrole ring, isoxazole ring, imidazole ring, thiophene ring and oxazole ring, optionally substituted with a halogen selected from halogen, methyl, C_1-6One or more of alkylaminoacyl and cyano substituted;

wherein the compound is not:

2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula Ia:

wherein:

R_a1selected from pyridine ring, pyrazole ring, thiazole ring, pyrrole ring, isoxazole ring, imidazole ring, thiophene ring and oxazole ring, optionally substituted with a halogen selected from halogen, methyl, C_1-6One or more of alkylaminoacyl and cyano substituted;

R_a2selected from fluorine and methyl; or

R_a1、R_a2Together with the carbon atom to which they are attached form a benzopyrazolyl, benzothiazolyl, benzopyrrole or benzisoxazole ring, which is optionally substituted with methyl;

R_a3、R_a4、R_a5independently selected from fluoro and methyl;

R₁is methyl;

R₂is fluorine;

R₃is OH;

R₄is methyl; and

R₅is selected from C_1-6An alkyl group;

wherein the compound is not:

3. a compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from the group consisting of:

4. a pharmaceutical composition comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 in the manufacture of a medicament for the treatment and/or prophylaxis of hepatitis virus infection.