KR102145025B1 - Novel nucleoside or nucleotide derivatives, and use thereof - Google Patents

Abstract

The present invention provides a novel nucleoside or nucleotide derivative, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for the prevention or treatment of viral infection-related diseases comprising the same as an active ingredient.

Description

Novel nucleoside or nucleotide derivatives, and use thereof

The present invention provides a novel nucleoside or nucleotide derivative, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof; A pharmaceutical composition for preventing or treating viral infection-related diseases comprising this as an active ingredient; And to the use thereof.

Nucleosides or nucleotide derivatives are used clinically for the treatment of viral infections or cancer-related diseases.

The antiviral activity of Gemcitabine has been reported for RNA viruses (eg, influenza virus, enterovirus, SARS and MERS coronavirus) and retrovirus (eg, human immunodeficiency virus) (Clouser et al., 2012). ; Kang et al., 2015, de Wilde et al., 2014). As a result of conducting a cell-based antiviral test, Gemcitabine showed a wide range of efficacy against influenza viruses (types A and B), enteroviruses (coxsackie virus, poliovirus) and coronaviride (coronavirus). .

However, extensive toxicity was observed for cultured cells, and in the case of influenza virus, in the case of Madin-Darby Canine Kidney (MDCK; derived from dog kidney cells) cells, about 50% when administered at a concentration of 100 μM for 3 days. Cell death was induced.

Therefore, antiviral efficacy was investigated by synthesizing a novel nucleoside or nucleotide derivative capable of improving cytotoxicity while maintaining antiviral activity.

An object of the present invention is to provide a novel nucleoside or nucleotide compound exhibiting antiviral activity, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for manufacturing the same.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating viral infection-related diseases comprising the compound of the present invention, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. .

As a result of the research efforts of the present inventors to achieve the above object, newly devised and synthesized nucleosides or nucleotide derivatives confirmed antiviral activity and completed the present invention.

Hereinafter, the present invention will be described in more detail.

Nucleoside or nucleotide derivative compounds

The present invention provides a compound represented by the following formula (1), a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

Y is heterocyclyl or -NHC(O)R ₃ ;

이고;R ₁ is hydrogen or

ego;

R ₂ is hydrogen or halo;

R ₃ is heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or 1 to 4 hydrogens are halo, amino, cyano, nitro, azido, thiol, hydroxy, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 aminoalkyl, C _1-6 hydroxyalkyl, C _1-6 di-hydroxyalkyl, C _1-6 alkoxy, C _1-6 cycloalkyl, heterocyclyl , C _1-3 alkoxy-C _1-3 may be substituted with a substituent selected from the group consisting of alkyl and aryl};

R ₄ , R ₅ and R ₆ are each independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, aryl or heteroaryl;

The halo is F, Cl, Br or I;

The heterocyclyl is a 3 to 10 membered single or fused ring form containing at least one hetero element selected from the group consisting of nitrogen, oxygen, sulfur, or a combination thereof, and heteroaryl is nitrogen, oxygen, sulfur, or a combination thereof. It may be in the form of a 5 to 10 membered single or fused ring containing at least one hetero element selected from the group consisting of a combination of;

Each of the cycloalkyl and heterocyclyl is optionally 1 to 3 C _1-6 alkyl, hydroxy, oxo, C _1-6 hydroxyalkyl, halo, cyano, nitro, C _1-6 haloalkyl, C _1-6 alkoxy, formyl, C _1-6 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl)amino, carbamoyl, C _{1- 6} alkylcarbamoyl, di(C _1-6 alkyl)carbamoyl or C _1-3 alkoxy-C _1-3 alkyl;

Each of the aryl and heteroaryl is optionally 1 to 3 C _1-6 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 hydroxyalkyl, C _1-6 Haloalkyl, halo, cyano, pyrazinyl, hydroxy, oxo, nitro, formyl, C _1-6 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-6 alkylamino, di(C _{May be} substituted with _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl, di(C _1-6 alkyl)carbamoyl or C _1-6 alkylsulfonyl.

According to an embodiment of the present invention, in the above formula,

Y is heterocyclyl or -NHC(O)R ₃ ;

이고;R ₁ is hydrogen or

ego;

R ₂ is hydrogen or halo;

R ₃ is heteroaryl or heterocyclyl, wherein heteroaryl or heterocyclyl is unsubstituted or 1 to 4 hydrogens are halo, amino, cyano, nitro, azido, thiol, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 di-hydroxyalkyl, C _1-4 cycloalkyl, C _1-4 alkoxy, heterocyclyl, C _1-3 alkoxy-C _1-3 may be substituted with a substituent selected from the group consisting of alkyl and aryl);

R ₄ , R ₅ and R ₆ are each independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, aryl or heteroaryl;

Halo is F, Cl, Br or I;

The heterocyclyl is a 3 to 10 membered single or fused ring form containing at least one hetero element selected from the group consisting of nitrogen, oxygen, sulfur, or a combination thereof, and heteroaryl is nitrogen, oxygen, sulfur, or a combination thereof. It may be in the form of a 5 to 10 membered single or fused ring containing at least one hetero element selected from the group consisting of a combination of;

Each of the cycloalkyl and heterocyclyl is optionally 1 to 3 C _1-4 alkyl, hydroxy, oxo, C _1-4 hydroxyalkyl, halo, cyano, nitro, C _1-4 haloalkyl, C _1-4 alkoxy, formyl, C _1-4 alkylformyl, carboxy, C _1-4 alkylcarboxy, amino, C _1-4 alkylamino, di(C _1-4 alkyl)amino, carbamoyl, C _{1- 4} alkylcarbamoyl, di(C _1-4 alkyl)carbamoyl or C _1-3 alkoxy-C _1-3 alkyl;

Each of the aryl and heteroaryl is optionally 1 to 3 C _1-6 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 hydroxyalkyl, C _1-6 Haloalkyl, halo, cyano, pyrazinyl, hydroxy, oxo, nitro, formyl, C _1-4 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-4 alkylamino, di(C _1-4 alkyl) amino, carbamoyl, C _1-4 alkylcarbamoyl, di(C _1-4 alkyl) carbamoyl or C _1-4 alkylsulfonyl which may be substituted,

It may be a compound, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, in the above formula,

R ₃ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl is unsubstituted or 1 to 4 hydrogens are Halo, amino, cyano, nitro, azido, thiol, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 di May be substituted with a substituent selected from the group consisting of hydroxyalkyl, C _1-4 cycloalkyl, C _1-4 alkoxy, heterocyclyl, C _1-3 alkoxy-C _1-3 alkyl and aryl);

The aryl is phenyl;

The heterocyclyl is tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyranyl, dioxanyl, ditianyl, dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, Oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, dioxotetrahydrothiophenyl, dioxothiolanyl, oxopiperidinyl, May be oxopyrrolidinyl, oxoimidazolidinyl or oxoxazolidinyl;

The heteroaryl is tetrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, iso Thiazolyl, thiadiazolyl, furazanyl, oxazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzoimidazolyl, Benzotriazolyl or azaindolyl;

Each of the above cycloalkyl and heterocyclyl may optionally be substituted with 1 to 3 C _1-4 alkyl, hydroxy, oxo, halo or C _1-4 haloalkyl;

Wherein each of the aryl and heteroaryl may optionally be substituted with 1 to 3 C _1-4 alkyl, C _1-4 haloalkyl, halo, hydroxy or oxo,

It may be a compound, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, in the above formula,

Y is oxopyrrolidinyl, oxoimidazolidinyl or -NHC(O)R ₃ , and the oxopyrrolidinyl and oxoimidazolidinyl are unsubstituted or 1 to 3 hydrogens are fluoro, methyl and tri May be substituted with a substituent selected from the group consisting of fluoromethyl;

R ₂ is hydrogen or fluoro;

R ₃ is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl is unsubstituted or 1 to 4 hydrogens are fluoro, chloro, methyl , Cyano, nitro, amino, methoxy, trifluoromethyl and may be substituted with a substituent selected from the group consisting of phenyl),

It may be a compound, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, in the above formula,

Y is oxopyrrolidinyl, oxoimidazolidinyl, nicotinoylamino, picolinoylamino, fluoronicotinoylamino, methylnicotinoylamino, pyridazinylcarbonylamino, fluoropicolinoylamino, Methylpicolinoylamino or trifluoromethylnicotinoylaminoin,

It may be a compound, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, the compound,

1) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)nicotinamide;

2) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)picolinamide;

3) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-fluoronicotinamide;

4) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methylnicotinamide;

5) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)pyridazine-3-carboxyamide;

6) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(2- Oxoimidazolidin-1-yl)pyrimidin-2(1H)-one;

7) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(2- Oxopyrrolidin-1-yl)pyrimidin-2(1H)-one;

8) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(3- Methyl-2-oxoimidazolidin-1-yl)pyrimidin-2(1H)-one;

9) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-fluoropicolinamide;

10) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-methylpicolinamide;

11) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide;

12) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-3-methylpicolinamide;

13) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methylpicolinamide;

14) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide;

15) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carboxamide;

16) Isopropyl ((S)-(((2R,3R,5R)-4,4-difluoro-3-hydroxy-5-(4-(nicotinamido)-2-oxopyrimidine- 1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoyl)-L-alaninate;

17) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-phenylpicolinamide;

18) 1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(3-methyl-2 -Oxopyrrolidin-1-yl)pyrimidin-2(1H)-one;

19) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-nitropicolinamide;

20) 5-Amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide. Hydrochloride;

21) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-methoxypicolinamide;

22) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methoxynicotinamide;

23) 6-chloro-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)nicotinamide;

24) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-2-methylpyrimidin-4-carboxamide;

25) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-phenylpicolinamide;

26) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)nicotinamide;

27) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-phenylpicolinamide;

28) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-phenylpicolinamide;

29) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-2-methylpyrimidin-4-carboxamide;

30) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-nitropicolinamide;

31) 5-Amino-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;

32) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methylnicotinamide;

33) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)pyridazine-3-carboxamide;

34) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methylpyrazine-2-carboxamide;

35) 5-Fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;

36) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)pyrimidine-4-carboxamide;

37) 5-cyano-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;

38) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-methylpicolinamide;

39) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-methoxypicolinamide;

40) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide;

41) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide;

42) 6-fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)nicotinamide;

43) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methoxynicotinamide; And

44) Isopropyl((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(4-(2-methylpyrimidine-4-carboxamido)- 2-oxopyridin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoyl)-L-alaninate may be selected from the group consisting of. However, it is not limited thereto.

The compound of Formula 1 of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention is a concentration that is relatively non-toxic and harmless to patients, and side effects caused by this salt do not degrade the beneficial efficacy of the compound represented by formula (1). It means all organic or inorganic acid addition salts.

At this time, an organic acid and an inorganic acid can be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used as the inorganic acid, and as the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid. However, it is not limited to these.

In addition, a pharmaceutically acceptable metal salt can be made using a base. At this time, the metal salt is particularly suitable for preparing sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The salt of the nucleoside or nucleotide derivative of the present invention is a pharmaceutically acceptable salt, and any salt of a nucleoside or nucleotide derivative exhibiting antiviral activity equivalent to that of a nucleoside or nucleotide derivative compound can be used without limitation. .

Method for preparing a nucleoside or nucleotide derivative compound

The compound of formula 1 of the present invention is prepared by a series of reactions to 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydro Furan-2-yl)pyrimidin-2(1H)-one or 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) It can be synthesized from tetrahydrofuran-2-yl)pyrimidin-2(1H)-one, and as a specific embodiment, it can be prepared according to Reaction Scheme 1 below.

However, the following Scheme 1 is only an exemplary method for preparing the compound of the present invention, and the method for preparing the compound of the present invention is not limited thereto, and may be performed using a method known in the art or appropriately changed.

As described above, 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran, which is the starting material of the compound of the present invention -2-yl)pyrimidin-2(1H)-one or 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetra The substituent (R ₃ ) may be introduced by further carrying out one or more reactions known in the art from hydrofuran-2-yl)pyrimidin-2(1H)-one.

For example, compound ( 2 ) is synthesized by performing a protective reaction on alcohol in compound ( 1 ) according to the following Scheme 1, and the title compound of the present invention, a nucleoside derivative compound ( 3 ) can be obtained.

[Scheme 1]

Preferably, various groups used as conventional protecting groups in the protection reaction can be used as the protecting group (P) without limitation, and in a specific embodiment according to the present invention, trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS ) Was used.

In addition, the reaction may be carried out by reacting the intermediate (2) with a carbonyl halide containing a substituent (R ₃ ) suitable for the desired title compound in a Pyridine/DCM solvent. Preferably, the reaction may be carried out through the reaction for 7 to 18 hours at -78 to 60.

For example, nucleotide, which is the title compound of the present invention, is synthesized by performing a phosphoramidite reaction in compound ( 4 ) according to Scheme 2 below to synthesize compound ( 5 ), and then through deprotection reaction after amide reaction using various carbonyl halides. The derivative compound ( 6 ) can be obtained.

[Scheme 2]

Preferably, the reaction is carbonyl halides containing the substituent (R ₃₎ appropriate to the compound (4), the title compound was synthesized by phosphoramidite compound (5) using the t-BuMgCl and optionally in THF solvent After reaction with, it can be carried out through a deprotection reaction. Preferably, the deprotection reaction may be carried out through a reaction for 0.5 to 1 hour using a TBAF (Tetrabutylammonium fluoride) solution at 0 to room temperature.

Composition containing nucleoside or nucleotide derivative compound, use thereof, and prevention or treatment method using the same

The present invention provides a pharmaceutical composition for the prevention or treatment of viral infection-related diseases comprising the compound represented by the following Formula 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

Formula 1 is as defined above.

The compound of Formula 1 of the present invention, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof may exhibit antiviral activity.

Therefore, the pharmaceutical composition comprising the compound of Formula 1 of the present invention, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient exhibits universal antiviral activity to prevent viral infection-related diseases Or it can be usefully used for treatment.

Specifically, the pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of diseases related to viral infection.

The viral disease is affected by HIV, HBV, HCV, influenza, picorna, flavi, alpha, phlebovirus, ebola, or corona virus. It may be a disease caused by, but is not limited thereto.

In the present invention, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of tanchyrase-related diseases by administration of the composition of the present invention, and the term "treatment" refers to It refers to any action in which the symptoms of the disease are improved or beneficially changed by the administration of the composition .

The pharmaceutical composition according to the present invention contains a compound represented by Formula 1, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient in 0.1 to 75% by weight based on the total weight of the composition, more preferably It may contain 1 to 50% by weight.

In addition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powders, granules, tablets, capsules, suspensions, according to a conventional method according to each purpose of use, It can be formulated and used in various forms such as oral formulations such as emulsion, syrup, aerosol, and injections of sterile injectable solutions, and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, etc. I can. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the composition of the present invention may further contain fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like.

The composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is Health status, type of disease, severity, drug activity, sensitivity to drugs, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field Can be determined according to. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight daily or every other day or 1 It can be administered in 1 to 6 times a day. However, since it may increase or decrease according to the route of administration, the severity of the disease, sex, weight, age, etc., the dosage amount does not limit the scope of the present invention in any way .

According to another embodiment of the present invention, the present invention comprises administering a compound represented by Formula 1, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof to an individual in need thereof. It provides a method of preventing or treating virus-related diseases in

In the present invention, the term "individual" refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, including humans in which the virus-related diseases are invented or may develop. It means all animals, including rabbits or guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention can be administered in combination with an existing therapeutic agent.

In the present invention, the term "administration" means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention is through any general route as long as it can reach the target tissue. Can be administered. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration may be administered, but are not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells. Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections, and the like.

According to the type of disease to be prevented or treated, the pharmaceutical composition of the present invention may be used as an active ingredient, except for a nucleoside or nucleotide derivative compound, a racemate thereof, a stereoisomer, or a pharmaceutically acceptable salt thereof. It may further include known drugs used for the prevention or treatment of diseases. For example, when used for the prophylaxis or treatment of viral diseases, a known antiviral agent in addition to a nucleoside or nucleotide derivative compound, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof may be further included as an active ingredient. And can be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapy, immunotherapy, and the like.

Since the novel nucleoside or nucleotide derivative of the present invention has excellent antiviral and anticancer activity, it can be usefully used for the prevention or treatment of viral infection-related diseases.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

Preparation Example 1: 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)tetrahydrofuran-2 -Yl) Preparation of pyrimidine-2(1H)-one (IA)

4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H) After -one hydrochloride (600 mg, 2.002 mmol) was dissolved in pyridine (10 ml), TMSCl (0.76 ml, 6.006 mmol) was added. Stirred for 17 hours at 55-60. The reaction solution was diluted in EtOAc and washed 5 times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 600 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 407.8 (M+H ⁺ )

Preparation Example 2: 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-((trimethylsilyl)oxy)-5-(((trimethylsilyl)oxy)methyl)tetrahydro Preparation of furan-2-yl)pyrimidin-2(1H)-one (IB)

4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydioxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H) After -one (1 g, 4.078 mmol) was dissolved in pyridine (10 ml), TMSCl (1.54 ml, 12.234 mmol) was added. The mixture was stirred at 70° C. for 6 hours. The reaction solution was diluted in EtOAc and washed 5 times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1.57 g of the title compound as a white solid.

LC-MS (ESI, m/z) = 390.1 (M+H ⁺ )

Example 1: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)nicotinamide

Step 1 : 4-Amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2 (1H)-one hydrochloride (1 g, 3.337 mmol) was dissolved in pyridine (16.7 ml) and then TMSCl (1.4 ml, 11.012 mmol) was added. After stirring at 55 to 60 for 3.5 hours, nicotinoyl chloride hydrochloride (720 mg, 4.044 mmol) was added, followed by stirring at the same temperature for 7 hours. The reaction solution was diluted in EtOAc and washed 5 times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1.67 g of the title compound as a white solid.

LC-MS (ESI, m/z) = 513.0 (M+H ⁺ )

Step 2 : After dissolving the compound (1.65 g, 3.219 mmol) obtained from step 1 in DCM (6 ml), 4 M HCl in dioxane (8 ml) was slowly added at 0. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with purified water, and a 2 N NaOH aqueous solution was added to adjust the pH to 6 to 7. The precipitated solid (precipitate) was filtered and dried to obtain 1.08 g of the title compound as a white solid.

LC-MS (ESI, m/z) = 369.0 (M+H ⁺ )

Example 2: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)picolinamide

Picolinoyl chloride hydrochloride (141.5 mg, 0.674 mmol) and I-A (260 mg, 0.683 mmol) were reacted in a similar manner to Example 1 to obtain 71.5 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 368.2 (M+H ⁺ )

Example 3: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-fluoronicotinamide

6-fluoronicotinoylchloride (133 mg, 0.834 mmol) and I-A (200 mg, 0.490 mmol) were reacted in a similar manner to Example 1 to obtain 38.6 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 386.2 (M+H ⁺ )

Example 4: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-methylnicotinamide

6-methylnicotinoylchloride (133 mg, 0.834 mmol) and I-A (100 mg, 0.245 mmol) were reacted in a similar manner to Example 1 to obtain 32 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 382.3 (M+H ⁺ )

Example 5: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)pyridazine-3-carboxyamide

Pyridazine-3-carbonyl chloride (210 mg, 1.472 mmol) and I-A (500 mg, 1.226 mmol) were reacted in a similar manner as in Example 1 to obtain 54.4 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 369.2 (M+H ⁺ )

Example 6: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-( Preparation of 2-oxoimidazolidin-1-yl)pyrimidine-2(1H)-one

Step 1: After dissolving IA (200 mg, 0.49 mmol) in chloroform (5 ml), 2-chloroethylisocyanate (0.04 ml, 0.49 mmol) was added and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and the next reaction proceeded without purification.

Step 2: After dissolving the compound obtained from step 1 in THF (2.5 ml), 60% NaH (37 mg, 1.47 mmol) was added at -20, and the temperature was gradually raised, followed by stirring at room temperature for 18 hours. Ice was added to the reaction mixture, stirred for 5 minutes, diluted with EtOAc, and the organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure. The concentrated residue was diluted with MeOH, DCM was added, and the precipitated solid (precipitate) was filtered and dried to give 96.1 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 332.2 (M+H ⁺ )

Example 7: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-( Preparation of 2-oxopyrrolidin-1-yl)pyrimidin-2(1H)-one

Step 1 : Picolinoyl 4-bromobutyrylchloride (0.4 ml, 3.434 mmol) and TEA (1.2 ml, 8.587 mmol) were slowly added to IA (162 mg, 0.397 mmol) dissolved in DCM (8.5 ml) at -50. The reaction solution was stirred at 10 for 24 hours, diluted with DCM, and washed with purified water. The organic layer was dehydrated with Na ₂ SO ₄ , concentrated under reduced pressure to obtain 800 mg, and the next reaction was carried out without purification.

Step 2 : The compound obtained from Step 1 (800 mg, 1.437 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 303.2 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 331.2 (M+H ⁺ )

Example 8: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-( Preparation of 3-methyl-2-oxoimidazolidin-1-yl)pyrimidine-2(1H)-one

Step 1: (2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-2-((3-fluorobenzoyl Oxy)methyl) tetrahydrofuran-3-yl 3-fluorobenzoate (200 mg, 0.394 mmol) was dissolved in DCM (4 ml), followed by pyridine (0.05 ml, 0.591 mmol) and phenyl chloroformate (0.06 ml, 0.472). mmol) was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. After dissolving the concentrate in pyridine (4 ml), 2-chloro-N-methylethanamine hydrochloride (256 mg, 1.97 mmol) was added, followed by stirring at 50 for 8 hours. The reaction solution was diluted in EtOAc and washed 5 times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 170 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 626.9 (M+H ⁺ )

Step 2: After dissolving the compound (170 mg, 0.288 mmol) obtained from Step 1 in MeOH (1 ml), 7 N NH ₃ in MeOH (2 ml) was added and stirred at room temperature for 18 hours, and the reaction solution was It was concentrated under reduced pressure. The concentrated residue was separated by column chromatography to obtain 64.3 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 346.2 (M+H ⁺ )

Example 9: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-5-fluoropicolinamide

After dissolving 6-fluoropicolinic acid (300 mg, 2.126 mmol) in DCM (4.25 ml), DMF (16.5 μl, 0.213 mmol) and oxalyl chloride (0.27 ml, 3.189 mmol) were slowly added at 0. The reaction solution was stirred at room temperature for 22 hours and then concentrated under reduced pressure. The obtained residue was washed with ether and dried to obtain 339 mg of a compound as an apricot solid. The obtained 6-fluoropicolinoyl chloride (88 mg, 0.552 mmol) and DIPEA (0.48 ml, 2.76 mmol) were slowly added to IA (150 mg, 0.368 mmol) dissolved in DCM (1.2 ml) at -78. The reaction solution was stirred at room temperature for 18 hours, diluted with DCM, and washed with purified water. The organic layer was dehydrated with Na ₂ SO ₄ , concentrated under reduced pressure, and separated by column chromatography to obtain 36.7 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 386.8 (M+H ⁺ )

Example 10: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-5-methylpicolinamide

5-methylpicolinoyl chloride (119 mg, 0.766 mmol) and IA (260 mg, 0.683 mmol) obtained by reacting 5-methylpicolinic acid (200 mg, 1.458 mmol) with oxalyl chloride (0.38 ml, 4.374 mmol) were prepared in Example 8 Reaction was carried out in a manner similar to that to obtain 67.5 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 382.8 (M+H ⁺ )

Example 11: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide

2-methyl-6-(trifluoromethyl)nicotinoyl chloride (164.7 mg, 0.737 mmol) obtained by reacting 2-methyl-6-(trifluoromethyl)nicotinic acid (205 mg, 1.000 mmol) with oxalyl chloride (0.36 ml, 3.000 mmol) And IA (200 mg, 0.491 mmol) were reacted in a similar manner as in Example 8 to obtain 75 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 450.6 (M+H ⁺ )

Example 12: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-3-methylpicolinamide

Step 1 : 3-methylpicolinoyl chloride (86 mg, 0.552 mmol) and IA (150 mg, 0.368 mmol) obtained by reacting 3-methylpicolinic acid (300 mg, 2.188 mmol) with oxalyl chloride (0.56 ml, 6.563 mmol) By reacting in a similar manner to Example 8, 80 mg of the compound was obtained as a yellow liquid.

LC-MS (ESI, m/z) = 455.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (80 mg, 0.165 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 44 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 383.0 (M+H ⁺ )

Example 13: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-methylpicolinamide

6-methylpicolinoyl chloride (68.7 mg, 0.442 mmol) and IA (150 mg, 0.368 mmol) obtained by reacting 6-methylpicolinic acid (300 mg, 2.188 mmol) with oxalyl chloride (0.56 ml, 6.563 mmol) were prepared in Example 8 Reaction was carried out in a manner similar to that to obtain 14.4 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 383.0 (M+H ⁺ )

Example 14: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1 : 6-(trifluoromethyl)nicotinoyl chloride (62 mg, 0.294 mmol) and IA (100 mg) obtained by reacting 6-(trifluoromethyl)nicotinic acid (150 mg, 0.784 mmol) with oxalyl chloride (0.13 ml, 1.569 mmol) , 0.245 mmol) was reacted in a similar manner to Example 9 to obtain 108 mg of a compound as an apricot-colored solid.

LC-MS (ESI, m/z) = 581.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (108 mg, 0.185 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 19.8 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 437.0 (M+H ⁺ )

Example 15: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carboxamide

Step 1 : 1-methyl-1H-pyrazole-4-carbonyl chloride (85) obtained by reacting 1-methyl-1H-pyrazole-4-carboxylic acid (300 mg, 2.380 mmol) with oxalyl chloride (0.4 ml, 4.720 mmol) mg, 0.588 mmol) and IA (200 mg, 0.490 mmol) were reacted in a similar manner as in Example 9 to obtain 148 mg of a compound as an apricot-colored solid.

LC-MS (ESI, m/z) = 516.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (148 mg, 0.287 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 18.2 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 372.1 (M+H ⁺ )

Example 16: Isopropyl ((S)-(((2R,3R,5R)-4,4-difluoro-3-hydroxy-5-(4-(nicotinamido)-2-oxopyrimi Preparation of din-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoyl)-L-alaninate

Step 1 : 4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3,3-difluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2( Dissolve 1H)-one (365 mg, 0.967 mmol) in THF (10 ml) and cool to 0 ^o C. 0.85 ml of t-BuMgCl (1.7 M in THF) was slowly added and stirred for 15 minutes. Isopropyl ((R)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate was dissolved in a small amount of THF, and then slowly added. After slowly raising the temperature to room temperature, the mixture was stirred at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 442 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 647.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (442 mg, 0.683 mmol) was reacted in a similar manner to Step 1 of Example 1 to obtain 497 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 752.2 (M+H ⁺ )

Step 3 : The compound obtained from Step 2 (442 mg, 0.683 mmol) was dissolved in THF (0.5 ml) and cooled to 0 ^o C. After slowly adding 0.16 ml of TBAF 1M in THF, the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 52 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 638.1 (M+H ⁺ )

Example 17: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-phenylpicolinamide

Step 1 : 6-phenylpicolinoyl chloride (159.9 mg, 0.735 mmol) and IA (200 mg, 0.49 mmol) obtained by reacting 6-phenylpicolinic acid (250 mg, 1.254 mmol) with oxalyl chloride (0.27 ml, 3.189 mmol) It was reacted in a manner similar to Example 9 to obtain a yellow liquid without purification, and the next step was carried out.

LC-MS (ESI, m/z) = 589.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (0.49 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 123 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 445.0 (M+H ⁺ )

Example 18: 1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(3-methyl Preparation of -2-oxopyrrolidin-1-yl)pyrimidin-2(1H)-one

Step 1 : 3-methyldihydrofuran-2(3H)-one (1 g, 9.988 mmol) with Hydrogen bromide solution (33 wt.% in acetic acid, 9.98 ml, 30.266 mmol), thionyl chloride (6 ml, 50.432 mmol) and 4-bromo-2-methylbutanoyl chloride (0.12 ml, 0.919 mmol) obtained by reaction and IA (250 mg, 0.513 mmol) were reacted in a similar manner to Example 9 to obtain 349 mg of a compound as an orange solid.

LC-MS (ESI, m/z) = 516.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (300 mg, 0.581 mmol) was dissolved in DMF (0.6 ml), TEA (0.2 ml, 1.402 mmol) was added, and the mixture was reacted with a microwave reactor at 200 for 1 hour. The reaction solution was diluted in EtOAc and washed with purified water. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 210 mg of the title compound as a yellow solid.

LC-MS (ESI, m/z) = 490.1 (M+H ⁺ )

Example 19: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-5-nitropicolinamide

Step 1 : 5-nitropicolinoyl chloride (98.6 mg, 0.442 mmol) and IA (150 mg, 0.368 mmol) obtained by reacting 5-nitropicolinic acid (300 mg, 1.785 mmol) with oxalyl chloride (0.46 ml, 5.353 mmol) By reacting in a similar manner to Example 8, 100 mg of the compound was obtained as a yellow solid.

LC-MS (ESI, m/z) = 558.0 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (100 mg, 0.179 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 59 mg of the title compound as a yellow solid.

LC-MS (ESI, m/z) = 414.0 (M+H ⁺ )

Example 20: 5-Amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-yl)picolinamide. Preparation of hydrochloride

The compound (90 mg, 0.197 mmol) obtained by reacting the compound (110 mg, 0.197 mmol) obtained from step 1 of Example 19 with 10% Pd/C (55 mg) under hydrogen gas was used as the step of Example 1. Reaction in a similar manner to 2 gave 82 mg of the title compound as a yellow solid.

LC-MS (ESI, m/z) = 384.1 (M+H ⁺ )

Example 21: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-5-methoxypicolinamide

Step 1 : 5-methoxypicolinoyl chloride (126 mg, 0.735 mmol) and IA (200 mg, 0.49 mmol) obtained by reacting 5-methoxypicolinic acid (200 mg, 1.305 mmol) with oxalyl chloride (0.28 ml, 3.264 mmol) By reacting in a manner similar to that of Example 8, 110 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 543.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (110 mg, 0.202 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 35 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 399.0 (M+H ⁺ )

Example 22: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-6-methoxynicotinamide

Step 1 : 6-methoxynicotinoyl chloride (168 mg, 0.980 mmol) obtained by reacting 6-methoxynicotinic acid (200 mg, 1.305 mmol) with oxalyl chloride (0.22 ml, 2.611 mmol) and 4-amino-1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one hydrochloride (200 mg, 0.668 mmol ) Was reacted in a similar manner to Example 1 to obtain 106 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 543.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (106 mg, 0.195 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 71.8 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 399.1 (M+H ⁺ )

Example 23: 6-chloro-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) Preparation of -2-oxo-1,2-dihydropyrimidin-4-yl)nicotinamide

6-chloronicotinoyl chloride (117 mg, 0.668 mmol) and 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran 2-yl)pyrimidine-2(1H)-one hydrochloride (200 mg, 0.668 mmol) was reacted in a similar manner to Example 1 to obtain 95 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 547.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (95 mg, 0.173 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 30.4 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 403.0 (M+H ⁺ )

Example 24: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-2-methylpyrimidine-4-carboxamide

Step 1 : 2-methylpyrimidine-4-carbonyl chloride (104 mg, 0.668 mmol) obtained by reacting 2-methylpyrimidine-4-carboxylic acid (200 mg, 1.448 mmol) with oxalyl chloride (0.24 ml, 2.896 mmol) and 4- Amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one Hydrochloride (200 mg, 0.668 mmol) was reacted in a similar manner to Example 1 to obtain 246 mg of the compound as a white solid.

LC-MS (ESI, m/z) = 527.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (246 mg, 0.466 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 83 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 384.1 (M+H ⁺ )

Example 25: N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo Preparation of -1,2-dihydropyrimidin-4-yl)-5-phenylpicolinamide

Step 1 : 5-phenylpicolinoyl chloride (138 mg, 0.637 mmol) and IA (200 mg, 0.490 mmol) obtained by reacting 5-phenylpicolinic acid (300 mg, 1.505 mmol) with oxalyl chloride (0.25 ml, 3.011 mmol) By reacting in a similar manner to Example 9, 190 mg of the compound was obtained as an apricot-colored solid.

LC-MS (ESI, m/z) = 589.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (190 mg, 0.322 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 49.7 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 445.1 (M+H ⁺ )

Example 26: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)nicotinamide

Step 1 : Nicotinoyl chloride HCL (158.6 mg, 0.891 mmol) and IB (315.5 mg, 0.81 mmol) were reacted in a similar manner as in Example 9 to obtain 130 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 493.1 (MH ⁺ )

Step 2 : The compound obtained from Step 1 (130 mg, 0.262 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 60 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 351.0 (M+H ⁺ )

Example 27: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-6-phenylpicolinamide

Step 1 : 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydioxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2 (1H)-one (200 mg, 0.407 mmol) was dissolved in pyridine (2 ml) and then TMSCl (0.3 ml, 1.223 mmol) was added. After stirring for 6 hours at 55 to 60, the mixture was cooled to 5, 6-phenylpicolinoyl chloride (177 mg, 0.407 mmol) was added, followed by stirring at the same temperature for 1 hour. The reaction solution was diluted in EtOAc and washed 5 times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 272 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 571.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (272 mg, 0.477 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 134 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 427.1 (M+H ⁺ )

Example 28: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-5-phenylpicolinamide

Step 1 : 5-phenylpicolinoyl chloride (111 mg, 0.513 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 5-phenylpicolinic acid (300 mg, 1.505 mmol) with oxalyl chloride (0.25 ml, 3.011 mmol) By reacting in a similar manner to Example 9, 125 mg of the compound was obtained as an apricot solid.

LC-MS (ESI, m/z) = 571.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (125 mg, 0.219 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 69.5 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 427.1 (M+H ⁺ )

Example 29: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-2-methylpyrimidine-4-carboxamide

Step 1 : 2-methylpyrimidine-4-carbonyl chloride (104 mg, 0.668 mmol) obtained by reacting 2-methylpyrimidine-4-carboxylic acid (200 mg, 1.448 mmol) with oxalyl chloride (0.24 ml, 2.896 mmol) and 4- Amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (200 mg, 0.816 mmol) was reacted in a similar manner to Example 27 to obtain 320 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 510.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (320 mg, 0.627 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 174.5 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 366.1 (M+H ⁺ )

Example 30: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-5-nitropicolinamide

Step 1 : 5-nitropicolinoyl chloride (143 mg, 0.4770 mmol) obtained by reacting 5-nitropicolinic acid (300 mg, 1.785 mmol) with oxalyl chloride (0.46 ml, 5.353 mmol) and IB (300 mg, 0.770 mmol) Reaction was carried out in a similar manner to Example 9 to obtain 213 mg of a compound as a yellow solid.

LC-MS (ESI, m/z) = 540.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (213 mg, 0.394 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 64.6 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 396.0 (M+H ⁺ )

Example 31: 5-Amino-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- Preparation of 2-oxo-1,2-dihydropyrimidin-4-yl)picolinamide

The compound obtained from step 2 of Example 30 (58 mg, 0.146 mmol) was reacted with 10% Pd/C (55 mg) under hydrogen gas, filtered through Celite, concentrated under reduced pressure, and 32.8 mg of the title compound as a white solid Was obtained.

LC-MS (ESI, m/z) = 366.1 (M+H ⁺ )

Example 32: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-6-methylnicotinamide

Step 1 : 6-methylnicotinoyl chloride (126 mg, 0.816 mmol) obtained by reacting 6-methylnicotinic acid (400 mg, 2.916 mmol) with oxalyl chloride (0.5 ml, 5.833 mmol) and 4-amino-1-((2R, 3R,4R,5R)-3-fluoro-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (200 mg, 0.816 mmol) By reacting in a similar manner to Example 27, 159 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 509.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (159 mg, 0.312 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 103.9 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 365.1 (M+H ⁺ )

Example 33: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)pyridazine-3-carboxamide

Step 1 : pyridazine-3-carbonyl chloride (586 mg, 3.303 mmol) obtained by reacting pyridazine-3-carboxylic acid (415 mg, 3.344 mmol) with oxalyl chloride (0.85 ml, 10.032 mmol) and 4-amino-1- ((2R,3R,4R,5R)-3-fluoro-4-hydioxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (700 mg, 2.753 mmol) was reacted in a similar manner to Example 27 to obtain 729 mg of a compound as a yellow solid.

LC-MS (ESI, m/z) = 496.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (729 mg, 1.470 mmol) was reacted in a similar manner to Step 2 of Example 1, and the precipitated solid was filtered and dried to obtain 523.2 g of the title compound as a white solid. Obtained.

LC-MS (ESI, m/z) = 352.1 (M+H ⁺ )

Example 34: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-6-methylpyrazine-2-carboxamide

Step 1 : 6-methylpyrazine-2-carbonyl chloride (88.4 mg, 0.564 mmol) obtained by reacting 6-methylpyrazine-2-carboxylic acid (200 mg, 1.448 mmol) with oxalyl chloride (0.24 ml, 2.896 mmol) and IB ( 200 mg, 0.513 mmol) was reacted in a similar manner to Example 9 to obtain 115 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 510.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (115 mg, 0.225 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 54 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 366.1 (M+H ⁺ )

Example 35: 5-Fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) Preparation of -2-oxo-1,2-dihydropyrimidin-4-yl)picolinamide

Step 1 : 5-fluoropicolinoyl chloride HCl (120.54 mg, 0.615 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 5-fluoropicolinic acid (141 mg, 1 mmol) with oxalyl chloride (0.257 ml, 3 mmol) By reacting in a similar manner to Example 9, 115 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 513.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (115 mg, 0.22 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 48 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 369.0 (M+H ⁺ )

Example 36: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)pyrimidine-4-carboxamide

Step 1 : pyrimidine-4-carbonyl chloride (137.6 mg, 0.769 mmol) obtained by reacting pyrimidine-4-carboxylic acid (200 mg, 1.611 mmol) with oxalyl chloride (0.4 ml, 4.833 mmol) and IB (200 mg, 0.513 mmol) was reacted in a similar manner as in Example 9 to obtain 106 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 496.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (115 mg, 0.225 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 54 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 352.1 (M+H ⁺ )

Example 37: 5-cyano-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) Preparation of -2-oxo-1,2-dihydropyrimidin-4-yl)picolinamide

Step 1 : 5-cyanopicolinoyl chloride HCl (125 mg, 0.615 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 5-cyanopicolinic acid (148 mg, 1 mmol) with oxalyl chloride (0.257 ml, 3 mmol) By reacting in a similar manner to Example 9, 100 mg of a compound was obtained as a yellow liquid.

LC-MS (ESI, m/z) = 520.0 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (100 mg, 0.192 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 52 mg of the title compound as a yellow solid.

LC-MS (ESI, m/z) = 376.0 (M+H ⁺ )

Example 38: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-5-methylpicolinamide

Step 1 : 5-methylpicolinoyl chloride (197 mg, 1.026 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 5-methylpicolinic acid (200 mg, 1.458 mmol) with oxalyl chloride (0.37 ml, 4.375 mmol) By reacting in a similar manner to Example 9, 215 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 509.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (215 mg, 0.422 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 106.4 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 365.1 (M+H ⁺ )

Example 39: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-5-methoxypicolinamide

Step 1 : 5-methoxypicolinoyl chloride (213 mg, 1.026 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 5-methoxypicolinic acid (200 mg, 1.305 mmol) with oxalyl chloride (0.33 ml, 3.915 mmol) By reacting in a similar manner to Example 9, 139 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 525.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (139 mg, 0.264 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 57 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 381.1 (M+H ⁺ )

Example 40: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide

Step 1 : 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (329 mg, obtained by reacting 2-methyl-6-(trifluoromethyl)nicotinic acid (200 mg, 0.974 mmol) with oxalyl chloride (0.25 ml, 2.922 mmol)) 1.572 mmol) and 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydioxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine- 2(1H)-one (200 mg, 0.816 mmol) was reacted in a similar manner to Example 27 to obtain 98 mg of a compound as a yellow solid.

LC-MS (ESI, m/z) = 577.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (98 mg, 0.169 mmol) was reacted in a similar manner to Step 2 of Example 1, to obtain 64.8 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 433.1 (M+H ⁺ )

Example 41: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1 : 6-(trifluoromethyl)nicotinoyl chloride (189 mg, 0.769 mmol) and 4-amino- obtained by reacting 6-(trifluoromethyl)nicotinic acid (200 mg, 1.046 mmol) with oxalyl chloride (0.26 ml, 3.139 mmol) 1-((2R,3R,4R,5R)-3-fluoro-4-hydioxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (200 mg, 0.816 mmol) was reacted in a manner similar to Example 27 to obtain 202 mg of a compound as a yellow solid.

LC-MS (ESI, m/z) = 563.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (202 mg, 0.359 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 66 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 419.0 (M+H ⁺ )

Example 42: 6-Fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) Preparation of -2-oxo-1,2-dihydropyrimidin-4-yl)nicotinamide

Step 1 : 6-fluoronicolinoyl chloride (100.5 mg, 0.513 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 6-fluoronicolinic acid (200 mg, 1.417 mmol) with oxalyl chloride (0.36 ml, 4.252 mmol) By reacting in a similar manner to Example 9, 175 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 513.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (175 mg, 0.342 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 15 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 369.0 (M+H ⁺ )

Example 43: N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- Preparation of 1,2-dihydropyrimidin-4-yl)-6-methoxynicotinamide

Step 1 : 6-methoxypicolinoyl chloride (213 mg, 1.026 mmol) and IB (200 mg, 0.513 mmol) obtained by reacting 6-methoxypicolinic acid (200 mg, 1.305 mmol) with oxalyl chloride (0.33 ml, 3.915 mmol) By reacting in a similar manner to Example 9, 125 mg of the compound was obtained as a white solid.

LC-MS (ESI, m/z) = 525.1 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (125 mg, 0.238 mmol) was reacted in a similar manner to Step 2 of Example 1 to obtain 31.4 mg of the title compound as a white solid.

LC-MS (ESI, m/z) = 381.1 (M+H ⁺ )

Example 44: Isopropyl ((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(4-(2-methylpyrimidine-4-carboxamido) )-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-alaninate

Step 1 : 4-Amino-1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2 -Yl)pyrimidine-2(1H)-one (395 mg, 1.10 mmol) was reacted in a similar manner to Step 1 of Example 16 to obtain 318 mg of a compound as a yellow solid.

LC-MS (ESI, m/z) = 629.2 (M+H ⁺ )

Step 2 : The compound obtained from Step 1 (307 mg, 0.488 mmol) was reacted in a manner similar to the method of obtaining the amide of Example 9 to obtain 345 mg of the compound as a yellow solid.

LC-MS (ESI, m/z) = 749.2 (M+H ⁺ )

Step 3 : Dissolve the compound (120 mg, 0.160 mmol) obtained from step 2 in THF (0.8 ml) and cool to -5 ^o C. After slowly adding 0.17 ml of TBAF 1M in THF, the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution, diluted with EtOAc, and washed three times with water. The organic layer was dehydrated with Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography to obtain 60 mg of a compound as a white solid.

LC-MS (ESI, m/z) = 635.0 (M+H ⁺ )

The above examples are summarized in Table 1 below by structure and name.

(Continued from Table 1)

(Continued from Table 1)

Experimental Example 1: Anti-influenza virus efficacy test

In order to determine whether the compounds of the examples exhibit activity against various influenza viruses, experiments were conducted as follows.

(1) Preparation of cells infected with influenza virus

MDCK (Madin-Darby canine kidney) cells were purchased from ATCC, USA, and cultured in MEM (minimal essential medium) containing 10% fetal bovine serum (FBS), and the temperature of the incubator was 37 and the carbon dioxide concentration was 5 Kept as %.

Influenza virus A/Puerto Rico/8/34 (H1N1) (hereinafter referred to as "PR8"), A/HongKong/8/68 (H3N2) (hereinafter referred to as "HK"), B/Lee/40 (hereinafter referred to as , "Lee") was purchased from ATCC. Influenza viruses PR8 and HK were inoculated into 10-day-old eggs and grown at 37. Influenza virus Lee infected MDCK cells and proliferated, and 2 μg/ml of TPCK-trypsin (Sigma, (St. Louis, MO) was added to the culture medium without serum. The culture temperature was maintained at 35.) After 3 days of infection, allantoic fluids or cell culture solutions of eggs were centrifuged at 1,000 rpm for 5 minutes to purify impurities to obtain proliferated virus, and the virus titer was hemagglutinin contained in chicken red blood cells. , HA) or by infecting MDCK cells with a virus to measure the number of viral plaques, each virus was dispensed and stored at 70.

(2) Measurement of reduction of cytopathic effect

After washing sufficiently grown MDCK cells in a 96-well plate with phosphate-buffered saline (PBS), 50-100 plaque forming units (PFU) of influenza virus were inoculated for each well. Viruses were allowed to infect cells for about 1 hour, and PR8, HK, and Lee viruses were allowed to infect at 35. After removing the virus-containing culture solution and washing with phosphate buffered saline, 2 mg/ml TPCK-trypsin-containing MEM culture solution in which each example compound was diluted in various concentrations was added to each well. On the third day after infection, cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheyltetrazolimbromide (MTT) [Y. Jang et al., 2016. Antiviral activity of KR-23502 targeting nuclear export of influenza B virus ribonucleoproteins, Antiviral Res 134:77-88].

To summarize the method, the cell culture solution was removed, 100 μl of MTT solution (2.5 mg/ml) was added to each well, and left at 37 for 1 hour. After stopping the reaction by adding 100 μl of MTT solvent (4 mM HCl, 0.1% Nondet P-40 (NP40) in isopropanol), a spectrophotometer at 540 nm-690 nm (Model: SpectraMax M3 plate reader, Manufacturer: Molecular Devices, Sunnyvale , CA) to measure the intensity of absorption. The 50% cytotoxic concentration (CC ₅₀ , the concentration of the compound that damages 50% of normal cells) and the 50% effective concentration (EC ₅₀ , the concentration that normalizes the cytotoxicity due to viral infection by 50%) were calculated. As a control group, conventional standard antiviral agents, amantadine (AMT; Sigma), oseltamivir carboxylate (OSV-C; US Biological, Swampscott, MA), and ribavirin (RBV; Sigma) were used. .

Anti-influenza virus efficacy of nucleosides or nucleotide derivatives Example Toxicity Anti-Flu activity (EC ₅₀ : μM) Selectivity index FluA FluA FluB FluA FluA FluB CC ₅₀
(μM) H1N1
(PR8) H3N2
(Hong Kong) Lee H1N1
(PR8) H3N2
(Hong Kong) Lee One >100.0 21.00 128.00 8.60 >14.3 >23.4 >34.9 2 >100.0 1.7 1.00 2.20 >176.5 >300 >136.4 3 >100.0 2.5 1.90 2.40 >40.0 >52.6 >41.7 4 >100.0 1.8 2.00 1.90 >166.7 >150.0 >157.9 5 >100.0 2.2 1.90 2.10 >136.4 >157.9 >142.9 7 >100.0 14.1 15.40 9.40 >7.1 >6.5 >10.6 9 >100.0 8.8 4.40 6.10 >11.4 >22.7 >16.4 10 >100.0 16.1 11.40 9.80 >6.2 >8.8 >10.2 12 >100.0 56.9 51.70 49.10 >1.8 >1.9 >2.0 13 >100.0 9.1 7.10 7.80 >11.0 >14.1 >12.8 14 >100.0 6 2.9 3.1 >16.7 >34.5 >32.3 15 >100.0 12 6.8 8 >8.3 14.7 12.5 17 >100.0 1.7 3.30 2.40 >58.8 >30.3 >41.7 18 >100.0 53.4 83.00 49.30 >1.9 >1.2 >2.0 19 >100.0 1.4 2.00 <1.2 >71.4 >50.0 >83.3 20 >100.0 9.7 18.80 19.50 >10.3 >5.3 >5.1 21 >100.0 20.7 27.90 22.30 >4.8 >3.6 >4.5 22 >100.0 20.1 36.40 24.40 >5.0 >2.7 >4.1 23 >100.0 6.3 8.20 6.20 >15.9 >12.2 >16.1 24 >100.0 <1.2 2.20 <1.2 >83.3 >45.5 >83 25 >100.0 6.5 9.50 6.10 >15.4 >10.5 >16.4 27 >100.0 20.1 15.70 15.60 >5.0 >6.4 >6.4 28 >100.0 67.5 18.00 27.80 >1.5 >5.6 >3.6 29 >100.0 15.4 2.60 5.60 >6.5 >38.5 >17.9 30 >100.0 19.5 3.50 6.50 >5.1 >28.6 >15.4 33 >100.0 10 2.60 7.80 >10.0 >38.5 >12.8 34 >100.0 23.6 5.60 11.10 >4.2 >17.9 >9.0 35 >100.0 65.5 19.20 37.40 >1.5 >5.2 >2.7 36 >100.0 33.3 6.80 11.40 >3.0 >14.7 >8.8 37 >100.0 47.3 6.00 15.10 >2.1 >16.7 >6.6 38 >100.0 56.1 40.0 52.2 >1.8 >2.5 >1.9 41 >100.0 46.3 16.0 18.9 >2.2 >6.3 >5.3 42 >100.0 46.2 17.9 18.3 >2.2 >5.6 >5.5 Gemcitabine 240.80 0.70 0.70 1.30 344 344 185.2 2'-FdC >100.0 3.7 13.10 5.20 >27 >7.6 >19.2 AMT >100.0 >100.0 1.1 >100.0 ND >90.9 ND RBV >100.0 42.6 21.2 40.6 >2.3 >4.7 >2.5 OSV-C >100.0 0.09 <0.005 1.46 >1,111 >20,000 >68.5

Experimental Example 2: Anticoronavirus efficacy test

In order to find out whether the compounds of the examples exhibit activity against various anticoronaviruses, experiments were performed as follows.

1. Preparation of coronavirus-infected cells.

Huh-7 (Human hepatoma-7) cells were purchased from the Japanese Cell Line Bank (JCRB) and were cultured in DMEM (Dulbecco's Modified Eagle's medium) containing 10% fetal bovine serum (FBS). MRC-5 cells were purchased from ATCC, USA, and cultured in MEM (minimal essential medium) containing 10% bovine serum. The temperature of the incubator was maintained at 37° C. and the carbon dioxide concentration was maintained at 5%.

The MERS virus (MERS-CoV/KOR/KNIH/002_05_2015) was distributed from the Korea Centers for Disease Control and Prevention, and the human coronavirus hCoV 229E, OC43, and feline infectious peritonitis (FIPV) were purchased from ATCC. The MERS virus was infected with Huh-7 cells and grown at 37°C. In the same way, hCoV 229E and OC43 proliferated by infecting MRC-5 cells, and FIPV proliferated in CRFK cells. 2-3 days after infection, the cell culture was centrifuged at 3,000 rpm for 20 minutes to remove cellular impurities, thereby obtaining a proliferated virus. Virus titer was measured by infecting the cells used for each virus propagation with the virus, and the number of viral plaques. Each virus was dispensed in small portions and stored at 70°C.

2. Measurement of reduction of cytopathic effect

Huh-7 (MERS), MRC-5 (hCoV 229E, O43), CRFK (FIPV) cells grown in 96-well plates were inoculated with the corresponding virus for each well, and then the compound of each example was diluted to various concentrations. The containing culture medium was added for each will. On the third day after infection, cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheyltetrazolimbromide (MTT). The absorbance intensity was measured by a spectrophotometer (model name: SpectraMax M3 plate reader, manufacturer: Molecular Devices, Sunnyvale, CA) at 540 nm-690 nm. The 50% cytotoxic concentration (CC ₅₀ , the concentration of the compound that damages 50% of normal cells) and the 50% effective concentration (EC ₅₀ , the concentration that normalizes the cytotoxicity due to viral infection by 50%) were calculated. As a control group, gemcitabine (Sigma) was used.

Anticoronavirus efficacy of nucleosides or nucleotide derivatives Example Coronaviruses MERS-CoV hCoV (229E) hCoV (OC43) FIPV CC ₅₀
(μM) EC ₅₀
(μM) SI CC ₅₀
(μM) EC ₅₀
(μM) SI CC ₅₀
(μM) EC ₅₀
(μM) SI CC ₅₀
(μM) EC ₅₀
(μM) SI One >100 10.4 >9.62 >100 4.6 >21.74 >100 76 >
1.32 56 25 2.24 2 >100 1.8 >55.56 >100 0.8 >125.0 >100 >100 ND >100 9.1 >10.99 3 >100 8.9 >11.24 >100 1.8 >55.56 >100 >100 ND >100 24 >
4.17 4 >100 2.2 >45.45 >100 11.1 >9.01 >100 >100 ND >100 8.1 >12.35 5 >100 1.4 >71.43 >100 8.9 >11.24 >100 17.2 5.81 >100 8.5 >11.76 7 >100 17.6 >5.68 >100 >100 ND >100 77 >
1.30 9 >100 2.4 >41.67 >100 >100 ND >100 18 >
5.56 10 >100 7.4 >13.51 >100 >100 ND 92 21 4.38 12 >100 12.2 >8.20 13 >100 5.8 >17.24 27 56.60 20.9 2.71 28 >100 <100 ND 29 >100 <100 ND 30 >100 <100 ND 31 >100 <100 ND 32 >100 <100 ND 33 >100 <100 ND 34 >100 <100 ND 35 >100 <100 ND 36 >100 <100 ND 37 >100 <100 ND Gemcitabine >100 1.10 90.91 >100 0.44 227.27 92 21 4.38

Experimental Example 3: Anti-mosquito-mediated virus (dengue, Zika, chikungunia) efficacy test

In order to find out whether the compounds of the examples exhibit activity against various anti-mosquito-mediated viruses, experiments were conducted as follows.

1. Preparation of cells infected with flavivirus and alphavirus.

Vero (African green monkey kidney) cells were purchased from ATCC, USA, and cultured in DMEM containing 10% bovine serum. The temperature of the incubator was maintained at 37° C. and the carbon dioxide concentration was maintained at 5%.

Dengue virus New Guinea C (NGC) (hereinafter referred to as “DENV”) belonging to the flavivirus genus was purchased from the National Collection of Pathogenic Viruses (NCPV), UK, and Zika virus (MR766) was purchased from ATCC in the United States. Chikungunia virus, which belongs to the genus Alphavirus, was distributed mainly from the National Pathogen Resource Bank of the Korea Centers for Disease Control and Prevention. Flavivirus and alpha virus were infected with Vero cells and grown at 37°C. Virus titer was determined by infecting Vero cells with virus and viral plaque count. Each virus was dispensed in small portions and stored at 70°C.

2. Measurement of viral infection reduction using Immunofluorescence Assay

Vero cells grown in 96-well plates were inoculated with dengue virus or Zika virus for each well, and then a culture solution containing the compound of each example diluted to various concentrations was added for each will. On the third day after infection, the infected cells were analyzed by immunofluorescence staining using a 4G2 monoclonal antibody that cross-reacts to the flavivirus membrane protein, and the fluorescence value was measured using an image analysis device, Operetta (PerkinElmer).

3. Measurement of reduction of cytopathic effect

Vero cells grown in 96-well plates were inoculated with chikungunia virus for each well, and then a culture solution containing the compound of each example diluted at various concentrations was added for each will. On the third day after infection, cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheyltetrazolimbromide (MTT). The absorbance intensity was measured by a spectrophotometer (model name: SpectraMax M3 plate reader, manufacturer: Molecular Devices, Sunnyvale, CA) at 540 nm-690 nm. The 50% cytotoxic concentration (CC ₅₀ , the concentration of the compound that damages 50% of normal cells) and the 50% effective concentration (EC ₅₀ , the concentration that normalizes the cytotoxicity due to viral infection by 50%) were calculated. As a control group, chloroquine (Sigma) was used.

Antimosquito-mediated virus efficacy of nucleosides or nucleotide derivatives Example Flavivirus Alphavirus DENV ZIKV CHIKV CC ₅₀
(μM) EC ₅₀
(μM) SI CC ₅₀
(μM) EC ₅₀
(μM) SI CC ₅₀
(μM) EC ₅₀
(μM) SI One >100 3.42 >29.24 2 >100 0.72 >138.89 3 >100 1.87 >53.48 4 >100 0.71 >140.85 5 >100 0.94 >106.38 7 >100 15.65 >6.39 9 >100 1.34 >74.63 10 >100 2.53 >39.53 12 >100 6.16 >16.23 13 >100 1.98 >50.51 17 58.9 <1.2 >49.08 18 11.1 35.5 0.31 19 <1.2 <1.2 ND 20 75.9 1.6 47.44 21 >100 1.3 >76.92 22 <1.2 <1.2 ND 23 <1.2 <1.2 ND 24 55.35 <1.2 >46.12 25 29.5 <1.2 >24.58 26 >100 57.7 >1.73 27 64.44 13.68 4.71 >100 >100 ND >100 >100 ND 28 >100 25.33 >3.95 >100 >100 ND >100 >100 ND 29 >100 >100 ND >100 >100 ND >100 23.97 >4.17 30 >100 77.9 >1.28 >100 >100 ND >100 62.45 >1.60 31 >100 >100 ND >100 57.59 >1.74 33 >100 >100 ND >100 >100 ND >100 86.37 >1.16 36 >100 >100 ND >100 >100 ND >100 57.74 >1.73 37 >100 >100 ND >100 >100 ND >100 51.73 >1.93

Claims (9)

A compound represented by the following formula (1), a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In the above formula,
Y is a heterocyclyl containing a carbonyl group or -NHC(O)R ₃ , wherein the heterocyclyl containing a carbonyl group is optionally 1 to 3 C _1-6 alkyl, hydroxy, oxo, C _{1 -6} hydroxyalkyl, halo, cyano, nitro, C _1-6 haloalkyl, C _1-6 alkoxy, formyl, C _1-6 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _{1 -6} Alkylamino, di(C _1-6 alkyl) amino, carbamoyl, C _1-6 alkylcarbamoyl, di(C _1-6 alkyl) carbamoyl or C _1-3 alkoxy-C _1-3 alkyl substituted Can be;
R ₁ is hydrogen or

ego;
R ₂ ′ is hydrogen or halo;
R ₂ "is halo
R ₃ is heteroaryl, wherein the heteroaryl is unsubstituted or 1 to 4 hydrogens are halo, amino, cyano, nitro, azido, thiol, hydroxy, C _1-6 alkyl, C _1-6 halo alkyl, C _1-6 aminoalkyl, C _1-6 hydroxyalkyl, C _1-6 di-hydroxyalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, heterocyclyl, C _1-3 alkoxy -C _1-3 may be substituted with a substituent selected from the group consisting of alkyl and aryl, wherein the C _3-6 cycloalkyl or heterocyclyl is optionally 1 to 3 C _1-6 alkyl, hydroxy, oxo, C _1-6 hydroxyalkyl, halo, cyano, nitro, C _1-6 haloalkyl, C _1-6 alkoxy, formyl, C _1-6 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl, di(C _1-6 alkyl)carbamoyl or C _1-3 alkoxy-C _1-3 alkyl Can be substituted);
R ₄ , R ₅ and R ₆ are each independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally 1 to 3 C _{1- 6} alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, halo, cyano, pyrazinyl, hydroxy, oxo, nitro , Formyl, C _1-6 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl)amino, carbamoyl, C _1-6 alkylcarbamoyl , Di(C _1-6 alkyl)carbamoyl or C _1-6 alkylsulfonyl;
The halo is F, Cl, Br or I;
The heterocyclyl containing a carbonyl group is a 3 to 7 membered single or fused ring form containing at least one hetero element selected from the group consisting of nitrogen, oxygen, or a combination thereof, and heteroaryl is nitrogen, oxygen or It may be a 5- to 7-membered single or fused ring containing one or more hetero elements selected from the group consisting of a combination thereof. The method of claim 1,
Y is heterocyclyl containing a carbonyl group or -NHC(O)R ₃ ;
R ₁ is hydrogen or

ego;
R ₂ ′ is hydrogen or halo;
R ₂ "is halo
R ₃ is heteroaryl, wherein heteroaryl is unsubstituted or 1 to 4 hydrogens are halo, amino, cyano, nitro, azido, thiol, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl , C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 di-hydroxyalkyl, C _3-4 cycloalkyl, C _1-4 alkoxy, heterocyclyl, C _1-3 alkoxy -C _{1 -3} may be substituted with a substituent selected from the group consisting of alkyl and aryl, wherein the C _3-4 cycloalkyl, or heterocyclyl is optionally 1 to 3 C _1-4 alkyl, hydroxy, oxo, C _1-4 hydroxyalkyl, halo, cyano, nitro, C _1-4 haloalkyl, C _1-4 alkoxy, formyl, C _1-4 alkylformyl, carboxy, C _1-4 alkylcarboxy, amino, C _1-4 alkylamino, di(C _1-4 alkyl)amino, carbamoyl, C _1-4 alkylcarbamoyl, di(C _1-4 alkyl)carbamoyl or C _1-3 alkoxy-C _1-3 alkyl May be substituted, and the aryl is optionally 1 to 3 C _1-6 alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 hydroxyalkyl, C _1-6 Haloalkyl, halo, cyano, pyrazinyl, hydroxy, oxo, nitro, formyl, C _1-4 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-4 alkylamino, di(C _1-4 alkyl) amino, may be substituted with carbamoyl, C _1-4 alkylcarbamoyl, di(C _1-4 alkyl)carbamoyl or C _1-4 alkylsulfonyl);
R ₄ , R ₅ and R ₆ are each independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally 1 to 3 C _{1- 6} alkyl, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, halo, cyano, pyrazinyl, hydroxy, oxo, nitro , Formyl, C _1-4 alkylformyl, carboxy, C _1-6 alkylcarboxy, amino, C _1-4 alkylamino, di(C _1-4 alkyl)amino, carbamoyl, C _1-4 alkylcarbamoyl , May be substituted with di(C _1-4 alkyl)carbamoyl or C _1-4 alkylsulfonyl;
Halo is F, Cl, Br or I;
The heterocyclyl containing a carbonyl group is a 3 to 7 membered single or fused ring form containing at least one hetero element selected from the group consisting of nitrogen, oxygen, or a combination thereof, and heteroaryl is nitrogen, oxygen or It may be a 5- to 7-membered single or fused ring form containing one or more hetero elements selected from the group consisting of a combination thereof,
A compound, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R ₃ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl is unsubstituted or 1 to 4 hydrogens are Halo, amino, cyano, nitro, azido, thiol, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 di Hydroxyalkyl, C _3-4 cycloalkyl, C _1-4 alkoxy, heterocyclyl, C _1-3 alkoxy-C _1-3 may be substituted with a substituent selected from the group consisting of alkyl and aryl, wherein the C _3-4 cycloalkyl, or heterocyclyl may optionally be substituted with 1 to 3 C _1-4 alkyl, hydroxy, oxo, halo or C _1-4 haloalkyl, wherein the aryl is optionally 1 to 3 Can be substituted with C _1-4 alkyl, C _1-4 haloalkyl, halo, hydroxy or oxo);
The aryl is phenyl;
The heterocyclyl is tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyranyl, dioxanyl, ditianyl, dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, Oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, dioxotetrahydrothiophenyl, dioxothiolanyl, oxopiperidinyl, May be oxopyrrolidinyl, oxoimidazolidinyl or oxoxazolidinyl;
The heteroaryl is tetrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, iso Thiazolyl, thiadiazolyl, furazanyl, oxazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzoimidazolyl, Benzotriazolyl or azaindolyl phosphorus
A compound, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof. The method of claim 1,
Y is oxopyrrolidinyl, oxoimidazolidinyl or -NHC(O)R ₃ , and the oxopyrrolidinyl and oxoimidazolidinyl are unsubstituted or 1 to 3 hydrogens are fluoro, methyl and tri May be substituted with a substituent selected from the group consisting of fluoromethyl;
R ₂ ′ is hydrogen or fluoro;
R ₃ is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl is unsubstituted or 1 to 4 hydrogens are fluoro, chloro, methyl , Cyano, nitro, amino, methoxy, trifluoromethyl and may be substituted with a substituent selected from the group consisting of phenyl),
A compound, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof. The method of claim 1,
Y is oxopyrrolidinyl, oxoimidazolidinyl, nicotinoylamino, picolinoylamino, fluoronicotinoylamino, methylnicotinoylamino, pyridazinylcarbonylamino, fluoropicolinoylamino, Methylpicolinoylamino or trifluoromethylnicotinoylaminoin,
A compound, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound of Formula 1,
1) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)nicotinamide;
2) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)picolinamide;
3) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-fluoronicotinamide;
4) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methylnicotinamide;
5) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)pyridazine-3-carboxyamide;
6) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(2- Oxoimidazolidin-1-yl)pyrimidin-2(1H)-one;
7) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(2- Oxopyrrolidin-1-yl)pyrimidin-2(1H)-one;
8) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(3- Methyl-2-oxoimidazolidin-1-yl)pyrimidin-2(1H)-one;
9) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-fluoropicolinamide;
10) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-methylpicolinamide;
11) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide;
12) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-3-methylpicolinamide;
13) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methylpicolinamide;
14) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide;
15) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carboxamide;
16) Isopropyl ((S)-(((2R,3R,5R)-4,4-difluoro-3-hydroxy-5-(4-(nicotinamido)-2-oxopyrimidine- 1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoyl)-L-alaninate;
17) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-phenylpicolinamide;
18) 1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(3-methyl-2 -Oxopyrrolidin-1-yl)pyrimidin-2(1H)-one;
19) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-nitropicolinamide;
20) 5-Amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide. Hydrochloride;
21) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-methoxypicolinamide;
22) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-6-methoxynicotinamide;
23) 6-chloro-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)nicotinamide;
24) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-2-methylpyrimidin-4-carboxamide;
25) N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1 ,2-dihydropyrimidin-4-yl)-5-phenylpicolinamide;
26) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)nicotinamide;
27) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-phenylpicolinamide;
28) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-phenylpicolinamide;
29) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-2-methylpyrimidin-4-carboxamide;
30) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-nitropicolinamide;
31) 5-Amino-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;
32) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methylnicotinamide;
33) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)pyridazine-3-carboxamide;
34) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methylpyrazine-2-carboxamide;
35) 5-Fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;
36) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)pyrimidine-4-carboxamide;
37) 5-cyano-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)picolinamide;
38) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-methylpicolinamide;
39) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-5-methoxypicolinamide;
40) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-2-methyl-6-(trifluoromethyl)nicotinamide;
41) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-(trifluoromethyl)nicotinamide;
42) 6-fluoro-N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2 -Oxo-1,2-dihydropyrimidin-4-yl)nicotinamide;
43) N-(1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-dihydropyrimidin-4-yl)-6-methoxynicotinamide; And
44) Isopropyl((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(4-(2-methylpyrimidine-4-carboxamido)- 2-oxopyridin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoyl)-L-alaninate, a racemate thereof , Stereoisomers or pharmaceutically acceptable salts thereof. For the prevention or treatment of diseases related to RNA virus infection comprising the compound of Formula 1 according to any one of claims 1 to 6, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition. The method of claim 7,
The RNA virus infection-related diseases are HIV, influenza, picorna, flavi, alpha, phlebo, ebola, or corona virus infection related diseases. The pharmaceutical composition that is. The method of claim 7,
A pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent or excipient.