KR20200021494A - Novel nucleoside or nucleotide derivatives, and use thereof - Google Patents

Abstract

The present invention relates to: novel nucleoside or nucleotide derivatives, racemates thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof; and a pharmaceutical composition for preventing or treating viral infection-associated diseases, containing the same as an active ingredient.

Description

Novel nucleoside or nucleotide derivatives, and use thereof

The present invention provides novel nucleosides or nucleotide derivatives, racemates, stereoisomers or pharmaceutically acceptable salts thereof; Pharmaceutical composition for preventing or treating a virus infection-related disease comprising the same as an active ingredient; And uses thereof.

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

Antiviral activity of gemstatabine has been reported for RNA viruses (eg influenzaviruses, enteroviruses, SARS and MERS coronaviruses) and retroviruses (eg human immunodeficiency viruses) (Clouser et al., 2012) Kang et al., 2015, de Wilde et al., 2014). Cell-based antiviral tests have shown that gemstatabine has a wide range of efficacy against influenza viruses (types A and B), enteroviruses (coxakiviruses, polioviruses) and coronavirides (coronaviruses). .

However, extensive toxicity has been observed in cultured cells, and influenza virus is about 50% of Madin-Darby Canine Kidney (MDCK) cells used for infection for 3 days at 100 μM. Cell death was induced.

Thus, antiviral efficacy was investigated by synthesizing novel nucleosides or nucleotide derivatives that could improve cytotoxicity while maintaining antiviral activity.

It is an object of the present invention to provide novel nucleoside or nucleotide compounds which exhibit antiviral activity, racemates, stereoisomers thereof or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a preparation method thereof.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating a virus infection-related disease comprising the compound of the present invention, racemates, stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient. .

As a result of our efforts to achieve the above object, newly designed 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 compound

The present invention provides a compound represented by the following formula (1), racemates, stereoisomers thereof or pharmaceutically acceptable salts 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 hydrogen is 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 alkyl and may be substituted with a substituent selected from the group consisting of aryl;

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

Said halo is F, Cl, Br or I;

The heterocyclyl is in the form of a 3- to 10-membered single or fused ring containing one or more heteroelements selected from the group consisting of nitrogen, oxygen, sulfur or combinations thereof, and heteroaryl is nitrogen, oxygen, sulfur or May be in the form of a 5- to 10-membered single or fused ring comprising at least one heteroelement selected from the group consisting of

Each of the cycloalkyl and heterocyclyl optionally comprises 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 said aryl and heteroaryl is optionally selected from one to three 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 hydrogen is 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 alkyl and may be substituted with a substituent selected from the group consisting of 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 in the form of a 3- to 10-membered single or fused ring containing one or more heteroelements selected from the group consisting of nitrogen, oxygen, sulfur or combinations thereof, and heteroaryl is nitrogen, oxygen, sulfur or May be in the form of a 5- to 10-membered single or fused ring comprising at least one heteroelement selected from the group consisting of

Each of the cycloalkyl and heterocyclyl optionally comprises 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 said aryl and heteroaryl is optionally selected from one to three 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,

Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts 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 hydrogen is 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);

Said aryl is phenyl;

The heterocyclyl may be tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyranyl, dioxanyl, ditianyl, dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, Oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, dioxotetrahydrothiophenyl, dioxothiolanyl, oxopiperidinyl, Oxopyrrolidinyl, oxoimidazolidinyl or oxooxazolidinyl;

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, benzooxazolyl, benzofuranyl, benzoimidazolyl, Benzotriazolyl or azaindolyl;

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

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

Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

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

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

R ₂ is hydrogen or flufuro;

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

Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts 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 trifluoromethylnicotinoylamino,

Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

According to one embodiment of the 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-carboxamide;

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-alanineate;

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-nitropycholineamide;

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-methylpyrimidine-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-methylpyrimidine-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-nitropycholineamide;

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. However, the present invention is not limited thereto.

The compound of formula 1 of the present invention may exist in the form of a pharmaceutically acceptable salt. As salts are acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). It means all the organic or inorganic acid addition salts.

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

Bases can also be used to make pharmaceutically acceptable metal salts. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto. Corresponding silver salts can also be obtained by reacting an alkali 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 the nucleoside or nucleotide derivative compound can be used without limitation. .

Method for preparing nucleoside or nucleotide derivative compound

The compound of formula 1 of the present invention is reacted 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 may be synthesized from tetrahydrofuran-2-yl) pyrimidin-2 (1H) -one, and in one specific embodiment, may be prepared according to Scheme 1 below.

 However, the following Reaction Scheme 1 is merely 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 by using a method known in the art or appropriately changing.

As described above, 4-amino-1-((2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran which is a 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 One or more reactions known in the art can be carried out from hydrofuran-2-yl) pyrimidin-2 (1H) -one to introduce substituents (R ₃ ).

For example, the compound ( 2 ) is synthesized by performing a protection reaction to alcohol in Compound ( 1 ) according to Scheme 1 below, and the nucleoside derivative compound as the title compound of the present invention through an amide reaction using various carbonyl halides ( 3 ) can be obtained.

Scheme 1

Preferably, various groups conventionally used as protecting groups in the protection reaction may be used as the protecting group (P) without limitation, and in one specific embodiment according to the present invention, trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS) ) Group was used.

The reaction may also be carried out by reaction of the intermediate (2) with a carbonyl halide comprising 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, the compound ( 5 ) is synthesized by carrying out a phosphoramidite reaction in compound ( 4 ) according to Scheme 2 below, and the nucleotide, which is the title compound of the present invention, is subjected to a deprotection reaction after an amide reaction using various carbonyl halides. A 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 the reaction with the deprotection may be carried out. Preferably, the deprotection reaction may be carried out through the reaction for 0.5 to 1 hour using a TBAF (Tetrabutylammonium fluoride) solution at 0 to room temperature.

Compositions comprising nucleoside or nucleotide derivative compounds, uses thereof, and methods for preventing or treating the same

The present invention provides a pharmaceutical composition for preventing or treating a virus infection-related disease comprising a compound of Formula 1, a racemate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

Formula 1 is as defined above.

Compounds of formula (1), racemates, stereoisomers or pharmaceutically acceptable salts thereof of the present invention may exhibit antiviral activity.

Therefore, the pharmaceutical composition comprising the compound of formula 1 of the present invention, racemates, stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient exhibits universal antiviral activity, thereby preventing diseases related to virus infection. Or may 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 infections.

The viral disease may be transmitted to 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 tankyrase-related diseases by administration of the composition of the present invention, and the term "treatment" refers to By any administration of the composition means any action that improves or advantageously alters the symptoms of the disease .

The pharmaceutical composition according to the present invention is a compound represented by the formula (1), a racemate, a stereoisomer or a pharmaceutically acceptable salt thereof as 0.1-75% by weight based on the total weight of the composition, more preferably Preferably from 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 conventional methods for each purpose of use, It can be formulated in various forms such as oral formulations such as emulsions, syrups, aerosols, and injections of sterile injectable solutions, and can be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Can be. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil and the like. In addition, the composition of the present invention may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, 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 the disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level refers to Factors including health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration and rate of administration, duration of treatment, combination or concurrent use of drugs, and other well-known factors in the medical field It can be determined according to. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered in single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one 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 weight of the patient, and generally 1 to 100 mg, preferably 5 to 60 mg / kg daily or every other day, or 1 It may be administered in 1 to 6 times a day. However, since the dose may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method .

According to another embodiment of the invention, the invention comprises administering to a subject in need thereof a compound represented by Formula 1, a racemate, stereoisomer thereof or a pharmaceutically acceptable salt thereof Provided is a method for preventing or treating a virus-related disease in.

In the present invention, the term "individual" means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, including humans, who may have invented or developed the virus-related diseases. By any animal, including rabbits or guinea pigs, and by administering a pharmaceutical composition of the present invention to an individual, the disease can be effectively prevented or treated. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

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. May be administered. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto. In addition, the pharmaceutical compositions of the present invention may be administered by any device in which the active substance may migrate to target cells. Preferred modes of administration and preparations are intravenous, subcutaneous, intradermal, intramuscular, injectable and the like.

The pharmaceutical compositions of the present invention may be prepared according to the type of disease to be prevented or treated, and are known as active ingredients other than nucleosides or nucleotide derivative compounds, racemates, stereoisomers or pharmaceutically acceptable salts thereof. It may further comprise known drugs used for the prevention or treatment of the disease. For example, when used in the prevention or treatment of a viral disease, as an active ingredient, a known antiviral agent may be further included in addition to the nucleoside or nucleotide derivative compound, racemate, stereoisomer or pharmaceutically acceptable salt thereof. And other treatments known 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 therapies, immunotherapy, and the like.

Since the novel nucleosides or nucleotide derivatives of the present invention have excellent antiviral and anticancer activity, they can be usefully used for the prevention or treatment of diseases related to viral infections.

Hereinafter, the configuration and effects of the present invention through the embodiments will be described in more detail. These examples are only for illustrating the present invention, but 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 Preparation of -yl) pyrimidin-2 (1H) -one (IA)

4-amino-1-((2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine-2 (1H) -On hydrochloride (600 mg, 2.002 mmol) was dissolved in pyridine (10 ml) followed by the addition of TMSCl (0.76 ml, 6.006 mmol). Stir at 55-60 for 17 hours. The reaction solution was diluted with EtOAc and washed five times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to yield 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-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine-2 (1H) -One (1 g, 4.078 mmol) was dissolved in pyridine (10 ml) followed by the addition of TMSCl (1.54 ml, 12.234 mmol). Stir at 70 ° C. for 6 hours. The reaction solution was diluted with EtOAc and washed five times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to yield 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 for 55 hours at 55 to 60, nicotinoyl chloride hydrochloride (720 mg, 4.044 mmol) was added and stirred at the same temperature for 7 hours. The reaction solution was diluted with EtOAc and washed five times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to yield 1.67 g of the title compound as a white solid.

LC-MS (ESI, m / z) = 513.0 (M + H ⁺ )

Step 2 : The compound obtained from Step 1 (1.65 g, 3.219 mmol) was dissolved in DCM (6 ml), and then 4 M HCl in dioxane (8 ml) was slowly added at 0. After stirring for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with purified water and the pH was adjusted to 6-7 by adding 2N NaOH aqueous solution. Precipitate was filtered and dried to yield 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-carboxamide

Pyridazine-3-carbonyl chloride (210 mg, 1.472 mmol) and I-A (500 mg, 1.226 mmol) were reacted in a similar manner to 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) pyrimidin-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 to proceed to the next reaction without purification.

Step 2: After dissolving the compound obtained in step 1 in THF (2.5 ml), 60% NaH (37 mg, 1.47 mmol) was added at -20 and the temperature was gradually raised and stirred for 18 hours at room temperature. Ice was added to the reaction, 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 and DCM was added, and the precipitated solid 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 to 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) pyrimidin-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 for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in pyridine (4 ml) and then 2-chloro-N-methylethanamine hydrochloride (256 mg, 1.97 mmol) was added and stirred at 50 to 8 hours. The reaction solution was diluted with EtOAc and washed five times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to give 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 in 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 then the reaction solution was Concentrated under reduced pressure. The concentrated residue was separated by column chromatography to give 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

Dissolve 6-fluoropicolinic acid (300 mg, 2.126 mmol) in DCM (4.25 ml), then slowly add DMF (16.5 μl, 0.213 mmol) and oxalyl chloride (0.27 ml, 3.189 mmol) at zero. 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 give 339 mg of 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 give 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 similar manner to give 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 to 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). Reaction was carried out in a similar manner to Example 8 to obtain 80 mg of the compound 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. Reaction was carried out in a similar manner to give 14.4 mg of the 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 the compound as an apricot 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 to Example 9 to obtain 148 mg of a compound as an apricot 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 Dean-1 (2H) -yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoyl) -L-alanineate

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 ^° 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 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 give 442 mg of 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 (442 mg, 0.683 mmol) obtained from step 2 was dissolved in THF (0.5 ml) and cooled to 0 ^° C. 0.16 ml of TBAF 1M in THF was slowly added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give 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) The reaction was carried out in a similar manner as in Example 9, to obtain a yellow liquid without purification, and proceeded to the next step.

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) was added with hydrogen bromide solution (33 wt.% In acetic acid, 9.98 ml, 30.266 mmol), thionyl chloride (6 ml, 50.432 mmol). 4-bromo-2-methylbutanoyl chloride (0.12 ml, 0.919 mmol) and IA (250 mg, 0.513 mmol) obtained by the reaction 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 (300 mg, 0.581 mmol) obtained from step 1 was dissolved in DMF (0.6 ml), and then TEA (0.2 ml, 1.402 mmol) was added and reacted with a microwave reactor at 200 for 1 hour. The reaction solution was diluted with EtOAc and washed with purified water. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to yield 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-nitropycholineamide

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). Reaction was performed in a similar manner to Example 8, to obtain 100 mg of the compound 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 reacted with 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) Reaction was carried out in the same manner as in Example 8, to obtain 110 mg of the compound 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) and 4-amino-1-((2R, obtained by reacting 6-methoxynicotinic acid (200 mg, 1.305 mmol) with oxalyl chloride (0.22 ml, 2.611 mmol)) 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 106 mg of the 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) pyrimidin-2 (1H) -one hydrochloride (200 mg, 0.668 mmol) was reacted in a similar manner to Example 1 to give 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) and 4- obtained by reacting 2-methylpyrimidine-4-carboxylic acid (200 mg, 1.448 mmol) with oxalyl chloride (0.24 ml, 2.896 mmol). 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). Reaction was performed in a similar manner to Example 9, to obtain 190 mg of the compound as an apricot 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 to 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-hydroxy-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 at 55 to 60 for 6 hours, the mixture was cooled to 5, 6-phenylpicolinoyl chloride (177 mg, 0.407 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with EtOAc and washed five times with saturated CuSO ₄ aqueous solution. The organic layer was dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to give 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) Reaction was performed in a similar manner to Example 9 to obtain 125 mg of the compound 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) Amino-1-((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxydioxy-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 the 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-nitropycholineamide

Step 1 : 5-nitropicolinoyl chloride (143 mg, 0.4770 mmol) and IB (300 mg, 0.770 mmol) obtained by reacting 5-nitropicolinic acid (300 mg, 1.785 mmol) with oxalyl chloride (0.46 ml, 5.353 mmol) were reacted. Reaction was performed 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. 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) and 4-amino-1-((2R, obtained by reacting 6-methylnicotinic acid (400 mg, 2.916 mmol) with oxalyl chloride (0.5 ml, 5.833 mmol) 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2 (1H) -one (200 mg, 0.816 mmol) Reaction was carried out in a similar manner to Example 27, to obtain 159 mg of the compound 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) and 4-amino-1- obtained by reacting pyridazine-3-carboxylic acid (415 mg, 3.344 mmol) with oxalyl chloride (0.85 ml, 10.032 mmol) ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2 (1H) -one (700 mg, 2.753 mmol) was reacted in a similar manner to Example 27 to yield 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 yield 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 the 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) Reaction was carried out in a similar manner to Example 9, to obtain 115 mg of the compound 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) and IB (200 mg, 0.513) obtained by reacting pyrimidine-4-carboxylic acid (200 mg, 1.611 mmol) with oxalyl chloride (0.4 ml, 4.833 mmol) mmol) was reacted in a similar manner to Example 9 to yield 106 mg of the 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) Reaction was carried out in a similar manner to Example 9, to obtain 100 mg of the compound 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) Reaction in a similar manner to Example 9 gave 215 mg of the compound 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) Reaction was performed in a similar manner to Example 9, to obtain 139 mg of a compound 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-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine- 2 (1H) -one (200 mg, 0.816 mmol) was reacted in a similar manner to Example 27 above to give 98 mg of the 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 give 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-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 202 mg of the 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 : Reaction of 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) Reaction was carried out in a similar manner to Example 9, to obtain 175 mg of a compound 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) Reaction was carried out in a similar manner to Example 9, to obtain 125 mg of the compound 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-alanine

Step 1 : 4-amino-1-((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -3-fluoro-5- (hydroxymethyl) tetrahydrofuran-2 -Yl) pyrimidin-2 (1H) -one (395 mg, 1.10 mmol) was reacted in a similar manner to Step 1 of Example 16 to give 318 mg of the 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 similar manner to the method for 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 : The compound obtained from Step 2 (120 mg, 0.160 mmol) is taken up in THF (0.8 ml) and cooled to -5 ^° C. 0.17 ml of TBAF 1M in THF was slowly added and stirred at the same temperature for 20 minutes. Water was added to the reaction mixture, diluted with EtOAc, and washed three times with water. The organic layer was dehydrated with Na ₂ SO ₄ , concentrated in dark and purified by column chromatography to give 60 mg of the compound as a white solid.

LC-MS (ESI, m / z) = 635.0 (M + H ⁺ )

The above embodiment is summarized as shown in Table 1 below by the structure and name.

(Continued in Table 1)

(Continued in Table 1)

Experimental Example 1: Anti-influenza virus efficacy test

In order to determine whether the compounds of the examples show activity against various influenza viruses, the following experiments were carried out.

(1) Preparation of cells infected with influenza virus

Maddin-Darby canine kidney (MDCK) cells were purchased from ATCC, USA, and cultured in MEM (minimal essential medium) containing 10% fetal bovine serum (FBS). Was maintained at%.

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 virus PR8 and HK were inoculated into 10 day old eggs and propagated at 37. Influenza virus Lee was infected by multiplying MDCK cells, and 2 μg / ml of TPCK-trypsin (Sigma, (St. Louis, MO) was added to the culture without serum. After 3 days of infection, allantoic fluids or cell cultures of the eggs were centrifuged at 1,000 rpm for 5 minutes to purify the impurities to obtain the proliferated virus. , HA) or by infecting MDCK cells with virus to determine the number of virus plaques, each virus was aliquoted and stored at 70.

(2) measuring the reduction of cytopathic effects

Fully grown MDCK cells in 96-well plates were washed with phosphate-buffered saline (PBS) and inoculated with 50-100 plaque forming units (PFU) of influenza virus per well. The virus was left to infect the cells for about 1 hour, at which time PR8, HK, and Lee viruses were infected at 35. After removing the culture medium containing the virus and washing with phosphate buffered saline, MEM culture medium containing 2 mg / ml TPCK-trypsin diluted to various concentrations of each compound was added per well. Three days 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, cell cultures were removed and 100 μl of MTT solution (2.5 mg / ml) was added per 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), spectrophotometer (Model: SpectraMax M3 plate reader, Manufactured by Molecular Devices, Sunnyvale) at 540 nm-690 nm , CA) was measured for the intensity of absorption. 50% cytotoxic concentration (CC ₅₀ , concentration of compound damaging 50% of normal cells) and 50% effective concentration (EC ₅₀ , concentration normalizing cytotoxicity due to viral infection 50%) were calculated. As a comparison group, conventional standard antiviral agents amantadine (AMT; Sigma), oseltamivir carboxylate (OSV-C; US Biological, Swampscott, Mass.) And ribavirin (RBV; Sigma) were used. .

Anti-Influenza Virus Efficacy of Nucleoside 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: anti-coronavirus efficacy test

In order to determine whether the compounds of the examples show activity against various anticoronaviruses, the following experiments were carried out.

1. Preparation of cells infected with coronavirus.

Huh-7 (Human hepatoma-7) cells were purchased from Bank of Japan Cell Line (JCRB) and 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 ℃, carbon dioxide concentration of 5%.

MERS-virus (MERS-CoV / KOR / KNIH / 002_05_2015) was distributed from the Center for Disease Control and human coronavirus hCoV 229E, OC43 and feline infectious peritonitis (FIPV) were purchased from ATCC. MERSvirus was infected with Huh-7 cells and propagated at 37 ° C. In the same way, hCoV 229E and OC43 proliferated by infecting MRC-5 cells, and FIPV proliferated in CRFK cells. After 2-3 days of infection, the cell culture was centrifuged at 3,000 rpm for 20 minutes to remove the cell impurities, thereby obtaining the proliferated virus. Virus titers were used to measure virus plaques by infecting the cells used to propagate each virus. Each virus was aliquoted and stored at 70 ° C.

2. Determination of the cytopathic effect

Huh-7 (MERS), MRC-5 (hCoV 229E, O43), and CRFK (FIPV) cells grown in 96-well plates were inoculated into each well for each well, and then each Example compound was diluted to various concentrations. Including culture was added every will. Three days after infection, cell viability was measured using 3- (4,5-dimethylthiazol-2-yl) -2,5-dipheyltetrazolimbromide (MTT). Absorption intensity was measured with a spectrophotometer (Model: SpectraMax M3 plate reader, manufacturer: Molecular Devices, Sunnyvale, CA) at 540 nm-690 nm. 50% cytotoxic concentration (CC ₅₀ , concentration of compound damaging 50% of normal cells) and 50% effective concentration (EC ₅₀ , concentration normalizing cytotoxicity due to viral infection 50%) were calculated. As a comparison, gemcitabine (Sigma) was used.

Anti-Coronavirus Efficacy of Nucleoside 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 example show activity against various anti-mosquito-borne viruses, the following experiments were carried out.

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 ℃, carbon dioxide concentration of 5%.

Dengue virus New Guinea C (NGC) (hereinafter referred to as "DENV") belonging to the genus Flavivirus was purchased from the National Collection of Pathogenic Viruses (NCPV), UK, and Zika virus (MR766) was purchased from ATCC, USA. Chikungunia virus, belonging to the genus Alphavirus, is a domestic patient isolate and was distributed by the National Hospital for Disease Control. Flaviviruses and alphaviruses were infected with Vero cells and propagated at 37 ° C. Virus titers were infected with the virus in Vero cells to determine the number of virus plaques. Each virus was aliquoted and stored at 70 ° C.

2. Determination of Virus Infection Reduction Using Immunofluorescence Assay

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

3. Measurement of reduction of cytopathic effect

Vero cells grown in 96-well plates were inoculated per well with chikungunia virus per well, and then each culture was diluted to various concentrations. Three days after infection, cell viability was measured using 3- (4,5-dimethylthiazol-2-yl) -2,5-dipheyltetrazolimbromide (MTT). Absorption intensity was measured with a spectrophotometer (Model: SpectraMax M3 plate reader, manufacturer: Molecular Devices, Sunnyvale, CA) at 540 nm-690 nm. 50% cytotoxic concentration (CC ₅₀ , concentration of compound damaging 50% of normal cells) and 50% effective concentration (EC ₅₀ , concentration normalizing cytotoxicity due to viral infection 50%) were calculated. Chloroquine (Sigma) was used as a comparative group.

Efficacy of Anti-Memophilic Virus in Nucleoside 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 Formula 1, racemates, stereoisomers thereof or pharmaceutically acceptable salts thereof:
[Formula 1]

In the above formula,
Y is heterocyclyl or -NHC (O) R ₃ ;
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 hydrogen is 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 alkyl and may be substituted with a substituent selected from the group consisting of aryl;
R ₄ , R ₅ and R ₆ are each independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, aryl or heteroaryl;
Said halo is F, Cl, Br or I;
The heterocyclyl is in the form of a 3- to 10-membered single or fused ring containing one or more heteroelements selected from the group consisting of nitrogen, oxygen, sulfur or combinations thereof, and heteroaryl is nitrogen, oxygen, sulfur or May be in the form of a 5- to 10-membered single or fused ring comprising one or more heteroelements selected from the group consisting of;
Each of the cycloalkyl and heterocyclyl optionally comprises 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 said aryl and heteroaryl is optionally selected from one to three 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. The method of claim 1,
Y is heterocyclyl or -NHC (O) R ₃ ;
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 hydrogen is 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 alkyl and may be substituted with a substituent selected from the group consisting of 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 in the form of a 3- to 10-membered single or fused ring containing one or more heteroelements selected from the group consisting of nitrogen, oxygen, sulfur or combinations thereof, and heteroaryl is nitrogen, oxygen, sulfur or May be in the form of a 5- to 10-membered single or fused ring comprising one or more heteroelements selected from the group consisting of;
Each of the cycloalkyl and heterocyclyl optionally comprises 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 said aryl and heteroaryl is optionally selected from one to three 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,
Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts 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 hydrogen is 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);
Said aryl is phenyl;
The heterocyclyl may be tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyranyl, dioxanyl, ditianyl, dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, Oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, dioxotetrahydrothiophenyl, dioxothiolanyl, oxopiperidinyl, Oxopyrrolidinyl, oxoimidazolidinyl or oxooxazolidinyl;
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, benzooxazolyl, benzofuranyl, benzoimidazolyl, Benzotriazolyl or azaindolyl;
Each of the cycloalkyl and heterocyclyl may be optionally substituted with 1 to 3 C _1-4 alkyl, hydroxy, oxo, halo or C _1-4 haloalkyl;
Wherein each of aryl and heteroaryl may be optionally substituted with 1 to 3 C _1-4 alkyl, C _1-4 haloalkyl, halo, hydroxy or oxo,
Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
Y is oxopyrrolidinyl, oxoimidazolidinyl or -NHC (O) R ₃ , wherein the oxopyrrolidinyl and oxoimidazolidinyl are unsubstituted or one to three hydrogens are fluoro, methyl and tri May be substituted with a substituent selected from the group consisting of fluoromethyl;
R ₂ is hydrogen or flufuro;
R ₃ is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl (wherein the pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl is unsubstituted or 1 to 4 hydrogen is fluoro, chloro, methyl , May be substituted with a substituent selected from the group consisting of cyano, nitro, amino, methoxy, trifluoromethyl and phenyl)
Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
Y is oxopyrrolidinyl, oxoimidazolidinyl, nicotinoylamino, picolinoylamino, fluoronicotinoylamino, methylnicotinoylamino, pyridazinylcarbonylamino, fluoropicolinoylamino, Methylpicolinoylamino or trifluoromethylnicotinoylamino,
Compounds, racemates, stereoisomers thereof, or pharmaceutically acceptable salts 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-carboxamide;
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) phosphosyl) -L-alanineate;
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-nitropycholineamide;
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-methylpyrimidine-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-methylpyrimidine-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-nitropycholineamide;
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) phosphosyl) -L-alanineate, a racemate thereof , Stereoisomers or pharmaceutically acceptable salts thereof. A pharmaceutical for the prophylaxis or treatment of a disease associated with a viral infection, comprising as an active ingredient a compound of formula 1, a racemate, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 Composition. The method of claim 7, wherein
The virus-related diseases include HIV, HBV, HCV, influenza, picorna, flavi, alpha, phlebo, ebola or corona virus diseases. Pharmaceutical composition. The method of claim 7, wherein
A pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent or excipient.