RU2553996C1 - Substituted (2r,3r,5r)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidates - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidate of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, having properties of nucleoside inihibitors of RNA polymerase NS5B of the hepatitis C virus. The invention also relates to a method of producing compounds, pharmaceutical compositions and a medicinal agent based on said compounds. In general formula 1

, R¹ is hydrogen, (CH₃)₂[(CH₃)₃C]Si, C₂-C₆acyl, optionally substituted with a benzyloxy group, NR⁵R⁶ group, wherein R⁵ and R⁶ are independently hydrogen or C₁-C₄alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R² and R³ are F or R² is F or OH and R³ is CH₃; R⁴ is hydrogen or methyl; Ar is phenyl, pyridyl or naphthyl, where the phenyl, pyridyl or naphthyl is optionally substituted with at least one of C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C_1-3alkyl)₂; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), wherein the amino group is optionally substituted with 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C(O)R⁸ radical, where R⁸ is C₁-C₄alkyl, optionally substituted with a NR⁶R⁷ group, where R⁶ and R⁷ are independently hydrogen or C₁-C₄alkyl; C_1-3alkoxy, optionally substituted with a phenyl; X is O or N-R⁹, where R⁹ is C₁-C₄alkyl, optionally substituted with OH or OCH₃; n=1, 2 or 3.

EFFECT: compounds can be used to prevent and treat viral infections, including hepatitis C.

12 cl, 1 tbl, 11 ex

Description

The present invention relates to new substituted phosphoramidic acid esters and their use as a treatment for viral diseases. These compounds are inhibitors of RNA-dependent viral RNA replication and are useful as inhibitors of the hepatitis C virus NS5B polymerase and for the treatment of hepatitis C. The hepatitis C virus, along with other important human pathogens, such as yellow fever virus, West Nile virus, Dengi virus (Dengue) and hepatitis B virus GBV-C, refers to Flaviviruses (genus Flaviviridae).

NS5B is known to be a hepatitis B protein [Vincent Soriano et al., Hepatitis C therapy with HCV NS5B polymerase inhibitors, Expert Opinion on Pharmacotherapy, June 2013, Vol.14, No.9, Pages 1161-1170]. The development of antiviral drugs for hepatitis C virus (HCV) is progressing at a faster pace. Among HCV polymerase inhibitors, sofosbuvir is positioned as a unique companion for ribavirin as a therapy for most HCV genotypes 2 or 3.

Modern treatment of chronic hepatitis C, based on a combination of pegylated interferon and ribavirin, is effective in only 50% of patients. Special targeted antiviral therapy is a promising approach to eradicating infection. Review [Legrand-Abravanel F, Nicot F, Izopet J. New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs. 2010 Aug; 19 (8): 963-75] focuses on progress regarding the development of hepatitis C virus polymerase inhibitors, which have undergone clinical trials in recent years. Nucleosis (t) idiologic analogues target the active site of HCV polymerase and act as chain terminating agents. They are highly active against all genotypes. Non-nucleoside inhibitors achieve polymerase inhibition by binding to one of at least four allosteric enzyme sites. Most of them have genotype-specific activity and they can quickly select resistant strains if HCV replication is not completely suppressed. However, they provide additional options for treating infected patients. NS5B polymerase inhibitors will be an integral part of more effective anti-HCV therapy in combination with interferon or other direct-acting antiviral agents.

In the last decade, intense efforts have been focused on the discovery of both: nucleosis (t) id and non-nucleoside inhibitors of HCV NS5B polymerase. These efforts have led to some promising agents undergoing a clinical trial phase. Review [Watkins WJ, Ray AS, Chong LS. HCV NS5B polymerase inhibitors. Curr Opin Drug Discov Devel. 2010 Jul; 13 (4): 441-65] traces the history of the optimization of chemical series that led to the development of clinical candidates, and summarizes recent studies in this area with an emphasis on clinical efficacy and impact on future combined studies.

Examples of drug candidates include nucleoside inhibitors of HCV NS5B polymerase: PSI-7977 from Pharmacet (USA) and NM283 (Valopicitabine) from Aidenix (USA) and others [M.J. Sofia, D. Bao, W. Chang, J. Du, D. Nagarathnam, S. Rachakonda, P.G. Reddy, B.S. Ross, P. Wang, H.-R. Zhang, S. Bansal, C. Espiritu, M. Keilman, A.M. Lam, H.M.M. Steuer, Congrong Niu, M.J. Otto, P.A. Furman. Discovery of a β-D-20-Deoxy-20-r-fluoro-20-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus. J. Med. Chem. 2010, 53, 7202-7218; Pat. US 7964580 B2; Pat US 8334270 B2.].

To date, hepatitis C is a serious public health problem. It leads to chronic liver disease, which leads to cirrhosis and hepatocellular carcinoma.

In this regard, the search for new highly effective antiflaviviral drugs is currently still one of the main directions of creating new pharmacological agents for the treatment of a wide and diverse range of viral infections, including HCV. Therefore, up to now, the synthesis of new compounds and their use as antiviral active components for pharmaceutical compositions and drugs, including HCV, is relevant.

The following are definitions of terms that are used in the description of this invention:

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents”) including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaryo , aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroaryl heterocyclyl, annelated arylcyl cycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1 ^{a N-, R k a R k}} + ₁ ^{a NC (= O) -,} R k a R k + ₁ ^a NC (= S) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meaning of which is defined in this section, for example , the hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the N atom to which they are bonded form through R _k ^a and R _{k + 1} ^a 4-7 goethe member rocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylcarbonyl. The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N- , R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.

“Alkyloxy (alkoxy)” means a C _n H _{2n + 1} O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different. Representative aryl groups are phenyl, substituted phenyl, naphthyl, and substituted naphthyl. Aryl can be anelated with a non-aromatic ring system or heterocycle.

“Aryloxy” means an aryl-O— group in which the meaning of aryl is defined in this section.

Representative aryloxy groups are phenoxy and 2-naphthyloxy.

"Hydrate" means stoichiometric or non-stoichiometric compositions of compounds or their salts with water.

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of an amino group”, “substituent carbamoyl”, “substituent of the cyclic system”.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

A “therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.

"Pharmaceutical composition" means a composition comprising a compound of formula 1 or 2 and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials nye agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and purpose of the method and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, or as a mixture with traditional pharmaceutical carriers . Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., Pharmaceutical Salts J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, hydroxide, potassium carbonate and bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the basic amino acids can be used - lysine, ornithine and arginine.

The subject of the present invention are compounds which are novel substituted amidophosphoric esters - (2R, 3R, 5R) -3-hydroxy- (5-pyrimidin-1-1-yl) tetrahydrofuran-2-ylmethyl aryl phosphoramidate of the general formula 1, or stereoisomers, or pharmaceutically acceptable salts,

Where:

R ¹ is hydrogen, (CH ₃ ) ₂ [(CH ₃ ) ₃ C] Si, C ₂ -C ₆ acyl optionally substituted with a benzyloxy group, NR ⁵ R ⁶ group, in which R ⁵ and R ⁶ are independently hydrogen or C ₁ -C ₄ alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl;

R ₂ and R ³ are F or R ² is F or OH and R ³ is CH ₃ ;

R ⁴ represents hydrogen or methyl;

Ar is phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, F, Cl, Br, I, nitro, cyano, —N (C _1-3 alkyl) ₂ ;

Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4- (4-amino-2-oxo-2H-pyrimidin-1-yl) in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C (O) R ⁸ radical, where R ⁸ is C ₁ -C ₄ alkyl optionally substituted with an NR ⁶ R ⁷ group, where R ⁶ and R ⁷ are independently hydrogen or C ₁ -C ₄ alkyl; C _1-3 alkoxy optionally substituted with phenyl;

X represents O or NR ⁹ , where R ⁹ represents C ₁ -C ₄ alkyl optionally substituted by OH or OCH ₃ ;

n = 1,2 or 3.

Preferred new substituted amidophosphoric esters are compounds of general formula 1.1 or general formula 2.1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

where R ¹ , R ² , R ³ and X have the above meaning.

Preferred new substituted amidophosphoric acid esters are compounds of general formula 1.2 or general formula 2.2, or a stereoisomer thereof, or a pharmaceutically acceptable salt,

where R ¹ , R ² , R ³ and X have the above meaning.

More preferred new substituted amidophosphoric acid esters are compounds of general formula 1 selected from the group consisting of: ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4 -difluoro-3-hydroxytetrahydrofuran-2-yl) methyl p-tolyl (S) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (1),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-chlorophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (2),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 2,4-dichlorophenyl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (3),

(2R, 3R, 5R) -5- (4-acetamido-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((S) - (S) -2-oxotetrahydrofuran-3 -amylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (4),

benzyl 1- (2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((S) - ((S) - (2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (5),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (6),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopiperidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (7),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopiperidin-3-ylphosphoramidate 1 (8),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2-oxooxepan-3- silt phosphoramidate 1 (9),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -5 - (((5,5-dimethyl-2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) -3,3-difluorotetrahydrofuran -2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (10),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (11),

(R) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((S) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (12),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopyrrolidin-3-ylphosphoramidate 1 (13),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5,5-dimethyl- 2-oxo-tetrahydrofuran-3-ylphosphoramidate 1 (14),

(R) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (15),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2- oxotetrahydrofuran-3-ylphosphoramidate 1 (16),

((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (17)

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (18),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (19),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopiperidin-3-ylphosphoramidate 1 (20),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (R ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (21)

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2- oxotetrahydrofuran-3-ylphosphoramidate 1 (22),

(2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((((S) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- (tert-butyldimethylsilyloxy) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (24),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (25),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (26),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (27),

(S) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((R) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (28),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (29), and

(S) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate

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An object of the present invention is a method for producing a compound of formula 1 or its stereoisomer by reacting a compound of formula 6 with a compound of formula 4 and then mixing it with an amine of formula 8,

where Ar, n, R ¹ , R ² , R ³ , R ⁴ , R ⁹ , and Pm have the above meaning.

An object of the present invention is a method for producing a compound of formula 1 or a stereoisomer thereof, wherein R ¹ is acyl, by acylating a compound of formula 1, where R ¹ is hydrogen.

An object of the present invention is a method for producing a compound of general formula 1 or a stereoisomer thereof, wherein R ¹ is dimethyl-tert-butyldimethylsilyl by mixing dimethyl-tert-butyldimethylsilyl chloride with a compound of formula 1, where R ¹ is hydrogen.

An object of the present invention is a method for producing a compound of general formula 1 or a stereoisomer thereof, reacting an amine of formula 3 with a compound of general formula 4 and then mixing it with a compound of formula 6,

where Ar, n, R ¹ , R ² , R ³ , R ⁴ , and Pm have the above meaning.

The separation of racemic mixtures of the compounds of general formula 1 into stereoisomers is carried out either by crystallization and / or LC, or by crystallization and / or HPLC.

The starting compounds used in the above process for the preparation of a new substituted amidophosphoric ester represented by the general formula 1, its stereoisomer, pharmaceutically acceptable salt, are commercially available compounds or they can be easily prepared by methods known from the literature. The quality of the compounds is monitored by LCMS and NMR spectra.

To determine the antiviral activity of substituted amidophosphoric esters of the general formula 1 (test compounds), HCV replicon analysis is used. As a test cell line used in the HCV replicon assay, a Huh7 human hepatoma cell line containing the HCV replicon (genotype 1b, strain Con1) is taken. Cells are seeded in 96-well plates with a density of 7.5 × 10 ³ cells per well in 50 μl of culture medium. Stock solutions of the test compounds are prepared immediately before use in a DMEM nutrient medium (DMEM IX, Cellgro; Cat. # 10-013-CV) in the form of two-fold 2X drains. In total, 11 series of 3-fold dilutions of test compounds from two-fold 2X stocks in a nutrient medium with a final concentration range of 20 nM - 0.2 pM are prepared. At least 4 hours after the cells were seeded, treatment with the compounds is initiated by adding 50 μl of a specific dilution of the compound to each plate. The final concentration of the tested compounds is from 10 nM to 0.1 pM after dilution 1: 1 with the existing nutrient medium. The final concentration of DMSO is 0.5%. Cells and inhibitors are incubated for three days at 37 ° C / 5% CO ₂ . The medium is removed from the dies by tapping gently. Cells are fixed by adding 100 μl acetone / methanol (1: 1) for 1 minute, then washed three times with PBS buffer solution, and then blocked by adding 150 μl / well of 10% fetal calf serum (FBS) in PBS solution for 1 hour at room temperature. Cells are washed three times with PBS buffer solution and incubated with antibodies to hepatitis C core antigen mAb 100 μl / well (Affinity BioReagents; Cat. # MA1-080, 1 mg / ml stock was diluted 1: 4000 in 10% FBS-PBS) for 2 hours at 37 ° C. Cells were washed 3 times with PBS and incubated with goat antibodies to mouse immunoglobulins (HRP-Goat Anti-Mouse antibody) in an amount of 100 μl / well (1: 3,500 dilution in 10% FBS-PBS) for 1 hour at 37 ° C. Cells are washed 3 times with PBS and incubated with OPD solution - 100 μl / well (1 OPD tablet + 12 ml citrate / phosphate buffer + 5 μl 30% H ₂ O ₂ per plate) for 30 minutes in the dark at room temperature. The reaction is stopped by the addition of 2 n. H ₂ SO ₄ in an amount of 100 μl / well, and absorbance at A ₄₉₀ X was measured on a Victor ³ V 1420 multichannel spectrophotometer (Perkin Elmer). EC ₅₀ values for each test compound are calculated based on the best fit equations using the XLFit program.

The cytotoxicity of the tested compounds was investigated in experiments on a culture of the human hepatoma Huh7 cell line. The number of living cells is determined using an ATPLite kit (Perkin-Elmer, Boston, USA), in accordance with the manufacturer's instructions. Cells are seeded in 96-well black microplates with a clear bottom with a density of 7.5 × 10 ³ cells per well in 50 μl of medium. After 18 hours, treatment with the compounds was initiated by adding 50 μl of a specific dilution of the compound to each plate. Each dilution of the compound is tested in three parallel experiments. Cells and inhibitors are incubated for 96 hours at 37 ° C / 5% CO ₂ . The plates are washed twice with PBS phosphate-buffered saline (0.2 ml / well), and then cells are lysed by adding 0.05 ml / well of cell buffer (all of these reagents are included in the ATPLite kit). After incubation for 5 minutes on a rotating platform, 0.05 ml / well of substrate buffer is added. After incubation for another 5 minutes, the plate is kept in the dark for 10 minutes and luminescence is measured on a TopCount NXT instrument (Packard, Perkin Elmer). The EC ₅₀ value for all tested compounds is determined using the XLfit 4.1 program.

The results of these studies show that the new substituted amidophosphoric esters of general formula 1 are potent in vitro HCV inhibitors with low cytotoxicity.

The inhibitory activity (EC ₅₀ ) under the conditions of HCV replicon analysis of some new substituted amidophosphoric acid esters of general formula 1 is presented in table 1. As can be seen from table 1, the new NS5B inhibitors of general formula 1 have micromolar cytotoxicity (CC ₅₀ ) and nanomolar activity (EC ₅₀ ) , which, as a rule, is significantly higher than the activity of the known inhibitor PSI-7851 [EC ₅₀ = 75 nM. E. Murakami, T. Tolstykh, H. Vao, S. Niu, HM Micolochick Steuer, D. Bao, W. Chang, C. Espiritu, S. Bansal, AM Lam, MJ Otto, MJ Sofia, PA Furman. Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977. J. Biol. Chem., 285 (45), 34337-34347 (2010)].

Table 1 Activity of NS5B inhibitors of general formula 1 to HCV genotype 1b (10% FBS) No. inhibitor Formula EC ₅₀ , nM 1 (4)

42.1 1 (7)

552.3

1 (8)

873.3 1 (8) * HCl

905.7 1 (10)

28.3 1 (12)

162.2

1 (16)

458.9 1 (17)

273.6 1 (19)

40.54 1 (22)

19.8

1 (23)

27.0 1 (24)

285.4 1 (30)

219.3 PSI-7851

59.4 * * - experimental data of the inventors.

The subject of the present invention is the use of a substituted amidophosphoric acid ester of the general formula 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, as an active component that has the properties of nucleoside inhibitors of hepatitis C virus NS5B RNA polymerase,

Where:

R ¹ represents hydrogen, (CH ₃ ) ₂ [(CH ₃ ) ₃ C] Si, C ₂ -C ₆ acyl optionally substituted with a benzyloxy group, an NR ⁵ R ⁶ group in which R ⁵ and R ⁶ are independently hydrogen or C ₁ -C ₄ alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl;

R ² and R ³ are F or R ² is F or OH and R ³ is CH ₃ ;

R ⁴ represents hydrogen or methyl;

Ar is phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3a alkoxy, F, Cl, Br, I, nitro, cyano, —N (C _1-3 alkyl) ₂ ;

Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4- (4-amino-2-oxo-2H-pyrimidin-1-yl) in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a radical C (O) R ⁸ where R ⁸ is C ₁ -C ₄ alkyl optionally substituted with an NR ⁶ R ⁷ group, where R ⁶ and R ⁷ are independently hydrogen or C ₁ -C ₄ alkyl; C _1-3 alkoxy optionally substituted with phenyl;

X represents O or NR ⁹ , where R ⁹ represents C ₁ -C ₄ alkyl optionally substituted by OH or OCH ₃ ;

n = 1, 2 or 3.

According to this invention, it is more preferable to use a compound represented by general formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl p-tolyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (1),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-chlorophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (2),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 2,4-dichlorophenyl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (3),

(2R, 3R, 5R) -5- (4-acetamido-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((S) - (S) -2-oxotetrahydrofuran-3 -amylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (4),

benzyl 1- (2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((S) - ((S) - (2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (5),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (6),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopiperidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (7),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopiperidin-3-ylphosphoramidate 1 (8),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2-oxooxepan-3- silt phosphoramidate 1 (9),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -5 - (((5,5-dimethyl-2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) -3,3-difluorotetrahydrofuran -2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (10),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (11),

(R) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((S) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (12),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopyrrolidin-3-ylphosphoramidate 1 (13),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5,5-dimethyl- 2-oxo-tetrahydrofuran-3-ylphosphoramidate 1 (14),

(R) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (15),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2- oxotetrahydrofuran-3-ylphosphoramidate 1 (16),

((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (17)

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (18),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (19),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopiperidin-3-ylphosphoramidate 1 (20),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (R ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (21)

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2- oxotetrahydrofuran-3-ylphosphoramidate 1 (22),

(2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((((S) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- (tert-butyldimethylsilyloxy) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (24),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (25),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (26),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (27),

(S) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((R) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (28),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (29), and

(S) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (30).

An object of the present invention is a pharmaceutical composition for the prophylaxis and / or treatment of viral infections, including hepatitis C, containing an active ingredient in a therapeutically effective amount represented by general formula 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from an excipient , carrier, solvent,

Where:

R ¹ represents hydrogen, (CH ₃ ) ₂ [(CH ₃ ) ₃ C] Si C ₂ -C ₆ acyl optionally substituted with a benzyloxy group, an NR ⁵ R ⁶ group in which R ⁵ and R ⁶ are independently hydrogen or C ₁ -C ₄ alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl;

R ² and R ³ are F or R ² is F or OH and R ³ is CH ₃ ;

R ⁴ represents hydrogen or methyl;

Ar is phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, F, Cl, Br, I, nitro, cyano, —N (C _1-3 alkyl) ₂ ;

Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4- (4-amino-2-oxo-2H-pyrimidin-1-yl) in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C (O) R ⁸ radical, where R ⁸ is C ₁ -C ₄ alkyl optionally substituted with an NR ⁶ R ⁷ group, where R ⁶ and R ⁷ are independently hydrogen or C ₁ -C ₄ alkyl; C _1-3 alkoxy optionally substituted with phenyl;

X represents O or NR ⁹ , where R ⁹ represents C ₁ -C ₄ alkyl optionally substituted by OH or OCH ₃ ;

n = 1, 2 or 3.

According to the present invention, a pharmaceutical composition containing the active ingredient in a therapeutically effective amount represented by the general formula 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a filler, carrier, solvent, wherein the substituted amidophosphoric ester is preferred, is General formula 1 is selected from:

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl p-tolyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (1),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-chlorophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (2),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 2,4-dichlorophenyl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (3),

(2R, 3R, 5R) -5- (4-acetamido-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((S) - (S) -2-oxotetrahydrofuran-3 -amylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (4),

benzyl 1- (2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((S) - ((S) - (2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (5),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (6),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopiperidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (7),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopiperidin-3-ylphosphoramidate 1 (8),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2-oxooxepan-3- silt phosphoramidate 1 (9),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -5 - (((5,5-dimethyl-2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) -3,3-difluorotetrahydrofuran -2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (10),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (11),

(R) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((S) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (12),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopyrrolidin-3-ylphosphoramidate 1 (13),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5,5-dimethyl- 2-oxo-tetrahydrofurai-3-ylphosphoramidate 1 (14),

(R) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (15),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2- oxotetrahydrofuran-3-ylphosphoramidate 1 (16),

((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (17)

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (18),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (19),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopiperidin-3-ylphosphoramidate 1 (20),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (R ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (21)

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2- oxotetrahydrofuran-3-ylphosphoramidate 1 (22),

(2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((((S) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- (tert-butyldimethylsilyloxy) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (24),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (25),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (26),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (27),

(S) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((R) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (28),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1 - methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (29), and

(S) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1 - methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (30).

A more preferred pharmaceutical composition may also further comprise at least one drug substance selected from the group consisting of: inosine 5-dehydrogenase inhibitor inosine, hepatitis C protease inhibitor NS3, hepatitis C protease inhibitor NS3 / 4A and NS5A RNA polymerase inhibitor.

The subject of the present invention is a medicament for the prophylaxis and treatment of viral infections, including hepatitis C, in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in a pharmaceutically acceptable package containing a therapeutically effective amount of an active component which is a compound formula 1, or a new pharmaceutical composition.

The subject of the present invention is a method for the prophylaxis and treatment of diseases caused by hepatitis C virus, which comprises administering in a therapeutically effective amount of an active ingredient, which is a compound of general formula 1, or a new pharmaceutical composition to a subject in need thereof,

Where:

R ¹ is hydrogen, (CH ₃ ) ₂ [(CH ₃ ) ₃ C] Si, C ₂ -C ₆ acyl optionally substituted with a benzyloxy group, NR ⁵ R ⁶ group, in which R ⁵ and R ⁶ are independently hydrogen or C ₁ -C ₄ alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl;

R ² and R ³ are F or R ² is F or OH and R ³ is CH ₃ ;

R ⁴ represents hydrogen or methyl;

Ar is phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, F, Cl, Br, I, nitro, cyano, —N (C _1-3 alkyl) ₂ ;

Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4- (4-amino-2-oxo-2H-pyrimidin-1-yl) in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C (O) R ⁸ radical, where R ⁸ is C ₁ -C ₄ alkyl optionally substituted with an NR ⁶ R ⁷ group, where R ⁶ and R ⁷ are independently hydrogen or C ₁ -C ₄ alkyl; C _1-3 alkoxy optionally substituted with phenyl;

X represents O or NR ⁹ , where R ⁹ represents C ₁ -C ₄ alkyl optionally substituted by OH or OCH ₃ ;

n = 1, 2 or 3.

According to this invention, a more preferred method for the prevention and treatment of diseases is the introduction of a therapeutically effective amount of an active component, which is a compound of general formula 1, or a new pharmaceutical composition to a subject in need thereof, where the compounds of general formula 1 are selected from:

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl p-tolyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (1),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-chlorophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (2),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 2,4-dichlorophenyl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (3),

(2R, 3R, 5R) -5- (4-acetamido-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((S) - (S) -2-oxotetrahydrofuran-3 -amylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (4),

benzyl 1- (2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((S) - ((S) - (2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (5),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (6),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopiperidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (7),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopiperidin-3-ylphosphoramidate 1 (8),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2-oxooxepan-3- silt phosphoramidate 1 (9),

benzyl 1 - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -5 - (((5,5-dimethyl-2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) -3,3-difluorotetrahydrofuran -2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (10),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (11),

(R) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((S) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (12),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl-2- oxopyrrolidin-3-ylphosphoramidate 1 (13),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5,5-dimethyl- 2-oxo-tetrahydrofuran-3-ylphosphoramidate 1 (14),

(R) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (15),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2- oxotetrahydrofuran-3-ylphosphoramidate 1 (16),

((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (17)

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (18),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (19),

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopiperidin-3-ylphosphoramidate 1 (20),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (R ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (21)

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2- oxotetrahydrofuran-3-ylphosphoramidate 1 (22),

(2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((((S) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23),

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- (tert-butyldimethylsilyloxy) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (24),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (25),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (26),

((2R, 3R, 4R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (27),

(S) - ((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl ((R) -2-oxotetrahydrofuran-3-yl) phosphoramidate 1 (28),

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (29), and

(S) - ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1- methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (30).

The clinical dosage of a pharmaceutical composition containing, as an active component, at least one substituted amidophosphoric acid ester of the general formula 1, or its stereoisomer, or a pharmaceutically acceptable salt, can be adjusted depending on: therapeutic efficacy and bioavailability of the active ingredients in the patient’s body, the rate of their metabolism and excretion from the body, as well as depending on the age, gender and severity of the patient's symptoms, while the daily dose in adults is usually 10 ~ 500 mg Therefore, during the preparation of the pharmaceutical compositions of the present invention as dosage units, the above effective dosage must be taken into account, with each dosage unit containing 10 ~ 500 mg of a substituted amidophosphoric ester of general formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt.

In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The subject of the present invention is a method for inhibiting hepatitis C NS5B RNA polymerase, comprising contacting hepatitis C NS5B RNA polymerase with compounds of the general formula 1, 1.1, 1.2, 2.1 or 2.2, or their stereoisomers, or pharmaceutically acceptable salts.

The subject of the present invention is also a therapeutic cocktail for the prevention and treatment of humans and animals infected with flavaviruses, including hepatitis C virus, comprising, as one component, a pharmacologically effective amount of a substituted amidophosphoric acid ester of general formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition comprising a substituted amidophosphoric ester of general formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt b.

Therapeutic cocktails for the prevention and treatment of the above flavavirus diseases, including hepatitis C, along with the drugs of this invention, may include other active components, such as: inosine-5-monophosphate dehydrogenase inhibitors, for example, ribavirin (allowed) and ribamidine ; hepatitis C protease NS3 inhibitors, for example, telaprevir and boceprevir; NS5A RNA polymerase inhibitors, for example, VX222, R7128, PF-868554, ANA598; alpha glucosidase inhibitors, for example, amino carbohydrate Selgozivir; as well as TLR receptor agonists, hepatoprotectors, cyclosporins, various proteins (e.g. interferons), antibodies, vaccines, etc.

For combination therapy, any classes of agents that may be useful when combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside hepatitis C polymerase inhibitors, protease inhibitors, helicase inhibitors, NS4A inhibitors and medical agents that functionally inhibit the internal ribosome entry site ( IRES), as well as other medications that inhibit cell attachment or virus entry, translation of hepatitis C RNA, replication or maturation of HCV, or isolation Irus.

Specific compounds in these classes and useful in this invention include, but are not limited to, macrocyclic, heterocyclic and linear HCV protease inhibitors such as Telaprevir (VX-950), Boceprevir (SCH-503034), Narloprevir. (SCH-900518), ITMN-191 (R-7227), TMC-435350 (aka TMC-435), MK-7009, BI-201335, BI-2061 (Siluprevir), BMS-650032, ASN-1625, ASY- 1095 (concomitant HCV protease factor NS4A inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-013420 (and related), and nucleoside polymerase inhibitors (replicases) HCVs useful in the present invention include, but are not limited to, R7128, PSI-7851, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleosides and nucleotides HCV analogues and inhibitors, including, but not limited to, derived from 2'-C-methyl modified nucleosides and nucleotides; and 7'-dease of modified nucleosides and nucleotides. HCV non-nucleoside polymerase (replicase) inhibitors useful in the present invention include, but are not limited to, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333 , ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.

In addition, the NS5B inhibitors of the present invention can be used in combination with cyclophillin and immunophillin antagonists (for example, without limitation of the DEBIO compound, NM-811, as well as cyclosporin and its derivatives), kinase inhibitors, heat shock protein inhibitors (e.g. HSP90, HSP70 ), other immunomodulatory agents, which may include, without limitation, interferons (alpha, beta, omega, gamma, lambda or synthetic), such as: Intron A ™, Roferon-A ™, Canferon-A300 ™, Advaferon ™ , Infergen ™, Humoferon ™, Sumiferon MP ™, Alfaferon ™, IFN-β ™, Feron ™, and the like, interferon polyethylene glycol derivatized (pegylated) compounds such as: PEG interferon-α-2a (Pegasys ™), PEG interferon-α-2b (PEGIntron ™), pegylated IFN-α-con 1 and the like; prolonged formulas and derivatives of interferon compounds, such as: albumin-condensed interferon, Albuferon ™, Locteron ™, and the like; interferons with various types of controlled delivery (e.g. ITCA-638, omega-interferon delivered by the subcutaneous DUROS delivery system); compounds that stimulate the synthesis of interferon in cells, such as Resiquimod and the like; interleukins; compounds that enhance the development of a response of a type 1 helper T cell, such as: SCV-07 and the like; TOLL-like receptor agonists, such as: CpG-10101 (effect), Isotorabine, ANA773 and the like; Thymosin α-1, ANA-245 and ANA-246, histamine dihydrochloride, Propagermanium; Tetrachlorodecaoxide; Ampligen; IMP-321; K.RN-7000; antibodies such as: Civacir, XTL-6865 and the like, and prophylactic and therapeutic vaccines such as: Inno Vac, HCV E1E2 / MF59 and the like. In addition, any of the methods described above, including the administration of an NS5B inhibitor, a type 1 interferon receptor agonist (e.g. IFN-α) and a type P interferon receptor agonist (e.g. IFN-γ), can be enhanced by the administration of an effective amount of a TNF-α antagonist. Typical, but not limited, TNF-α antagonists that are suitable for use in such combination therapy include ENBREL ™ and HLJMIRA ™.

In addition, the NS5B inhibitors of the present invention can be used in combination with antiprotozoans and other antiviruses that are considered effective in treating HCV infection, such as the Nitazoxanide prodrug. Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, as well as in combination with other agents useful in treating HCV infection such as: Peginterferon alfa-2a and Ribavarin (e.g. Rossignol, JF and Keeffe, EB, Future Microbiol. 3: 539-545, 2008).

The NS5B inhibitors of the present invention can also be used in combination with alternative forms of interferons and pegylated interferons, Ribavirin or its analogs (e.g. Tarabavarin, Levovirion), microRNAs, harmless RNA compounds (e.g. SIRPLEX-140-N and the like), nucleotide analogues or nucleosides, immunoglobulins, hepatoprotectors, anti-inflammatory agents and other NS5A inhibitors. Inhibitors of other targets in the HCV life cycle include NS3 helicase inhibitors; co-factor NS4A inhibitors, antisense oligonucleotide inhibitors such as: ISIS-14803, AVI-4065 and the like; vector-encrypted short RNA hairpin (shRNA); specific HCV ribozymes, such as: Heptazyme, RPI, 139199 and the like; entry inhibitors such as: HepX-C, HuMax-Heps and the like; alpha glucosidase inhibitors such as: Celgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors. Other representative HCV inhibitor compounds include those disclosed in well-known scientific and patent publications.

Additionally, combinations of, for example, Ribavirin and interferon can be administered as a combination therapy with at least one substituted amidophosphoric acid ester of general formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt. The present invention is not limited to the above classes or compounds, and contemplates known and novel compounds and combinations of biologically active agents. It is intended that the combination therapies of the present invention include any chemically compatible combinations of the compounds of this patentable group with other compounds of the patentable group or other compounds outside the patentable group, and the combination does not exclude the antiviral activity of the compounds of this patentable group or the antiviral activity of the pharmaceutical composition itself.

Combination therapy may be sequential, i.e. treatment first with one agent and then with another (for example, when each treatment step involves a different compound of the present invention or when one treatment step includes a compound of the present invention and the other involves one or more biologically active agents) or there may be a treatment with both agents simultaneously. Sequential therapy may include a significant amount of time after the completion of the first stage of therapy and before the start of the second stage of therapy. Treatment with both agents at the same time can be carried out in a single daily dose or in different doses. Combination therapy does not need to be limited to two agents and may include three or more agents. Doses for simultaneous and sequential combination therapy will depend on absorption, distribution, metabolic rates and excretion of the components of combination therapy, as well as other factors well known to the specialist. The size of the dose will also vary depending on the severity of the condition that needs to be alleviated. For each particular subject, the specific dosage regimen and schedule can be adjusted in time according to the needs of the individual and the professional judgment of the person who treats or monitors the treatment using the combination therapy method.

The following examples illustrate but do not limit the invention.

Example 1. General method for producing compounds of General formula 1

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2- oxotetrahydrofuran-3-ylphosphoramidate 1.2 (1).

2.18 mmol (300 mg) of amine 3 are mixed with 2.18 mmol of aryl dichlorophosphate 4 in 15 ml of dichloromethane and cooled in an argon atmosphere to -70 ° C. To the resulting mixture was added a solution of 0.6 ml of triethylamine (4.36 mmol) in 3 ml of dichloromethane and the reaction mixture was stirred for 30 minutes at -70 ° C. The cooling was removed and the reaction mixture was allowed to warm to room temperature. The dichloromethane was evaporated, the residue was added to ether, filtered, a precipitate was obtained, which was washed with ether. The filtrate was evaporated and the residue was chromatographed on silica gel using 1: 1, 2: 1 ethyl acetate-hexane eluent. Aryl amidochlorophosphate 5 is obtained. Aryl amidochlorophosphate 5 (2.9 mmol), substituted with 1 - ((2R, 4S, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine-2,4 (1H, 3H) is dissolved. ) -dione 6 (1) (2.9 mmol) or substituted 4-amino-1 - ((2R, 4S, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2 (1H) - he 6 (2) (2.9 mmol) and 433 ml (2.9 mmol) of DBU in 20 ml of acetonitrile and the reaction mixture is boiled for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo. Purification of the product is carried out using the HPLC method without acid in the mobile phase. Get the compound of General formula 1, including:

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl p-tolyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (1), LC-MS (ESI) [M + H] ⁺ 517;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-chlorophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (2), LC-MS (ESI) [M + H] ⁺ 537;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 2,4-dichlorophenyl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate 1 (3), LC-MS (ESI) [M + H] ⁺ 572;

benzyl 1- (2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((S) - ((S) - (2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (5), LC-MS (ESI) [M + H] ⁺ 771. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.04 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.39 (m, 13H), 7.23 (m, 2H), 7.18 (m, 1H), 7.13 (d, J = 7.2 Hz, 1Н), 6.35 (t, J = 8.6 Hz, 1 Н), 6.15 (dd, J ₁ = 12.4 Hz, J ₂ = 10.4 Hz, 1Н), 5.38 (m, 1Н), 5.24 (АВ sys, J = 12.0 Hz, 2H), 5.21 (s, 2H), 4.58 (m, 1H), 4.51 (m, 1H), 4.43 (m, 1H), 4.27 (m, 2H), 4.15 (m, 1H), 2.36 (m, 1H); 2.01 (m, 1H);

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2-oxooxepan-3- IL-phosphoramidate 1 (9), LC-MS (ESI) [M + H] ⁺ 531;

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5, 5-dimethyl-2-oxotetrahydrofuran-3-ylphosphoramidate 1 (11), LC-MS (ESI) [M + H] ⁺ 532;

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 2- oxotetrahydrofuran-3-ylphosphoramidate 1 (16), LC-MS (ESI) [M + H] ⁺ 504;

((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (17), LC-MS (ESI) [M + H] ⁺ 500, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.47 (s, 1H ), 7.55 (d, J = 7.6 Hz, 1H), 7.39 (m, 2H), 7.26 (m, 2H), 7.19 (m, 1H), 6.13 (m, 1H), 6.03 (m, 1H), 5.89 (m, 1H), 5.58 (m, 1H), 4.30 (m, 5H), 4.05 (m, 1H), 3.83 (br m, 1H), 2.33 (m, 1H), 2.00 (m, 1H), 1.25 (m, 3H);

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopyrrolidin-3-ylphosphoramidate 1 (19), LC-MS (ESI) [M + H] ⁺ 631;

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropopyrimidin-l (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (R ) -2-oxo-tetrahydrofuran-3-ylphosphoframidate 1 (21), LC-MS (ESI) [M + H] ⁺ 504, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.61 (s, 1H), 7.55 ( m, 1H), 7.38 (m, 2H), 7.23 (m, 3H), 6.50 (br m, 1H), 6.13 (m, 2H), 5.65 (m, 1H), 4.25 (m, 7H), 2.34 ( m, 1H); 2.00 (m, 1H);

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-

hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (22), LC-MS (ESI) [M + H] ⁺ 503, ¹ H NMR (DMSO-d ₆ , 400 MHz) : δ 7.70 (d, J = 7.2 Hz, 1H), 7.40 (m, 4H), 7.25 (m, 3H), 6.38 (m, 1H), 6.22 (m , 1H), 5.80 (dd, J ₁ = 7.6 Hz, J ₂ = 2.8 Hz, 1H), 5.20 (bs, 1H), 5.05 (m, 1H) 4.28 (m, 2H); 3.58-4.22 (m, 4H); 2.40 (m, 1H); 2.04 (m, 1H);

((2R, 3R, 5R) -5- (2,4-dioxo-3,4-dihydropopyrimidin-l (2H) -yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2-yl) methyl phenyl (S ) -2-oxo-tetrahydrofuran-3-ylphosphoramidate, LC-MS (ESI) [M + H] ⁺ 498;

((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difftop-3-hydroxytetrahydrofuran-2-yl) methyl pyridin-2-yl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 504;

((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difftop-3-hydroxytetrahydrofuran-2-yl) methyl naphthalene-1-yl (S ) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 553;

((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difftop-3-hydroxytetrahydrofuran-2-yl) methyl 4-vinylphenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 529;

((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difftop-3-hydroxytetrahydrofuran-2-yl) methyl 3-ethynylphenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 527;

((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difftop-3-hydroxytetrahydrofuran-2-yl) methyl3-methoxyphenyl (S) -2 -oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 533;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-nitrophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 548;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl 4-cyanophenyl (S) - 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 528;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-

hydroxytetrahydrofuran-2-yl) methyl 4- (dimethylamino) phenyl (8) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 546.

Example 2. General method for producing compounds of General formula 1

To a solution of 0.8 mmol of aryl phosphordine chloride 4 in 5 ml of MeCN, a solution of 0.67 mmol of alcohol 6 and N-methylimidazole (55 mg, 0.67 mmol) in 4 ml of MeCN at -10 ° C was added dropwise and the mixture was stirred at -10 ° C for 5 h. After which a solution of 0.8 mmol of amine hydrochloride 8 and N-methylimidazole (131 mg, 1.6 mmol) in 10 ml of DCM was added and the mixture was stirred at room temperature for 12 hours. The mixture was evaporated in vacuo. Purification of the product is carried out using the HPLC method without acid in the mobile phase. Compounds of the general formula 1.1.1 and 1.2 are prepared, including: benzyl 1 - ((2R, 3R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopyrrolidin-3 -amylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (6), LC-MS (ESI) [M + H] ⁺ 784;

benzyl 1 - ((2R, 3R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methyl-2-oxopiperidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran- 2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (7), LC-MS (ESI) [M + H] ⁺ 798;

((2R, 3R, 5R) -3- (tert-butyldimethylsilyloxy) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl 1-methyl-2-oxopiperidin-3-ylphosphoramidate 1 (20), LC-MS (ESI) [M + H] ⁺ 645;

((2R, 3R, 5R) -5- (4- (1-pyrrol-2-ylcarbonylamino) -2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3- (1-pyrrole-2 -alkarbonyloxy) tetrahydrofuran-2-yl) methyl phenyl 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 689;

benzyl 1 - ((2R, 3R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-hydroxymethyl-2-

oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate, LC-MS (ESI) [M + H] ⁺ 800;

benzyl1 - ((2R, 3R, 5R) -4- (benzyloxycarbonyloxy) -3,3-difluoro-5 - (((1-methoxymethyl-2-

oxopyrrolidin-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate, LC-MS (ESI) [M + H] ⁺ 814.

Example 3. (2R, 3R, 5R) -5- (4-Acetamido-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((S) - (S) -2- oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (4) and (2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - (((((S) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23). To a solution of compound 1 (22) (100 mg, 0.2 mmol) in 2 ml of pyridine was added Ac ₂ O (41 mg, 0.4 mmol) and the mixture was stirred for 12 hours. The solution was evaporated in vacuo, the residue was dissolved in DCM, washed with water, dried over Na ₂ SO ₄ , evaporated in vacuo and separated by HPLC without acid. Compound 1 (23) was obtained, LC-MS (ESI) [M + H] ⁺ 545, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.44 (m, 5H), 7.23 (m, 3H), 6.18 ( m, 2H), 5.74, 5.79 (2d, J = 7A Hz, 1H), 5.38 (brm, 1H), 4.40 (m, 3H), 4.26 (m, 2H), 4.15 (m, 2H), 2.35 (m , 1H), 2.14, 2.15 (2 s, 3H), 2.01 (m, 1H) and compound 1 (4), LC-MS (ESI) [M + H] ⁺ 587, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.05 (s, 1H), 7.93, 8.04 (2d, J = 7.6 Hz, 1H), 7.38 (m, 2H), 7.23 (m, 5H), 6.34 (m, 1H), 6.17 (m, 1H), 5.42 (m, 1H), 4.45 (m, 3H), 4.27 (m, 2H), 4.16 (m, 2H), 2.35 (m, 1H), 2.15, 2.16 (2 s, 3H), 2.12 ( s, 3H), 2.01 (m, 1H);

In a similar manner, from the corresponding starting compounds, ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3- (methylaminoethylcarbonyloxy) tetrahydrofuran-2- is obtained il) methyl phenyl (S) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 588;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3- (piperidin-3-ylcarbonyloxy) tetrahydrofuran-2-yl) methyl phenyl (S) -2-oxo-tetrahydrofuran-3 ^ yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 614;

((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3- (piperidin-4-ylcarbonyloxy) tetrahydrofuran-2-yl) methyl phenyl (S) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 614;

((2R, 3R, 5R) -5- (4- (methylaminoethylcarbonylamino) -2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3- (methylaminoethylcarbonyloxy) tetrahydrofuran-2-yl) methyl phenyl ( S) -2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M + H] ⁺ 673.

Example 4. ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- (tert-butyldimethylsilyloxy) -4,4-difluorotetrahydrofuran-2-yl) methyl phenyl (S) -2-oxotetrahydrofuran-3-ylphosphoramidate 1 (24). To a solution of compound 1 (22) (112 mg, 0.22 mmol) in 1 ml of pyridine was added TBDMSCl (84 mg, 56 mmol) and the mixture was stirred at 50 ° C for 48 hours. The solution was evaporated in vacuo, the residue was dissolved in DCM, washed water, dried over Na ₂ SO ₄ , evaporated in vacuo and purified by chromatography on SiO ₂ (eluent MeCN: i-PrOH = 10: 1). Compound 1 (24) was obtained, LC-MS (ESI) [M + H] ⁺ 617, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.50 (m, 1H), 7.40 (m, 4H), 7.22 ( m, 3H), 6.20 (m, 1H), 6.12 (m, 1H), 5.78 (m, 1H), 4.38 (m, 2H), 4.26 (m, 3H), 4.12 (m, 2H), 2.33 (m , 1H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

Example 5. Benzyl l - ((2R, 4R, 5R) -4- (benzyloxycarbonyloxy) -5 - (((5,5-dimethyl-2-oxo-tetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) -3, 3-difluorotetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-ylcarbamate 1 (10) and ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidine-l (2H ) -yl) -4,4-difop-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 5,5-dimethyl-2-oxo-tetrahydrofuran-3-ylphosphoramidate 1 (14) is prepared according to the following scheme.

A solution of 673 mg (1.27 mmol) of bis-CBZ-gemcitabine 9, 500 mg (1.65 mmol) of phenyl 5,5-dimethyl-2-oxo-tetrahydrofuran-3-ylphosphoramidochloridate 10 and 135 mg (1.65 mmol) of N-methylimidazole in 20 ml dry MeCN is boiled for 48 hours. The mixture is evaporated in vacuo, dissolved in 40 ml of DCM, washed twice with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was dissolved in a 1: 1 mixture of CHCl ₃ / Me ₂ CO and filtered through a 2 cm layer of SiO ₂ , evaporated in vacuo. Compound 1 (10), LC-MS [M + H] ⁺ 799, which is hydrogenated in 25 ml of i-PrOH over 100 mg of 10% Pd / C, is obtained. HPLC separation was carried out without acid to give compound 1 (14), LC-MS (ESI) [M + H] ⁺ 531, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.48 (m, 1H), 7.39 (m , 4H), 7.23 (m, 3H), 6.43 (m, 1H), 6.14 (m, 2H), 5.75 (m, 1H), 4.35 (m, 3H), 4.19 (m, 1H), 4.05 (m, 1H), 2.33 (m, 1H), 1.85 (m, 1H), 1.35 (s, 3H), 1.31 (s, 3H).

Example 6. ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl (S) -2-oxo-tetrahydrofuran-3-ylphosphoramidate 1 (22). A solution of 2 g (2.6 mmol) of compound 1 (5) is hydrogenated in 150 ml of isopropanol over 200 mg of 10% Pd / C. After completion of the reaction (LC-MS control), the mixture was filtered through celite, evaporated in vacuo and purified by chromatography on a column of SiO ₂ (eluent MeCN: t-BuOH = 5: 1) to obtain compound 1 (22), LC-MS (ESI ) [M + H] ⁺ 503, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.44, 7.49 (2d, J = 7.6 Hz, 1H), 7.39 (m, 4H), 7.23 (m, 3H), 6.40, 6.44 (2d, J = 6.0 Hz, 1H), 6.14 (m, 2H), 5.73, 5.77 (2d, J = 7.6 Hz, 1H), 4.42 (m, 1H), 4.35 (m, 1H), 4.27 (m, 2H), 4.17 (m, 2H), 4.05 (m, 1H), 2.35 (m, 1H), 2.01 (m, 1H).

Example 7. ((2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl -2-oxopyrrolidin-3-ylphosphoramidate 1 (13), its (S) - 1 (15) and (R) -isomer 1 (30). A solution of compound 1 (6) (108 mg, 0.14 mmol) was hydrogenated in 20 ml of dioxane over 100 mg of 10% Pd / C to give compound 1 (13), LC-MS (ESI) [M + H] ⁺ 516. ¹ N NMR (DMSO-d ₆ , 400 MHzz) δ 7.47 (m, 2H), 7.37 (m, 3H), 7.27 (m, 2H), 7.19 (m, 1H), 6.42 (m, 1H), 6.18 (m, 1H), 5.89 (m, 1H), 5.75 (m, 1H), 4.32 (m, 3H), 4.05 (m, 1H), 3.82 (m, 1H), 3.20 (m, 2H), 2.73 (s, 3H ), 2.19 (m, 1H), 1.67 (m, 1H). HPLC separation without acid gives a fast-moving isomer, presumably the (R) -isomer 1 (30), LC-MS (ESI) [M + H] ⁺ 516, and a slow-moving isomer, presumably (8) -isomer 1 (15), LC-MS (ESI) [M + H] ⁺ 516.

Example 8. ((2R, 3R, 5R) -5- (4-amino-2-oxocopyrimidin-l (2H) -yl) -4,4-difop-3-hydroxytetrahydrofuran-2-yl) methyl phenyl 1-methyl -2-oxopiperidin-3-ylphosphoramidate 1 (8). A solution of compound 1 (7) (194 mg, 0.24 mmol) was hydrogenated in 20 ml of ethanol over 100 mg of 10% Pd / C. HPLC separation without acid gives compound 1 (8), LC-MS (ESI) [M + H] ⁺ 530. Compound 1 (8) is dissolved in a small amount of methanol and an equivalent amount of 0.2 M hydrogen chloride in methanol is added. The solvent was distilled off, the resulting product was washed with ether and dried in vacuo. The yield of hydrochloride 1 (8) * HCl 90%.

Example 9. Obtaining a pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of (2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 are mixed - ((((8) -2-oxotetrahydrofuran-3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23). The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each.

Example 10. Obtaining a pharmaceutical composition in the form of capsules. Thoroughly mix (2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-l (2H) -yl) -4,4-difop-2 - ((((S) -2-oxotetrahydrofuran-3- ilamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23) with lactose powder in a ratio of 2: 1. The resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.

Example 11. Obtaining a pharmaceutical composition in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mixed 500 mg mixed (2R, 3R, 5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4,4-difluoro-2 - ((((S) -2-oxotetrahydrofuran- 3-ylamino) (phenoxy) phosphoryloxy) methyl) tetrahydrofuran-3-yl acetate 1 (23) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

Claims (12)

1. The compounds of General formula 1, or their stereoisomers, or pharmaceutically acceptable salts

Where:
R ¹ is hydrogen, (CH ₃ ) ₂ [(CH ₃ ) ₃ C] Si, C ₂ -C ₆ acyl optionally substituted with a benzyloxy group, NR ⁵ R ⁶ group, in which R ⁵ and R ⁶ are independently hydrogen or C ₁ -C ₄ alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl;
R ² and R ³ are F or R ² is F or OH and R ³ is CH ₃ ;
R ⁴ represents hydrogen or methyl;
Ar is phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, F Cl, Br, I, nitro, cyano, —N (C _1-3 alkyl) ₂ ;
Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4- (4-amino-2-oxo-2H-pyrimidin-1-yl) in which the amino group is optionally substituted 1 -pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C (O) R ⁸ radical, where R ⁸ is a C ₁ -C ₄ alkyl optionally substituted with an NR ⁶ R ⁷ group, where R ⁶ and R ⁷ independently represent hydrogen or C ₁ -C ₄ alkyl; C _1-3 alkoxy optionally substituted with phenyl;
X represents O or NR ⁹ , where R ⁹ represents C ₁ -C ₄ alkyl optionally substituted by OH or OCH ₃ ;
n = 1,2 or 3. 2. The compounds of claim 1 of general formula 1.1 or general formula 2.1, or a stereoisomer thereof, or a pharmaceutically acceptable salt

where R ¹ , R ² , R ³ and X have the above meaning. 3. The compounds of claim 1 of general formula 1.2 or general formula 2.2, or a stereoisomer thereof, or a pharmaceutically acceptable salt

where R ¹ , R ² , R ³ and X have the above meaning. 4. The compounds of claim 1, which are:

5. A method for producing a compound of general formula 1 or its stereoisomer by reacting a compound of formula 6 with a compound of formula 4 and subsequent mixing with an amine of formula 8

where Ar, n, R ¹ , R ² , R ³ , R ⁴ , R ⁹ and Pm have the above meaning, and the resulting compound of formula 1, where R ¹ is hydrogen, is optionally converted to the corresponding acyl or dimethyl-tert-butylsilyl compound . 6. A method of producing according to claim 5 a compound of general formula 1 or a stereoisomer thereof, wherein R ¹ is acyl, by acylating a compound of formula 1, where R ¹ is hydrogen. 7. The method of producing according to claim 5 a compound of general formula 1 or its stereoisomer, wherein R ¹ is dimethyl-tert-butylsilyl by mixing dimethyl-tert-butylsilyl chloride with a compound of formula 1, where R ¹ is hydrogen. 8. The active component having the properties of nucleoside inhibitors of RNA polymerase NS5B of hepatitis C virus, which is a compound of the general formula 1, 1.1, 1.2, 2.1 or 2.2 according to any one of paragraphs. 1-4, or their stereoisomers, or pharmaceutically acceptable salts. 9. A pharmaceutical composition for the prevention and treatment of viral infections, including hepatitis C, containing the active ingredient of claim 8 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient. 10. A medicament for the prevention and treatment of viral infections, including hepatitis C, in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in a pharmaceutically acceptable package containing in an effective amount the active ingredient of claim 8 or the pharmaceutical composition of p. 9. 11. A method for the prevention and treatment of diseases caused by hepatitis C virus, the introduction of a therapeutically effective amount of the active ingredient according to claim 8 or the pharmaceutical composition according to claim 9 or the drug according to claim 10. 12. A method of inhibiting hepatitis C virus NS5B RNA polymerase C by contacting hepatitis C virus NS5B RNA polymerase with compounds of the general formula 1, 1.1, 1.2, 2.1 or 2.2 according to any one of paragraphs. 1-4, or their stereoisomers, or pharmaceutically acceptable salts.