NZ625844B2 - 4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication - Google Patents

Abstract

Provided are 4'-azido, 3'-fluoro substituted nucleoside phosphoramidate derivative compounds of the general formula I, where the variables are as defined in the specification. Examples of the compounds include S)-2-{[(2R,3S,4S,SR)-2-Azido-S-(2,4-dioxo-3 ,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester and (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-1-6ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid ethyl ester. The compounds are inhibitors of hepatitis C virus (HCV) RNA replication. xy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester and (S)-2-[[(2R,3S,4S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3-fluoro-4-hydroxy-tetrahydro-furan-2-1-6ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid ethyl ester. The compounds are inhibitors of hepatitis C virus (HCV) RNA replication.

Description

FIELD OF THE INVENTION The ion s to nucleoside derivatives as inhibitors of HCV replicon RNA replication. In particular, the invention is concerned with the use of purine and pyrimidine nucleoside derivatives as inhibitors of subgenomic Hepatitis C Virus (HCV) RNA replication and pharmaceutical compositions containing such compounds.

Hepatitis C virus is the leading cause of chronic liver disease throughout the world.

Patients infected with HCV are at risk of developing cirrhosis of the liver and subsequent cellular carcinoma and hence HCV is the major indication for liver transplantation. Only two approved therapies are currently available for the treatment ofHCV infection (R. G. Gish, Sem. Liver. Dis, 1999, 19, 35). These are interferon-0L monotherapy and, more recently, combination therapy of the nucleoside ue, ribavirin (Virazole), with interferon—0..

Many of the drugs approved for the treatment of viral infections are nucleosides or nucleoside ues and most of these nucleoside analogue drugs inhibit viral ation, following conversion to the corresponding triphosphates, h inhibition of the viral polymerase enzymes. This conversion to the triphosphate is commonly mediated by cellular s and therefore the direct evaluation of nucleosides as inhibitors of HCV replication is only conveniently carried out using a cell—based assay. For HCV the availability of a true cell- based viral replication assay or animal model of infection is lacking.

Hepatitis C virus belongs to the family of Flaviridae. It is an RNA virus, the RNA genome encoding a large polyprotein which after processing produces the necessary replication machinery to ensure synthesis of progeny RNA. It is ed that most of the non—structural ns encoded by the HCV RNA genome are involved in RNA replication. n et al.

[V. Lohrnann et al., Science, 1999, 285, 110—113] have described the construction of a Human Hepatoma (Huh7) cell line in which subgenomic HCV RNA molecules have been introduced and shown to replicate with high efficiency. It is believed that the mechanism of RNA JZ/05.ll.2012 ation in these cell lines is identical to the ation of the full length HCV RNA genome in infected hepatocytes. The subgenomic HCV cDNA clones used for the isolation of these cell lines have formed the basis for the development of a cell-based assay for identifying nucleoside analogue tors of HCV replication.

SUMMARY OF THE INVENTION The compounds of Formula I are useful for the treatment of diseases mediated by the Hepatitis C Virus (HCV) and for pharmaceutical compositions comprising such compounds.

The application provides a compound of Formula I wherein: R1 is H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthyl, optionally tuted with one or more lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo, lower kyl, ; -N(Rl")2, acylamino, ~SOzN(R"‘)2, COR"), —SOg(R1°), —NHSOz(R‘C), nitro or cyano; each Rla is independently H or lower alkyl; each Rlb is independently —OR1a or -N(R’a)2; each R10 is lower alkyl; R2a and R2b are (2') independently H, lower alkyl, —(CH2),N(R1a)2, lower hydroxyalkyl, — CstH, —(CH2)S(O)pMe, ~(CH2)3NHC(=NH)NH2, (lH—indol-3—yl)methyl, (1H—indol—4— yl)methyl, -(CH2)mC(=O)Rlb and aryl lower alkyl, n aryl may optionally be , aryl tuted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R2a is H and sz and R4 together form (CH2)3; (iii) R2a and R2b together form (CH2)n; or, (iv) R221 and R2b both are lower alkyl; R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl; R4 is H, lower alkyl, or R2b and R4 together form (CH2)3; R5 is H, C(=O)R1C, C(=O)Rlb or P(=O)(OR‘)(OR1a); R6 is o NH2 a N’ I | t \NILNHZ 0 1y 0 qt 1?} ,or * § 7': , 7.: misOto3; nis4or5; pisOtoZ; and rislt06; or a pharmacologically acceptable salt thereof.

Also described herein is a method for treating a Hepatitis C Vilus (HCV) infection comprising stering to a patient in need thereof a therapeutically effective amount of a IO nd of Formula I.

The ation provides a composition comprising a compound of Formula I and a pharmaceutically acceptable excipient.

DETAILED PTION OF THE INVENTION The compounds of Formula I have been shown to be inhibitors of subgenomic Hepatitis C Virus replication in a hepatoma cell line. These compounds have the potential to be efficacious as antiviral drugs for the treatment of HCV infections in human.

The term "alkyl" as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms. Preferably, the term "alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Most preferred are , ethyl, propyl, isopropyl, n—butyl, yl, tert-butyl or pentyl. The alkyl may be unsubstituted or substituted. The substituents are selected from one or more of cycloalkyl, nitro, amino, alkyl amino, dialkyl amino, alkyl carbonyl and lkyl carbonyl.

The term "cycloalkyl" as used herein denotes an optionally substituted lkyl group containing 3 to 7 carbon atoms, e. g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "alkoxy" as used herein denotes an optionally substituted straight or branched chain alkyl—oxy group wherein the "alkyl" portion is as defined above such as methoxy, ethoxy, n—propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert—butyloxy, pentyloxy, xy, heptyloxy including their isomers.

The term "alkoxyalky " as used herein denotes an alkoxy group as defined above which is bonded to an alkyl group as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, butyl, propyloxybutyl, butyloxybutyl, tert—butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers.

The term y " as used herein denotes an unsubstituted or substituted hydrocarbon chain radical having from 2 to 7 carbon atoms, preferably from 2 to 4 carbon atoms, and having one or two c double bonds, preferably one olefinic double bond. Examples are vinyl, l— propenyl, 2—propenyl (allyl) or 2—butenyl (crotyl).

The term "alkynyl" as used herein denotes to unsubstituted or substituted hydrocarbon chain radical having from 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, and having one or where le two triple bonds, preferably one triple bond. es are ethynyl, l—propynyl, ynyl, l—butynyl, 2—butynyl or 3—butynyl.

The tenn "hydroxyalkyl" as used herein denotes a straight or branched chain alkyl group as defined above wherein l, 2, 3 or more hydrogen atoms are substituted by a hydroxy group.

Examples are ymethyl, l—hydroxyethyl, 2-hydroxyethyl, l—hydroxypropyl, 2- hydroxypropyl, 3—hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like.

The term "haloalkyl" as used herein denotes a straight or branched chain alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a halogen. Examples are l-fluoromethyl, 1-chloromethyl, omethyl, l-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, l—fluoroethyl, l-chloroethyl, 1-bromoethyl, thyl , 2—fluoroethyl, 2—chloroethyl, 2—bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3- bromopropyl or 2,2,2—trifluoroethyl and the like.

The term "alkylthio" as used herein s a straight or branched chain (alkyl)S- group n the "alkyl" portion is as defined above. es are methylthio, ethylthio, n- propylthio, i-propylthio, n-butylthio, lthio or te1t.-buty1thio.

The term "aryl" as used herein denotes an optionally substituted phenyl and naphthyl (e. g. thyl, 2—naphthyl or 3—naphthy1). Suitable substituents for aryl can be selected from those named for alkyl, in addition however, halogen, hydroxy and optionally substituted alkyl, lialoalkyl, alkenyl, alkynyl and aryloxy are substituents which can be added to the selection.

The tenn ocyclyl" as used herein denotes an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocyclic systems which n one or more hetero atoms selected from nitrogen, oxygen and sulfur which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic carbocycle or heterocycle.

Examples of suitable heterocycles are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3- dioxolanyl, dihydropyranyl, 2-thienyl, 3—thienyl, pyrazinyl, isothiazolyl, dihydrooxazolyl, pyrimidinyl, tetrazolyl, l-pyrrolidinyl, 2-pyrrolidinyl, 3—pyrrolidinyl, idinonyl, (N-oxide)— pyridinyl, l—pyrrolyl, 2—pyrrolyl, triazolyl e. g. 1,2,3—triazolyl or 1,2,4—triazolyl, l—pyrazolyl, 2— lyl, 4—pyrazolyl, piperidinyl, morpholinyl (e. g. 4—morpholinyl), rpholinyl (e. g. 4— thiomorpholinyl), thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, piperazinyl, azolyl, 2-imidazolyl, 4—imidazolyl, thiadiazolyl e. g. 1,2,3—thiadiazolyl, 4- methylpiperazinyl, 4-hydroxypiperidin— 1 ~yl.

Suitable substituents for heterocyclyl can be selected from those named for alkyl, in addition however, optionally substituted alkyl, l, alkynyl, an oxo group (=0) or aminosulphonyl are substituents which can be added to the selection.

The term "acyl" ("alkylcarbonyl") as used herein denotes a group of formula C(=O)R wherein R is hydrogen, an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms or a phenyl group. Most preferred acyl groups are those wherein R is hydrogen, an unsubstituted straight chain or ed hydrocarbon residue containing 1 to 4 carbon atoms or a phenyl group.

The term n stands for fluorine, chlorine, bromine or iodine, preferable fluorine, chlorine, bromine.

In the pictorial representation of the compounds given throughout this application, a thickened tapered line ( """' ) indicates a substituent which is above the plane of the ring to which the asymmetric carbon belongs and a dotted line ( """' ) indicates a tuent which is below the plane of the ring to which the asymmetric carbon belongs.

Compounds of a 1 exhibit stereoisomerism. These compounds can be any isomer of the nd of formula I or mixtures of these isomers. The compounds and intermediates of the present invention having one or more asymmetric carbon atoms may be obtained as racemic mixtures of stereoisomers which can be resolved.

Compounds of a 1 t tautomerism that means that the compounds of this invention can exist as two or more chemical compounds that are capable of facile interconversion. In many cases it merely means the exchange of a hydrogen atom between two other atoms, to either of which it forms a covalent bond. Tautomeric compounds exist in a mobile equilibrium with each other, so that attempts to prepare the separate substances usually result in the formation of a mixture that shows all the chemical and physical properties to be expected on the basis of the structures of the components.

The most common type of tautomerism is that involving carbonyl, or keto, compounds and rated hydroxyl compounds, or enols. The structural change is the shifi of a hydrogen atom between atoms of carbon and oxygen, with the ngement of bonds. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is the predominant one; in phenols, the enol form is the major component. nds of formula I which are basic can form pharmaceutically acceptable salts with inorganic acids such as hydrohalic acids (6.g. hydrochloric acid and hydrobromic acid), sulphuric acid, nitric acid and phosphoric acid, and the like, and with organic acids (e.g. with acetic acid, ic acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid and p—toluene sulphonic acid, and the like). The formation and isolation of such salts can be d out according to methods known in the art.

Inhibitors of HCV The application provides a compound of Formula I R2" [Slap 1?! \0"- 1 R4 O N;"‘ s‘ ’r F o~R5 wherein: R1 is H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower l, lower alkynyl, lower alkoxy, halo, lower haloalkyl, -N(Rlfl)2, acylamino, -SOzN(R1a)2, -COR"’, -SOz(R1°), -NHSOz(R1°), nitro or cyano; each Rla is independently H or lower alkyl; each Rlb is independently —ORla or -N(Rla)2; each RIc is lower alkyl; R221 and R2]) are (1') independently H, lower alkyl, —(CH2).N(R1292, lower hydroxyalkyl, — CstH, —(CH2)S(O)pMe, —(CH2)3NHC(=NH)NH2, (lH—indol—3—yl)methyl, (1H—indol—4— yl)methyl, ~(CH2)mC(=O)RIb and aryl lower alkyl, wherein aryl may optionally be , aryl substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R23 is H and R2b and R4 together form (CH2)3; (iii) R223 and R2b together form (CH2)n; or, (iv) R221 and R2b both are lower alkyl; R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl; R4 is H, lower alkyl, or R2b and R4 together form (CH2)3; R5 is H, C(=O)R‘°, C(=O)R1b or OR1)(OR"‘); R6 is o NH2 Hi: | A | g \ N’)\NH2 0 15 0 1}; I? ,01‘ ‘5‘ i: , * m is 0 to 3; n is 4 or 5; p is 0 to 2; and r is l to 6; or a pharmacologically acceptable salt thereof.

The application provides a compound of Formula I, wherein R4 is H.

The application provides a compound of Formula I, wherein R6 is O NH 1:15 i’ r O I? 0 D3 ,2 or 7» The application es a compound of Formula I, wherein R6 is OgltlHNJE The application provides a compound of Formula I, wherein R6 is OxlflNd The application provides a compound of a I, wherein R4 is H and R6 is 0 NH2 If] N’ 01$ 0&1?»I The application provides a compound of Formula I, wherein R4 is H and R6 is ,2 .

The application provides a compound of Formula I, n R4 is H and R6 is The application provides a compound of Formula I, wherein R1 is naphthyl or phenyl.

The application provides a compound of Formula I, wherein R1 is naphthyl.

The application provides a nd of Formula I, wherein R1 is phenyl.

The ation provides a compound of Formula I, wherein R1 is phenyl and R4 is H.

The application provides a compound of Formula I, wherein R1 is phenyl, R4 is H, and R6 HNJ] O N The application provides a compound of Formula I, wherein R1 is phenyl, R4 is H, and R6 is 0 1r The application es a compound of Formula I, wherein R1 is naphthyl and R4 is H.

The application provides a nd of Formula I, wherein R1 is naphthyl, R4 is H, and R6 is CAI?HNJ‘] p .

The application es a compound of Formula I, wherein R1 is naphthyl, R4 is H, and R6 is 0 1r The application provides a compound of Formula I, wherein R2a is H.

The application provides a compound of Fonnula I, wherein R21) is methyl.

The ation provides a compound of Fonnula I, wherein R2Z1 is H and R2b is methyl.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, and R6 is HNJ] O N The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, sz is methyl, and R6 is CARIEH] * .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R28 is H and R2b is methyl, and R6 is 0A1?HNfi * .

The application provides a compound of Formula I, wherein R3 is isopropyl.

The application provides a nd of Formula I, wherein R3 is ethyl.

The application provides a compound of Formula I, wherein R3 is benzyl.

The application provides a compound of a I, wherein R1 is naphthyl and R3 is pyl.

The application es a compound of a I, wherein R1 is naphthyl, R4 is H, and R3 is isopropyl.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R3 is isopropyl, and R6 is HNJ] O N The application es a compound of Formula I, wherein R1 is naphthyl, R4 is H, R3 is ethyl, and R6 is 0A1};HN/lj * .

The application provides a compound of Formula I, n R1 is naphthyl, R4 is H, R3 is benzyl, and R6 is CAI?HNJ‘] ,9 .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R3 is isopropyl, and R6 is The application provides a compound of Formula l, wherein R1 is naphthyl, R4 is H, R3 is ethyl, and R6 is 02WN43 The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R3 is benzyl, and R6 is 0a,?Nfi The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, R3 is isopropyl, and R6 is 0;,HM] ¥ The application es a compound of Formula I, wherein R1 is naphthyl, R4 is H, R23 is H, R2b is methyl, R3 is isopropyl, and R6 is OAR}HNfi 72 .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, Rza is H, R3 is isopropyl, and R6 is OAT};NJ} The application provides a compound of Formula I, wherein R1 is yl, R4 is H, R2a is H, sz is , R3 is isopropyl, and R6 is 0 1F The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, R3 is pyl, and R6 is 4N \ NA‘NHZ The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R23 is H, R2b is methyl, R3 is isopropyl, and R6 is The application provides a compound of Formula I, wherein R5 is H.

The application provides a compound of Formula I, wherein R1 is naphthyl and R5 is H.

The ation provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, and R5 is H.

The application provides a compound of a I, wherein RI is naphthyl, R4 is H, R5 is H, and R6 is HNJJ O N The application es a compound of Formula I, wherein R1 is naphthyl, R4 is H, Rza is H, R5 is H, and R6 is oJ‘iyHNJ] ,, .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, R?" is methyl, R5 is H, and R6 is 0%}?HN/U] ,4 .

The application provides a compound of Formula I, wherein R1 is yl, R4 is H, R2a is H, R2b is methyl, R3 is isopropyl, R5 is H, and R6 is ,‘ .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R22‘ is H, R" is methyl, R3 is ethyl, R5 is H, and R6 is ,, .

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, R2b is methyl, R3 is benzyl, R5 is H, and R6 is —16- HNJ] O N The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R28 is H, R2b is methyl, R3 is isopropyl, R5 is H, and R6 is The application provides a nd of Formula I, wherein R1 is naphthyl, R4 is H, R221 is H, R213 is , R3 is ethyl, R5 is H, and R6 is The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R221 is H, R2b is methyl, R3 is , R5 is H, and R6 is 0%,,NJ} The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R23 is H, R2b is methyl, R3 is isopropyl, R5 is H, and R6 is 4/ \ N 1‘1’)‘NH2 The ation provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R23 is H, R2b is methyl, R3 is ethyl, R5 is H, and R6 is 4N \ NA‘NHZ The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R28 is H, R21) is methyl, R3 is , R5 is H, and R6 is The application provides a compound of Formula I, wherein R5 is C(=O)R‘°.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R2a is H, R" is methyl, R3 is isopmpyl, R5 is C(=O)R‘°a and R6 is I]N/ 0 1i The application provides a compound of Formula I, wherein R10 is ethyl.

The application provides a nd of Formula I, n R1 is naphthyl, R4 is H, R221 is H, R2b is methyl, R3 is isopropyl, R5 is C(=O)CH2CH3, and R6 is oél‘iyN2} —18- The application provides a compound selected from the group ting of: (S)-2— {[(2R,3 8,48,5R)-2—Azido—5-(2,4-dioxo-3,4-dihydro-2H—pyrimidiny1)—3— 4-hydroxy-tetrahydro—furan—2-ylmethoxy]-phenoxy-phosphorylamino } -propionic acid isopropyl ester; (S)—2- {[(2R,3 S,4S,5R)-2—Azido—5—(2,4—dioxo-3 ,4—dihydro-2H—pyri1nidin- l —y1)—3 - fluoro~4-hydroxy—tetrahydro-furan—2~ylmethoxy]-phenoxy-phosphorylamino } —propionic acid ethyl ester; (S)—2-[[(2R,3 S,4S,5R)—2—Azido~5-(2,4-dioxo—3 ,4-dihydro-2H—pyrimidin-l-y1)—3 - fluoro—4-hydroxy—tetrahydro—furanylmethoxy] -(naphthalen- 1 —yloxy)- phosphorylamino]-propionic acid ethyl ester; (S)-2—[[(2R,3 S,4S,5R)-5—(4-Amino—2—oxo-2H—pyrimidin— l —azido—3-fluoro-4— hydroxy-tetrahydro-fiiran—Z-ylmethoxy]"(naphthalen- l -yloxy)—phosphorylamino] — propionic acid isopropyl ester; (S)—2—[[(2R,3 S,4S,5R)-5—(4-Aminooxo—2H—pyrimidin— l —yl)—2-azido—3-fluoro~4— hydroxy—tetrahydro-furany1methoxy]—(naphthalen- l —yloxy)—phosphorylamino] — nic acid benzyl ester; (S)—2—[[(2R,3 S,4S,5R)(4—Amino—2~oxo—2H—pyrimidin— l -yl)—2—azido—3-fluoro—4— hydroxy—tetrahydro—fiiran—Z—ylmethoxy]—(naphthalen— l -y10xy)—phosphorylamino] — propionic acid ethyl ester; (S)-2— {[(2R,3 8,48,5R)-5—(4—Amino—2-oxo—2H~pyrimidin- l —yl)—2-azido—3—fluoro—4— hydroxy—tetrahydro—fiiran—Z-ylmethoxy]~phenoxy-phosphorylamino } —propionic acid pyl ester; (S)~2— { [(2R,3 S,4S,5R)~5~(4—Amino~2~oxo—2H—pyrimidin— l ~yl)azido—3 —fluoro—4— hydroxy—tetrahydro-furan—Z—ylmethoxy]—hydroxy~phosphorylamino } ~propionic acid isopropyl ester; and (S)[[(2R,3 S,4S,5R)-5—(4—Amino—2-oxo—2H~pyrimidin- l ~y1)—2—azid0—3-flu0ro~4- propionyloxy-tetrahydro-furan—Z-ylmethoxy]—(naphthalen—l )—phosphoryla1nino]~ propionic acid isopropyl ester.

Also described herein is a method for treating a Hepatitis C Virus (HCV) infection comprising administering to a patient in need thereof a therapeutically ive amount of a compound of Formula I.

The above method, may further comprise administering an immune system modulator or an ral agent that inhibits replication of HCV, or a combination thereof.

In the above method, the immune system modulator is may be an interferon or chemically derivatized interferon.

In the above methods, the ral agent may be selected from the group consisting of a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor, a HCV fusion inhibitor, and a ation thereof.

Also described herein is a method for inhibiting replication of HCV in a cell comprising administering a compound of Formula I.

The ation provides a composition comprising a compound of Formula I and a pharmaceutically acceptable ent.

The application provides a use of the compound of Formula I in the manufacture of a medicament for the treatment of HCV.

The application provides a compound or composition, as described herein.

Compounds es of representative compounds encompassed by the present invention and within the scope of the invention are provided in the ing Table. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative f.

In l, the nomenclature used in this Application is based on AUTONOMTM v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.

If there is a discrepancy between a depicted structure and a name given that structure, the ed structure is to be accorded more weight. In addition, if the stereochemistry of a _20- structure or a portion of a structure is not indicated with, for e, bold or dashed lines, the structure or p01tion of the structure is to be interpreted as encompassing all stereoisomers of it.

TABLE I depicts examples of compounds ing to generic Formula I.

Compound no. Structure Name A O 0 (S) {[(2R,3 S,4S,5R)—2—Azido-5— 0 j? / (2,4-dioxo-3,4-dihydro-2H— pyrimidin- l ~yl)—3 ~fluoro-4—hydroxy— tetrahydro~furan-2—y1methoxy]— N'N \‘ ’1 phenoxy—phosphorylamino}— propionic acid isopropyl ester l (S){[(2R,3S,4S,5R)—2—Azido~5— 0 0 OJSVNJL0 / (2,4—dioxo—3,4-dihydro-2H— pyriml‘d'1n— 1 - - uoro—41—iydroxy- 1—2 0 N—go 4N" tetrahydro-furan—2—ylmethoxy]- ‘N I, .

N ¢ F OH y-phosphorylammo}- propionic acid ethyl ester ( (S)—2-[[(2R,3S,4S,5R)—2-Azido—5— O O (2,4~dioxo—3 ,4—dihydro-2H— pyrimidin- l -y1)—3 -fluoro—4—hydroxy- 1-3 G W" tetrahydro-furan—Z-ylmethoxy] - (naphthalenel —yloxy)— phosphorylamino]-propionic acid ethyl ester (S)-2—[[(2R,3 S,4S,5R)-5—(4-Amino- 2~oxo—2H-pyrimidin—l —y1)azido «mfluoro—4-hydroxy-tetrahydro—furan-2— ylmethoxy]—(naphtha1en- l —yloxy)— orylamino]—propionic acid isopropyl ester (S)—2-[[(2R,3S,4S,5R)—5—(4—Amino— 2-0xo—2H—pyrimidiny1)—2—azido—3- HN fluorohydroxy-tetrahydr0-furan @03a?! 1: ylmethoxy]-(naphthalen—1-y10xy)— CO N orylamino]-propionic acid benzyl ester 0 NH2 (S)—2—[[(2R,3S,4S,5R)-5—(4—Amino— AOJS/g‘ flN 2—ox0~2H—pyrimidin—1—yl)—2—azid0-3 ~ O N— General Schemes The methods discussed above are described in more details below: The commercially available side 3’-flu0ro—3’-deoxyuridine (1) can also be prepared ing to the procedures bed by Gosselin, G. et a1, Collect. Czech. Chem. . (2006), Vol. 71, No. 7, 991—1010. lodination followed by elimination of iodide under basic condition can lead to ediate 3. Introduction of azido group at 4’ D position in intermediate 3, followed by oxidative displacement of 5’—iodide with m—chloroperbenzoic acid in intermediate 4 to afford 5 can be accomplished according to the methods described by Smith, D. B: et al, J.

Med. Chem. (2009), 52(9), 2971—2978. Deprotection of 5’ m-chlorobenzoyl groups in intermediate 5 gives uridine intermediate 6 (Scheme 1).

Scheme 1.

O 0 NH NH I A El (IL'NJso N 0 12, PPh3 N 0 NaOMe HO I 0 O ——--—-> O ———-> w MeCN / ne MeOH c ,’ F OH I4" ’OH rt, 12 h F‘ ’OH 70 0C, 2 h 1 O 12, [Bn(Et)3N]N3 MCPBA /MCBA N O NMI ——-—> ——-p 0 THF / MeCN Bu4NHSO4 0-9 0C, 16 h F‘ ’OH EEPO4, rt C1 O 0 4 N 0 NH N o N3"\ MeOH, rt N? F‘ ’()H 2 h F 0H Cytidine intermediate 10 has been disclosed by Smith, D. B. et al in J. Med. Chem. (2009), 52(9), 978. Altematively, 10 can also be ntly prepared by the synthetic route outlined in Scheme 2.

Scheme 2.

O O O ' f l f 0%) [till N 0 BzCl,DMAP BzONa N o N 0 I 1 0 O -——--> 0 —-—> 0 N3" DCM, 0 0C, 5 min N?" DMSO 0 1‘13"" o e a e a 100 0C, 18 h e 9 F 0H F O F O N— T 4 / I}; 7 8 N‘ I\HzT lH—tetrazole @O l l NH3 I A N 0 —--> N 0 HO 0 MeOH, rt 0 (4-Cl—PhO)P(=O)Clz 16 h N "9 N3"S Pyridine 3 x 4 ~ 0 Guanosine intermediate 12 can be prepared by transamination reaction from intermediate 8 with protected guanine followed by the deprotection reaction (Scheme 3).

Scheme 3.

F‘ ’o BSA,MeCN, 100 0c F‘ ’0 ' <’N I NH H0 N 0 N/ NH NH3 2 N3‘"\ _.._.

MeOH, rt F" 90H Phosphoramidate compounds of the present invention can be prepared by sation of nucleoside 6 or 10 or 12 with a suitably tuted phosphochloridate compound 11 in the carried out on the unprotected presence of a strong base (Scheme 4). The condensation can be nucleoside 6 or 10 or 12. The coupled product 16 in formula I are initially obtained as a mixture of two reomers under the coupling reaction and can be separated into their corresponding chiral omers by chiral column, chiral HPLC, or chiral SFC chromatography.

Scheme 4. 2b 28 R45 R IN]: ‘RS 21) 2a RIOH R1\ 9 0 R Cl NEt3, ether Cl mg "021% 0 rt, 18 h R O 2bR‘ 13 14 R2a I; (3 15 0 R3’O\n>\1}1: ‘0 R6 N30" tert—BuMgCl O R NM R6 = Nucleobase (U, C, G) x‘ ’l 3 F OH e g , THF F OH 6 or 10 or 12 The condensation reaction can also be conducted on the protected nucleoside 6 or 10 or 12.

For example, nucleoside 6 can be protected at 2’ position to give intermediate 17. The condensation on with 17 can lead to compound 18 in formula I with improved yield. In the case R5 is triethylsilyl group, 18 can be ively deprotected to remove 2’— triethylsilyl by treatment with acetic acid or formic acid at room temperature to generate compound 16 wherein R6 is cytidine (Scheme 5).

Scheme 5.

[Elk\v \N R3’0)?‘N>"<:R‘ g 0 I I N 0 HO N 0 HO N 0 tert—BuMgCl ' 4 0 0 R5Cl O 0 R _....__—p _____.

N 09 N3"v 3 N30" s , s a Base s a 15,THF _ R5: SiEt or C =0 C1-6alk 3 ( ) y1 17 13 Dosage and Administration: As shown in above Table the compounds of formula I have the potential to be efficacious as antiviral drugs for the treatment of HCV infections in humans, or are metabolized to a compound that exhibit such activity.

In another embodiment of the invention, the active compound or its derivative or salt can be administered in combination with another antiviral agent, such as an anti—hepatitis agent, including those of formula I. When the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound. This can easily be assessed by preparing the derivative and testing its anti~ HCV activity according to the method described herein. stration of the active compound may range from continuous (intravenous drip) to several oral strations per day (for example, Q.l.D) and may include oral, topical parenteral, intramuscular, intravenous, subcutaneous, ennal (which may include a penetration enhancement , buccal and suppository stration, among other routes of administration.

The 4'—substituted side derivatives, as well as their phamiaceutically e salts, can be used as medicaments in the form of any pharmaceutical ation. The pharmaceutical formulation can be administered enterally, either orally, e.g. in the fonn of tablets, coated tablets, dragées, hard and soft ne capsules, solutions, emulsions, syrups, or suspensions, or rectally, e. g. in the form of suppositories. They can also be administered parenterally muscularly, intravenously, subcutaneously or intrasternal injection or infusion techniques), e. g. in the form of injection solutions, nasally, e, g. in the form of nasal sprays, or inhalation spray, topically and so forth.

For the manufacture of ceutical preparations, the 4'—substituted nucleoside derivatives, as well as their phannaceutically useable salts, can be formulated with a therapeutically inert, nic or organic excipient for the production of s, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.

The compounds of formula I can be formulated in admixture with a phannaceutically acceptable carrier. For e, the compounds of the present invention can be administered orally as phannacologically acceptable salts. Because the compounds of the present invention are mostly water soluble, they can be administered intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of , one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the t compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ry skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a paiticular compound in order to manage the cokinetics of the present nds for maximum beneficial effect in patients.

For parenteral formulations, the carrier will usually comprise e water or aqueous sodium chloride solution, though other ients including those which aid dispersion may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. able suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. le excipients for tablets, coated tablets, dragées, and hard gelatin capsules are, for example, lactose, corn starch and derivatives thereof, talc, and c acid or its salts.

If desired, the tablets or capsules may be enteric—coated or ned release by standard techniques.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi~solid and liquid polyols. le excipients for injection solutions are, for example, water, saline, alcohols, polyols, glycerine or vegetable oils.

Suitable excipients for suppositories are, for example, natural and hardened oils, waxes, fats, semi-liquid or liquid polyols.

Suitable excipients for solutions and syrups for enteral use are, for example, water, s, saccharose, invert sugar and glucose.

The pharmaceutical preparations of the present invention may also be provided as sustained release formulations or other appropriate formulations.

The phannaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, nts, flavourants, salts for adjustment of the osmotic re, buffers, masking agents or antioxidants.

The pharmaceutical preparations may also contain other therapeutically active agents known in the art.

The dosage can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. For oral administration, a daily dosage of between about 0.01 and about 100 mg/kg body weight per day should be riate in monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more red 0.1 and about 100 mg/kg body weight and most prefeired 1.0 and about ~28— 100 mg/kg body weight per day. A typical preparation will contain from about 5% to about 95% active compound (w/w). The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day.

In certain pharmaceutical dosage fonns, the pro-drug form of the compounds, especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred. One of ordinary skill in the art will recognize how to readily modify the t compounds to pro—drug forms to facilitate delivery of active compounds to a target site within the host sm or patient. One of ordinary skill in the art will also take age of ble pharmacokinetic parameters of the pro—drug forms, where applicable, in delivering the present compounds to targeted site within the host organism or patient to maximize the intended effect of the compound.

Indications and Method of Treatment The compounds of the invention and their isomeric fonns and ceutically acceptable salts f are useful in treating and preventing HCV infection.

Described herein is a method for treating a Hepatitis C Virus (HCV) infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Formula I.

Also described herein is a method for ting replication of HCV in a cell comprising administering a compound of any one of a 1.

Combination Therapy The compounds of the ion and their isomeric forms and phannaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV lifecycle. s of compounds useful in the invention include, without limitation, all classes ofHCV antivirals.

For combination therapies, mechanistic classes of agents that can be useful when combined with the compounds of the invention include, for example, nucleoside and non—nucleoside inhibitors of the HCV polymerase, protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinal agents that functionally inhibit the internal ribosomal entry site (IRES) and other ments that inhibit HCV cell ment or virus entry, HCV RNA translation, HCV RNA transcription, replication or HCV maturation, assembly or virus release. Specific compounds in these classes and useful in the invention include, but are not limited to, macrocyclic, heterocyclic and linear HCV protease inhibitors such as telaprevir (VX—950), evir (SCH—503034), revir (SCH~9005 18), ITMN— l9l (R-7227), TMC—435350 (aka. TMC-435), MK— 7009, BI-201335, 1 (ciluprevir), EMS—650032, ACH—l625, 95 (HCV NS4A protease co~factor inhibitor), VX—500, VX-8 l3, PHX-l766, PHX2054, IDX— 136, IDX—3 16, ABT—450 EP-O 13420 (and congeners) and VBY-3 76; the Nucleosidic HCV polymerase (replicase) tors useful in the invention include, but are not limited to, R7128, PSI-785 l, IDX—184, IDX—102, R1479, UNX—OS 189, PSI—6130, PSI-938 and PSI—879 and s other nucleoside and nucleotide analogs and HCV inhibitors including (but not limited to) those derived as 2'-C— methyl modified nucleos(t)ides, 4'-aza modified nucleos(t)ides, and 7'—deaza modified s(t)ides. Non-nucleosidic HCV polymerase (replicase) inhibitors useful in the invention, include, but are not limited to, HCV—796, HCV—371, VCH—759, 6, VCH- 222, ANA- 598, MK-3281, ABT—333, ABT-072, PF-00868554, BI-207l27, GS-9l90, A- 837093, JKT—109, GL-59728 and GL—60667.

In addition, compounds of the invention can be used in combination with cyclophyllin and immunophyllin antagonists (e.g., without limitation, DEBIO nds, NM—811 as well as porine and its derivatives), kinase inhibitors, inhibitors of heat shock proteins (e. g., HSP90 and HSP70), other immunomodulatory agents that can include, without limitation, interferons (— alpha, beta, —omega, ~gamma, a or synthetic) such as Intron A, Roferon-A, Canferon— A300, Advaferon, Infergen, ron, Sumiferon MP, Alfaferone, lFN-fl, Feron and the like; polyethylene glycol derivatized (pegylated) interferon nds, such as PEG interferon-oz—Za ys), PEG interferori—a—Zb (PEGlntron), pegylated lFN~oz —conl and the like; long acting formulations and derivatizations of interferon compounds such as the albumin—fused eron, Albuferon, Locteron, and the like; interferons with various types of controlled delivery systems 3O (e. g., ITCA—63 8, omega-interferon delivered by the DUROS subcutaneous delivery system); compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of type 1 helper T cell response, such as SCV—07 and the like; TOLL—like receptor agonists such as CpG-lOlOl (actilon), isotorabine, ANA773 and the like; thymosin a-l; ANA—245 and ANA-246; histamine dihydrochloride; propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as c C, HCV ElEZ/MF59 and the like. In on, any of the described methods involving administering an NSSA inhibitor, a Type I interferon receptor agonist (e. g., an IFN—oz) and a Type II interferon receptor agonist (e.g., an IFN—y) can be augmented by administration of an effective amount of a TNF—oz nist. Exemplary, non—limiting TNF—a antagonists that are suitable for use in such combination therapies e , REMICADE, and HUMIRA.

In on, compounds of the invention can be used in combination with antiprotozoans and other antivirals thought to be effective in the treatment of HCV infection such as, without limitation, the prodrug nitazoxanide. 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 oz-Za and rin.

Compounds of the invention can also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e. g., tarabavarin, ron), microRNA, small interfering RNA compounds (e. g., SIRPLEX—l40-N and the like), nucleotide or nucleoside analogs, immunoglobulins, protectants, anti-inflammatory agents and other inhibitors of NSSA. Inhibitors of other targets in the HCV lifecycle include N83 helicase inhibitors; NS4A co~factor inhibitors; antisense oligonucleotide tors, such as ISIS—14803, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such as heptazyme, RPI, 13919 and the like; entry inhibitors such as HepeX—C, HuMax—HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT—23 1B and the like; KPE~02003002 and BIVN 401 and IMI’DH inhibitors. Other illustrative HCV inhibitor nds include those disclosed in the following publications: US. Pat. Nos. 5,807,876; 6,498,178; 6,344,465; and 6,054,472; PCT Patent Application ation Nos. WO97/40028; WO98/4038 1; WOOD/56331, WOO2/04425; W003/007945; WOO3/01014l; WOO3/000254; WOOl/32153; WOOD/06529; W000/1823l; W000/10573; WOOD/13708; WOOl/85172; WOO3/037893; WOO3/037894; W003/037895; W002/100851; W002/100846; WO99/01582; WOOO/09543; 8369; WO98/l7679, WOOO/056331; WO98/22496; WO99/07734; W005/073216, W005/073 195 and WOO8/021927. onally, combinations of, for example, rin and interferon, may be administered as multiple combination therapy with at least one of the compounds of the invention. The present invention is not limited to the aforementioned classes or nds and contemplates known and new compounds and ations ofbiologically active . It is intended that combination therapies of the present invention include any chemically compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the ive group, as long as the combination does not eliminate the anti-viral activity of the compound of this inventive group or the anti—viral activity of the pharmaceutical composition itself.

Combination therapy can be sequential, that is treatment with one agent first and then a second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agents) or it can be treatment with both agents at the same time (concurrently). Sequential therapy can include a reasonable time after the completion of the first therapy before beginning the second therapy. Treatment with both agents at the same time can be in the same daily dose or in separate doses. Combination therapy need not be limited to two agents and may include three or more agents. The dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism and excretion rates of the components of the combination y as well as other factors known to one of skill in the art. Dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage ns and les may be adjusted over time according to the individual’s need and the judgment of the one skilled in the art administering or supervising the administration of the combination therapy.

Described herein is a method for treating a Hepatitis C Virus (HCV) infection comprising stering to a patient in need thereof a therapeutically ive amount of a nd of any one of Formula I.

The above method may further comprise administering an immune system modulator or an antiviral agent that inhibits replication of HCV, or a combination thereof.

In the above method, the immune system modulator may be an interferon or chemically derivatized interferon.

In the above methods, the antiviral agent may be ed from the group consisting of a HCV se inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV e inhibitor, a HCV fusion inhibitor, and a combination thereof.

EXAMPLES General Conditions nds of the invention can be made by a variety of methods depicted in the illustrative synthetic reactions described below in the Examples section.

The staiting materials and reagents used in ing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis; Wiley & Sons: New York, 1991, Volumes l~15; Rodd's Chemistry ofCarbon nds, Elsevier Science Publishers, 1989, Volumes 1—5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes l—40. It should be appreciated that the synthetic reaction schemes shown in the Examples n are merely illustrative of some methods by which the compounds of the invention can be synthesized, and various modifications to these tic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this application.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, ion, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein are typically ted under an inert here at atmospheric pressure at a on temperature range of from about —78 °C to about 150 °C, often from about 0 °C to about 125 °C, and more often and conveniently at about room (or ambient) temperature, e.g., about 20 °C.

Various substituents on the compounds of the invention can be present in the starting nds, added to any one of the intermediates or added after formation of the final products by known methods of substitution or conversion reactions. If the substituents themselves are reactive, then the substituents can lves be protected according to the techniques known in the art. A variety of ting groups are known in the art, and can be employed. Examples of in. Organic Synthesis" by Green many of the possible groups can be found in "Protective Groups et al., John Wiley and Sons, 1999. For example, nitro groups can be added by nitration and the nitro group can be converted to other groups, such as amino by reduction, and halogen by diazotization of the amino group and replacement of the diazo group with halogen. Acyl groups can be added by Friedel—Crafts acylation. The acyl groups can then be transformed to corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction. Amino groups can be alkylated to form mono- and di-alkylamino form corresponding ethers. groups; and mercapto and hydroxy groups can be alkylated to Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or des, and secondary alcohols can be ed to form s. Thus, substitution or alteration reactions can be employed to provide a variety of substituents hout the molecule of the starting material, intermediates, or the final t, ing isolated products.

Abbreviations Abbreviations used in this application include: acetyl (Ac), acetic acid (HOAc), azo-bis- isobutyrylnitrile (AIBN), l~N—hydroxybenzotriazole , atmospheres (Atm), high pressure liquid chromatography (HPLC), 9—borabicyclo[3.3.l]nonane (9—BBN or BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert-butyl pyrocarbonate or boc ide (BOCzO), l-(3—dimethylaminopropyl)—3~ethylcarbodiimide hydrochloride (EDCI), benzoyl (Bz), benzyl (Bn), m—chloroperbenzoic acid (MCPBA), m-chlorobenzoic acid (MCBA), butyl (Bu), methanol , benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl diimidazole (CD1), MeSOz- (mesyl or Ms), l,4-diazabicyclo[2.2.2]octane (DABCO), mass spectrum (ms) diethylaminosulfur trifluoride (DAST), methyl t-butyl ether (MTBE), dibenzylideneacetone (Dba), N-carboxyanhydride (NCA), l,5—diazabicyclo[4.3.0]non-5—ene (DBN), N- bromosuccinimide (NBS), l,8—diazabicyclo[5.4.0]undecene (DBU), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), 1,2—dichloroethane (DCE), pyridinium chlorochromate (PCC), N,N'—dicyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC), romethane (DCM), propyl (Pr), diethyl azodicarboxylate (DEAD), phenyl (Ph), di-z‘so- propylazodicarboxylate inch (psi), di-iso—propylethylamine (DIPEA), , DIAD, pounds per square pyridine (pyr), di—iso-butylaluminumhydride room temperature, rt or RT, N,N— , DIBAL-H, dimethyl acetamide (DMA), tert—butyldimethylsilyl or t—BuMezsi, (TBDMS), 4—N,N- dimethylaminopyridine (DMAP), triethylamine (13th or TEA), N,N—dimethylformamide (DMF), triflate or CF3SOz— (Tf), dimethyl ide (DMSO), trifluoroacetic acid (TFA), 1,1 '—biS— (diphenylphosphino)ethane (dppe), 2,2,6,6-tetramethylheptane—2,6-dione (TMHD), is- (diphenylphosphino)ferrocene (dppt), thin layer tography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF), diethyl ether , trimethylsilyl or Megsi (TMS), ethyl (Et), p- toluenesulfonic acid monohydrate (TsOH or stOH), m thyl disilazane (LiHMDS), 4—Me—C6H4802- or tosyl (Ts), iso—propyl (i-Pr), N—urethane—N~carboxyanhydride (UNCA), ethanol (EtOH). Conventional nomenclature including the prefixes normal (n), iso (i—), secondary (580-), tertiary (tert—) and neo have their ary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford).

Preparative Examples Preparation 1 Preparation of intermediate chiral l~((2R,3S,4S,5S)—4—fluoro-3—hydr0xy—5—i0domethyl- ydro—furan—2-yl)— l H—pyri1nidine-2,4~dione F‘bH M.W. 356.09 C9H10FIN204 Chiral 3’—deoxy-3 ’- :l-fluoro-uridine (Green ChemPharma) (5.2 g, 21 mmol) and PPh3 (7.7 g, 29 mmol) were dissolved in CH3CN/Pyridine (95:5, 250 mL). Iodine (7.0 g, 27.5 mmol) was added and the reaction mixture was stirred at room temperature under N2 for 12 h. Water (80 mL) was added, and the solvent was evaporated to dryness under reduced pressure. Azeotropic distillation with CH3CN and then with CHC13 was performed to remove the ing water.

The residue was purified by silica gel column tography (2—4% EtOH in CH2C12) to give the title product (5 g).

IH NMR (300 MHz, DMSO—d6):6 11.45 (s, 1H), 7.72—7.69 (d, J=8.1Hz, 1H), 5.87—5.84 (d, J=8.1Hz, 1H), 5.74—5.71 (1n, 2H), 5.00—4.80 (dd, J = 54.3Hz, 4.2Hz, 1H), 4.53—4.41 (m, 1H), 4.32—4.19(m, 1H), 3.56-3.40 (in, 2H).

Preparation 2 Preparation of intermediate chiral 1—((2R,3 S,4S)fluoro-3—hydroxy~5—methylene— tetrahydro-furan-Z-yl)—l H—pyrimidine-ZA-dione N 0 F‘ bH M.W. 228.18 C9H9FN204 Chiral 1—((2R,3 S)—4—fluoro-3~hydroxy-5—iodomethyl-tetrahydro—furan—2—yl)- 1 H— pyrimidine—2,4—dione (10.7 g) in methanol (650 mL) was added NaOMe (16.2 g, 30 mmol). The reaction mixture was heated at reflux for 2 h. The mixture was cooled to room temperature, Resin (H+, washed by water) was added portionwise at 0 0C until pH reaches 6~7. The Resin was removed by ion and washed with methanol, and the e was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl 2O acetate as eluent) to give the title compound as a yellow solid (2.3 g) 1H NMR (300 MHz, DMSO-d6):5 11.53 (s, 1H), 7.79—7.76 (d, J=8.1Hz, 1H), 6.14—6.12(d, J=6.3Hz, 1H), 6.08-6.06 (d, z, 1H), 5.74—5.71 (d, J=8.1Hz, 1H), 5.40—5.19 (dd, J = 55.8Hz, 4.5Hz, 1H), 4.71-4.54 (m, 3H).MS [M+H]+ = 229.2 Preparation 3 Preparation of intermediate chiral 1—((2R,3S,4S,5S)—5—azido—4-fluoro~3-hydroxy iodomethyl—tetrahydro—furan—2—yl)-1H-pyrimidine-2,4-dione —36- N o F‘ ’/ M.W. 397.11 C9H9FIN504 [Bn(Et)3N]Cl (17 g, 75 mmol) and NaN3 (4.5 g, 69 mmol) were suspended in anhydrous CH3CN (200 mL) and stirred at room temperature overnight. The resulting fine suspension was filtered into a dry THF (30 mL) solution of chiral 1-((2R,3S,4S)-4~fluoro-3—hydroxy—5~ methylene-tetrahydro—furan—2~yl)—1H-pyrimidine—2,4—dione (2 g, 8.8 mmol). 4-methyhnorpholine (0.3 mL, 2.6 mmol) was added, the ing solution was cooled on an ice-water bath, and a solution of iodine (8 g, 31 mmol) in anhydrous THF (30 mL) was added dropwise over a period of 60 min. The reaction mixture was stirred at 0—9 0C for 16 h. N—Acetyl—L-cysteine was added, and the solution was stirred until bubbling subsided. The solvent was concentrated under reduced saturated aqueous NaHCOz pressure to half of the volume, then a solution of 0.1M NazSzO3 and solution were added. The mixture was extracted with H in CH2C12 and washed by brine.

The c layers were dried over , filtered and evaporated to dryness under reduced acetate pressure. The mixture was d by silica gel column chromatography [ethyl : CH2C12 :EtOH; 200:10023] to get crude d product. The crude product was purified by silica gel chromatography (0~3%EtOH in CH2C12) twice to give the title nd as a white solid (0.73 g, 21%) 1H NMR (300 MHz, CDCl3):5 9.09 (s, 1H), 7.38—7.35 (d, J=8.1Hz, 1H), 5.83—5.80 (d, J=8.1Hz, 1H), 5.76—5.75 (d, J=4.2Hz, 1H), 5.45—5.26 (dd, J = 52.2Hz, 5.7Hz, 1H), 4.84—4.77 (m, 1H) 3.60—3.48 (m, 1H). ation 4 Preparation of intermediate chiral 3—chloro-benzoic acid (2R,3S,4S,5R)—2-azid0—5-(2,4— dioxo-3 ,4-dihydro-2H-pyrimidinyl)fluoro~4-hydroxy-tetrahydro—fi1ranylmethy1 ester M.W. 425.76 C16H13C1FN506 A solution of chiral 1—((2R,3S,4S,5S)—5—azido—4—fluoro—3~hydroxy-5—iod0methyl- tetrahydro—furan—Z—yl)—1H~pyrimidine-2,4~dione (0.76 g, 1.9 mmol) in CH2Clz (120 mL) was combined with a mixture of (Bu)4NHSO4 (796 mg, 2.35 mmol) and m—chlorobenzoic acid (500 stirred vigorously at mg, 3.2mmol) in K2HPO4 (1.75 M, 40 mL). The two—phase system was room temperature and one n of m-chloroperbenzoic acid (3.6 g) [55% in balance with 3- chlorobenzoic acid (10%) and water (3 5%)] was added. After 1 h, 3x1.2 g of this reagent mixture was added at l h intervals. After the last addition, the mixture was vigorously stirred at room temperature for 18 h. The solution ofNa2$203 (0.1 M) and ted aqueous NaHCO3 were added (pH 7~8). The mixture was stirred vigorously at room temperature for 15 min. The organic layer was separated, and the water layer was extracted with CH2C12. The combined organic extract was washed with saturated aqueous NaHCO3. The organic layer was ted and trated under reduced pressure. The residue was purified by silica gel column chromatography (0~3%EtOH in CHzClz) to give the title compound as a white solid (0.35 g, 43%) 1H NMR (300 MHZ, CDC13)I5 9.00 (s, 1H), 8.09—7.91 (m, 2H), 7.59—7.56 (in, 1H), 7.44— 7.39 (m, 1H), 7.32-7.29 (d, ~l—"‘~8.le, 1H), 5.79—5.73 (m, 2H), 5.61-5.42 (dd, J = 51.9Hz, 5.7Hz, 1H), 4.81—4.78 (1n, 1H).

Preparation 5 Preparation of ediate chiral l—((2R,3S,4S,5R)—5—azid0-4—fluoro—3-hydroxy-5— hydroxymethyl—tetrahydro-furan—2—y1)~1H—pyriinidine—2,4-dione -3 8.

\‘ I F ’OH MW. 287.21 C9H10FN505 A on ofNH3 in MeOH (7N, 10 mL) was added to chiral 3-chlor0—benzoic acid (2R,3 S,4S,5R)—2~azido-S-(2,4-di0xo-3 ,4-dihydro—2H-pyrimidin-l —yl)—3 —4-hydroxy- tetrahydro-furan—2-ylmethyl ester (100 mg, 0.24 mmol). The reaction e was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by prep- HPLC to give the title compound as a white solid (34.5 mg, 51%) MS [M+H]Jr = 288.0; 1H NMR (300 MHz, DMSO—d6):5 11.52 (s, 1H), 7.84—7.82 (d, J=8.le, 1H), 6.18—6.15 (m, 2H), 5.88-5.77 (m, 2H), 5.23—5.03 (dd, J = 53.7Hz, 4.5Hz, 1H), 4.60-4.40 (m, 1H), 3.54-3.53 (d, J = 5.1 Hz,2H).

Preparation 6 Preparation of intermediate chiral benzoic acid (2R,3S,4S,5S)—5—azido-2—(2,4—dioxo—3,4- dihydro—ZH—pyrimidin— l —y1)-4—fluoro—5-iodomethyl~tetrahydro~furan-3~y1 esterine—2,4—dione M.W. 501.22 C16H13FIN505 To a solution of chiral ,3S,4S,5S)-5—azido—4-fluoro—3 -hydroxyiodomethyl- 2O tetrahydro—fi1ran—2-yl)~lH-pyrimidine—2,4—dione prepared in Preparation 3 (1.5 g, 3.78 mmol) and DMAP (0.87 g, 7.56 mmol) in dry THF (20 mL) under nitrogen atmosphere at 0 °C was added BzCl (0.67 inL, 5.67 mmol) dropwise. The reaction mixture was stirred at 0 °C for 5 min.

The mixture was then diluted with EA, washed with brine and s HCl (0.1 M). The organic layer was separated, dried over NazSO4 and concentrated. The residue was purified by silica gel chromatography column (PE : EA = 5 : l to 2 : 1) to afford the title compound as a white solid (1.78 g, 94 %).

MS [M+H]+ = 502 Preparation 7 Preparation of intermediate chiral benzoic acid (2R,3S,4S,5S)azido—2—(2,4—diox0—3,4~ dihydro—ZH—pyrimidin— l -f1uoro—5—benzoy1methyl~tetrahydro~furan~3 -y1 esterine—2,4—dione M.W. 495.43 C23H18FN507 To a mixture of chiral benzoic acid (2R,3S,4S,5S)—5—azido~2—(2,4—dioxo-3,4—dihydro—2H— pyrimidin- 1 —yl)-4—fluoro—5—iodomethyl-tetrahydro~furan—3-yl esterine-2,4—dione (1.78 g, 3 .55 mmol) in DMSO, sodium benzoate (2.56 g, 17.76 mmol) and 18~Crown-6 (0.187 g, 0.71 mmol) was added. The reaction mixture was heated under nitrogen at 100 0C for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate, then washed with brine and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE : EA = 5 : l) to afford the title compound as a white solid (1.30 g, 74 %).

MS [M+H]+ = 496 Preparation 8 ation of intermediate chiral no-l -((2R,3 R)azidofluoro-3 -hydroxy— 5—hydroxymethyl~tetrahydro—furan—2—yl)— l H—pyrimidin—2—one N;"‘ ¢ 4, F GE M.W. 286.22 C9H11FN604 To a solution of chiral benzoic acid (2R,3S,4S,5S)-5—azido—2-(2,4—dioxo~3,4—dihydro-2H— pyrimidin-l~y1)—4—fluoro-5—benzoylmethyl~tetrahydro—furan—3-y1 esterine-2,4—dione (0.2 g, 2.6 mmol) and razole (0.283 g, 26 mmol) in dry pyridine (5 mL) under en atmosphere at 0 0C was added 4—chlorophenylphosphorodichloridate (0.297 g, 7.9 mmol). The on mixture was stirred at 0 - 5 °C for 5 min, then allowed to warm to room temperature and stirred for 5 h.

The mixture was concentrated under reduced pressure. The residue was partitioned between DCM and saturated NaHCO3. The organic layer was separated, washed with brine, dried over Na2804 and concentrated to afford the crude lH-tetrazole intermediate 9 in Scheme 2 and used directly without further purification for next step. The lH-tetrazole product 9 (0.2 g) was dissolved in e (70 mL) at room temperature, NHszO (10 mL) was added. The reaction mixture was stirred at room ature for 0.5 h. TLC analysis ted the starting material was completely consumed. The solvent was d under reduced pressure, and the residue was dissolved in methanolic solution (7 N, 10 mL) of NH3. The reaction mixture was stirred at room temperature for 16 h. The mixture was trated, and the residue was purified by pre- HPLC to afford the title compound as a white solid (50 mg, 50 %).

MS [Mi—H]+ = 287.2; 1H NMR (300 MHz, DMSO—de):6 7752—7727 (d, l H, J= 7.5), 7352 (br, 2 H), 6220—6195 ((1, l H, J: 7.5), 6018-5997 ((1, l H, J= 6.3), 5816-5791 ((1, l H, J: 7.5), 5758-5719 (t, l H), 5195-5001 (dd, 1 H, J: 4.5, J: 53.4), 4548-4436 (m, l H), 3539—3462 (m, 2 H) Preparation 9 Preparation of intermediate chiral benzoic acid (2R,3S,4S,5R)-2—(2-acetylaminooxo- 1,6-dihydro-purinyl)azidofluorobenzoylmethyl-tetrahydro—furany1 ester M.W. 576.51 C26H21FN807 To a mixture ofN—(6—0xo-6,9—dihydro~1H—puriny1)—acetamide (154 mg, 0.8 mmol) in MeCN (20 mL) was added BSA (325 mg, 0.8 mmol). The mixture was heated at 60 °C until it became a clear on. A solution of chiral benzoic acid (2R,3S,4S,5S)azido-2—(2,4—dioxo~ 3 ,4—dihydro-2H—pyrimidin—1-y1)—4—fluoro—5-benzoylmethyl—tetrahydro-furan—3-y1 esterine-2,4— dione in Preparation 7 (200 mg, 0.4 mmol) in MeCN was added, followed by the addition of TMSOTf (357 mg, 1.6 mmol). The resulting reaction mixture was heated under ave irradiation at 100 °C for 1 h. The mixture was cooled to room temperature, then quenched with sat. NaHCO3 on (10 ml). The mixture was extracted with EA (10 ml><3). The organic layer was ted, washed with brine (10ml), dried with Na2804, and concentrated. The residue was purified by column chromatography (DCMzMeOH = 50:1) to afford the crude title compound (120 mg, 51%) LC-MS (M+H)+= 577.2; LC—MS (M+Na)+= 599.1 Preparation 10 Preparation of intermediate chiral 2-amino—9—((2R,38,4S,5R)—5—azido—4—fluoro-3~hydroxy- -hydroxymethyl-tetrahydro~fiiranyl)- 1 ,9—dihydro—purin~6—one <’ | NH HO N 0 NANHZ N,\"‘ F‘ $OH M.W. 326.25 C10H11FNgO4 To a solution of the crude chiral benzoic acid (2R,3S,4S,5R)—2—(2-acety1aminooxo—1 ,6- o—purin—9-y1)-5—azido-4—fluoro-5~benzoylmethyl—tetrahydro—furanyl ester (120 mg, 0.26 mmol) in MeOH (2 ml) was added methanolic solution (2 ml, 7 N) of a. The reaction mixture was stirred at 25°C for 18 h. TLC analysis indicated that the reaction was completed.

The mixture was concentrated in vacuo, purified by Pre—HPLC to afford the title compound as a white solid (15 mg, 22%).

LC—MS (M+H)+= 327.0 Example 1 Preparation of (S)-2~ {[(2R,3S,4S,5R)~2—azido~5~(2,4—dioxo—3,4—dihydro—2H-pyrimidin-1 - yl)-3 ~fluorohydroxy—tetrahydro—furan-2—y1methoxy]-phenoxy—phosphorylamino}~propionic acid isopropyl ester M.W. 556.45 C21H26FN609P Step A. opropyl 2—aminopropanoate hydrochloride (Oakwood, 300 mg, 1.95 mmol) and phenyl phosphorodichloridate ch, 397 mg, 280 pl, 1.79 mmol) was suspended in anhydrous DCM (10 mL). The reaction was cooled to ~78 0C. Triethylamine (3 62 mg, 498 pl, 3.58 mmol) was added dropwise. The reaction mixture was stirred at ~78 0C for 1 h, then allowed to warmed up to room temperature and stirred for 5 h. The solvent was removed, the residue was washed with dry ether. The filtrate was trated to give crude (28)—isopropyl 2— (chloro(phenoxy)phosphorylamino)propanoate as a light yellow oil (0.5 g, 91%) and used without further purification.

Step B.

To a solution of chiral 1—((2R,3S,4S,5R)Azido—4-fluoro—3—hydroxy-5—hydroxymethyl- tetrahydro-furan—2-yl)~lH—pyrimidine-2,4-dione prepared in Preparation 5 (54mg, 188 umol) in anhydrous THF (3.75 mL) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (470 pl, 470 nmol) dropwise. The mixture was stirred at room temperature for 15 min, then the THF solution (0.5 M) of crude (28)-isopropy1 2— (chloro(phenoxy)phosphory1amino)propanoate (940 pl, 470 nmol) was added dropwise. The reaction mixture was stirred at room ature for 3 h. Then MeOH (2 mL) was added. The solvent was d. The residue was purified by flash tography a gel, 40 g, 0— % MeOH in DCM) to give the title nd as a off—white solid (22 mg, 21%) LC—MS (M+H)+ = 557.0 Example 2 Preparation of (S)-2— { [(2R,3 S,4S,5R)—2-azido—5-(2,4—dioxo~3,4-dihydro-2H—pyrimidin- 1- yl)-3 —fluoro~4—hydroxy-tetrahydro-furan—2-ylmethoxy]—phenoxy—phosphorylamino } —propionic acid ethyl ester "0"?" 0 Ni0 r"/ NH O NA O O \‘ ’a F 0H M.W. 542.42 C20H24FN609P Step A.

(S)—Ethy1 2—aminopropanoate hydrochloride (Aldrich, 300 mg, 1.95 mmol) and phenyl phosphorodichloridate (Aldrich, 434 mg, 306 pl, 1.95 mmol) was suspended in anhydrous DCM (20 mL). The reaction was cooled to -78 OC. Triethylamine (395 mg, 544 nl, 3.91 mmol) was added dropwise. The reaction mixture was stirred at -78 0C for l h, then allowed to warmed up to room temperature and stirred for 5 h. The solvent was removed, the residue was washed with dry ether. The e was concentrated to give crude (2S)—ethyl 2— (chloro(phenoxy)phosphorylamino)propanoate as a light yellow oil (0.5 g, 88%) and used without further purification.

Step B.

To a solution of chiral 1-((2R,3S,4S,5R)—5-Azido—4—fluoro—3—hydroxy-5—hydr0xymethyl- tetrahydro-fura11yl)-1H-pyri1nidine-2,4-dione prepared in ation 5 (50mg, 174 umol) in anhydrous THF (5 mL) was added a THF on (Aldrich, 1 M) of tert-butylmagnesium de (435 pl, 435 mmol) dropwise. The mixture was stirred at room temperature for 15 min, then the THF solution (0.5 M) of crude (28)—ethyl 2- (chloro(phenoxy)phosphory1amino)propanoate (870 pl, 435 umol) was added dropwise. The reaction mixture was stirred at room temperature for overnight. Then MeOH (2 mL) was added.

The solvent was removed. The residue was purified by flash tography (silica gel, 40 g, 0- 15% MeOH in DCM) to give the title compound as an off—white solid (7 mg, 7.4%).

LC-MS (M+H)+ = 5430 Example 3 Preparation of (S)—2—[[(2R,3S,4S,5R)-2—azido(2,4-dioxo-3,4—dihydro—2H—pyrimidin y1)—3 —fluoro—4-hydroxy-tetrahydro—fi1ran—2—ylmethoxy]—(naphthalen- l —yloxy)—phosphorylamino] - propionic acid ethyl ester M.W. 592.48 C24H25FN609P Step A.

Naphthalen-l-ol (Aldrich, 0.72 g, 4.99 mmol) and phosphoms (V) oxychloride (Aldrich, 767 mg, 466 pl, 5.00 mmol) were suspended in anhydrous ether (20 mL), and the temperature was cooled to ~78 0C. Triethylamine (505 mg, 695 pl, 4.99 mmol) was added se and the reaction mixture was stirred at -78 0C for 0.5 h. The on mixture was warmed up to room temperature and stirred for overnight. The mixture was filtered, and the filtrate was concentrated to give crude naphthalen-l-yl phosphorodichloridate as a light yellow oil (1.3 g, 100%) and used for the next step without further purification.

Step B.

(S)—Ethy1 2—aminopropanoate hydrochloride (Aldrich, 300 mg, 1.95 mmol) and naphthalen- l—yl phosphorodichloridate (510 mg, 1.95 mmol) was suspended in anhydrous DCM (30 mL).

The reaction was cooled to —78 OC. Triethylamine (395 mg, 544 ul, 3.91 mmol) was added dropwise. The reaction mixture was stirred at —78 0C for l h, then allowed to warm up to room temperature and stirred for 5 h. The solvent was removed, and the residue was washed with dry ether. The filtrate was concentrated to give crude (ZS)—ethyl 2~(chloro(naphthalen—l— yloxy)phosphorylamino)propanoate as a light yellow oil (0.6 g, 90%) and used without further purification.

Step C.

To a solution of chiral l—((2R,3S,4S,5R)—5—Azido—4-fluorohydroxy—5-hydroxymethyl- tetrahydro-fiiran-Q—y1)—1H-pyrimidine-2,4—dione prepared in Preparation 5 (90 mg, 313 umol) in anhydrous THF (6.25 mL) was added a THF on (Aldrich, l M) of terr—butylmagnesium chloride (783 pl, 783 umol) se. The mixture was stirred at room temperature for 15 min, then the THF on (0.5 M) of crude (ZS)-ethy1 2-(chloro(naphtha1en—l- yloxy)phosphorylamino)propanoate (1.57 mL, 783 mmol) was added dropwise. The reaction mixture was stirred at room ature for 3 h. Then MeOH (2 mL) was added. The t was d. The residue was purified by flash chromatography (silica gel, 40 g, 0— 15% MeOH in DCM) to give the title compound as a light brown solid (70 mg, 38%).

LC-MS (M+H)+= 593.0 Preparation 11 Preparation of intermediate chiral 4—amino—l—((2R,3S,4S,5R)—5—azido-4—fluoro-5— hydroxymethyl—3 —triethylsi1anyloxy—tetrahydro~furan-2~yl)- l H-pyrimidin-Z—one —46- M.W. 400.49 C15H25FN604Sl To a solution of chiral 4-amino-l-((2R,3S,4S,5R)-5—azidofluorohydroxy-5~ hydroxymethyl—tetrahydro—fiiran—2—yl)-1H-pyrimidin-Z—one prepared in Preparation 8 (300 mg, 1.05 mmol) in pyridine (24.5 mL) at -5 0C was added chlorotriethylsilane (Fluka, 440 mg, 2.92 mmol) dropwise over a period of 15 min. The reaction mixture was stirred at 0 0C for 2 h, then quenched by the addition of methanol (5 mL). The mixture was purified directly by flashy chromatography (5—15% MeOH in DCM) to give the title compound as a white solid (0.29 g, 69%) Preparation 12 Preparation of ediate (S)~2-[[(2R,3S,4S,5R)~5~(4—amino—2—oxo—2H—pyrimidin—1-yl)— 2—azidofluoro—4-triethy1silanyloxy—tetrahydro~furan—2—ylmethoxy]-(naphtha1en- l —yloxy)- phosphorylamino]~propionic acid isopropyl ester M.W. 719.79 C31H43FN70$PSi Step A.

(S)—isopropy1 opropanoate hydrochloride (Oakwood, 0.706 g, 4.21 mmol) and naphthalen-l—yl orodichloridate prepared in Example 3 Step A (1.1 g, 4.21 mmol) was ded in anhydrous DCM (25 mL). The reaction was cooled to ~78 OC. Triethylamine (852 —78 0C for 1 h, mg, 1.17 ml, 8.42 mmol) was added dropwise. The reaction mixture was stirred at then warmed up to room temperature and stirred for 5 h. The solvent was removed, and the residue was washed with dry ethyl ether and filtered. The filtrate was concentrated to give crude (28)-isopropyl 2—(chloro(naphthalen—1-y1oxy)phosphorylamino)propanoate as a light yellow oil (1.3 g, 87%) and used without further purification.

Step B.

To a solution of chiral 4-amino—1—((2R,3S,4S,5R)—5-azido—4—fluoro—5—hydroxymethyl—3— triethylsilanyloxy-tetrahydro-furan—2-yl)-lH—pyrimidinone prepared in Preparation 11 (0.29 g, 724 umol) in anhydrous THF (42 mL) was added a THF solution (Aldrich, l M) of tert- butylmagnesium chloride (1 .8l mL, 1.81 mmol) se. The mixture was stirred at room temperature for 15 min, then the THF solution (0.5 M) of crude (ZS)—isopropyl 2— (chloro(naphthalen—l—yloxy)phosphorylamino)propanoate (3.62 mL, 1.81 mmol) was added dropwise. The on mixture was stirred at room temperature for 1 h, then followed by the addition ofTHF on (Aldrich, l M) of tert-butylmagnesium chloride (0.9 mL, 0.9 mmol) IO and THF solution (0.5 M) of crude (ZS)-isopropyl 2-(chloro(naphthalen yloxy)phosph0ry1amino)propanoate (1.81 mL, 0.9 mmol) sequentially. The reaction mixture was stirred at room temperature for additional 2 h. MeOH (5 mL) was added. The solvent was removed. The residue was purified by flash chromatography a gel, 40 g, 2—18% MeOH in DCM) to give the title nd as an off white solid (430 mg, 83%).

LC—MS (M+H)+= 720.3 Example 4 Preparation of (S)—2-[[(2R,3S,4S,5R)-5—(4-aminooxo—2H—pyrimidin-1—yl)—2-azido—3- fluoro-4—hydroxy—tetrahydro—furan—2—ylmethoxy] —(naphtha1en-1 ~yloxy)-phosphory1amino] ~ propionic acid pyl ester M.W. 605.52 C25H29FN708P (S)—2-[[(2R,3S,4S,5R)(4-Amino~2-oxo-2H—pyrimidiny1)azidofluoro triethylsilanyloxy-tetrahydro-furanylmethoxy]—(naphthalen- l -yloxy)-phosphorylamino] - nic acid isopropyl ester prepared in Preparation 12 (0.43 g, 597 umol) was dissolved into acetic acid (80%, 28 mL). The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure, and the residue acetic acid was removed by ~48- azeotropic concentration with MeOH three times. The residue was purified by flash chromatography (silica gel, 2—18% MeOH in DCM) to give the title compound as a white solid (0.2 g, 55%).

LC-MS (M+H)+ = 606.1 Example 5 Preparation of (S)—2—[[(2R,3S,4S,5R)—5—(4~amino—2~oxo-2H~pyrimidin-1—yl)—2—azido—3— fluoiro~4—hydroxy-tetrahydro—furan—2-ylmethoxy]—(naphthalen— 1 )~phosphorylamino] — propionic acid benzyl ester 97°er NH2 0 F‘N «t317x‘ NKO F OH M.W. 653.57 C29H29FN703P Step A.

(S)—Benzyl opropanoate hydrochloride (Chem lmpex, 0.66 g, 3.06 mmol) and alen-l-yl phosphorodichloridate prepared in Example 3 Step A (0.8 g, 3.06 mmol) was ded in anhydrous DCM (15 mL). The reaction was cooled to —78 0C. Triethylamine (619 mixture was stirred at -78 0C for l h, mg, 852 ul, 6.12 mmol) was added dropwise. The reaction then warmed up to room temperature and d for 5 h. The solvent was removed, and the residue was washed with dry ethyl ether and filtered. The filtrate was concentrated to give crude (ZS)— benzyl 2—(chloro(naphthalen—l~yloxy)phosphorylamino)propanoate as alight yellow oil (1 g, 81%) and used without further purification.

Step B.

To a solution of chiral 4-amino-l-((2R,3S,4S,5R)azidofluorohydroxy hydroxymethyl-tetrahydro-furany1)~1H—pyrimidinone prepared in Preparation 8 (85 mg, 292 umol) in anhydrous THF (8.5 mL) was added a THF solution (Aldrich, 1 M) of tert- hutylmagnesium chloride (742 uL, 742 umol) dropwise. The mixture was stirred at room temperature for 1 h, then the THF solution (0.5 M) of crude (2S)-benzyl 2-(chloro(naphtha1en—1 — yloxy)phosphorylamino)propanoate (1.48 mL, 742 umol) was added drOpwise. The reaction mixture was stiired at room temperature for 1 h, then followed by the addition of THF solution ch, 1 M) of tert—butylmagnesium chloride (371 uL, 371 umol) and THF solution (0.5 M) of crude (ZS)—benzy1 2—(chloro(naphthalen—1-yloxy)phosphorylamino)propanoate (0.74 mL, 371 umol) sequentially. The reaction mixture was stirred at room temperature for additional 2 h.

MeOH (2 mL) was added. The t was removed. The residue was purified by flash chromatography (silica gel, 0—20% MeOH in DCM) to give the title compound as a light yellow solid (10 mg, 5%).

LC—MS (M+H)+= 654.1 Example 6 Preparation of (S)—2-[[(2R,3S,4S,5R)(4-aminooxo-2H-pyrimidiny1)azido—3- fluoro—4-hydroxy—tetrahydro-furan—2-y1methoxy] ~(naphthalen- 1 —yloxy)—phosphorylamino]- propionic acid ethyl ester M.W. 591.50 C24H27FN703P To a solution of chiral o—1~((2R,3S,4S,5R)—5-azido—4—fluoro—3~hydroxy~5~ hydroxymethyl-tetrahydro~furan—2-yl)—1H—pyrimidin—2-one prepared in Preparation 8 (50 mg, 175 umol) in anhydrous THF (5 mL) was added a THF solution (Aldrich, l M) of terr— butylmagnesium chloride (437 uL, 437 umol) dropwise. The mixture was stirred at room ature for 15 min, then the THF solution (0.5 M) of crude (ZS)—ethyl 2—(chloro(naphthalen— 1—yloxy)phosphorylamino)propanoate prepared in e 3 Step B (873 uL, 437 umol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then followed by the addition of THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (219 uL, 219 umol) and THF on (0.5 M) of crude (ZS)-benzyl 2-(chloro(naphthalen—1— yloxy)phosphorylamino)propanoate (437 uL, 219 umol) sequentially. The reaction mixture was d at room temperature for additional 2 h. MeOH (2 mL) was added. The solvent was removed. The residue was purified by flash chromatography a gel, 0—1 6% MeOH in DCM) to give the title compound as a white solid (5 mg, 5%).

LC-MS (M+H)+ = 592.2 Example 7 Preparation of (S)—2-{[(2R,3 S,4S,5R)—5~(4—amino-2—oxo-2H—pyrimidin—l—y1)—2—azido—3— fluoro-4—hydroxy-tetrahydro-furan—2—y1methoxy]-phenoxy-phosphorylamino}—propionic acid isopropyl ester F‘ ’OH M.W. 555.46 C21H27FN708P To a solution of chiral 4-amino-l-((2R,3S,4S,5R)azidofluoro—3-hydroxy-5— hydroxymethyl-tetrahydro—fi1ran—2—yl)-lH—pyrimidin—2-one prepared in Example 8 (43 mg, 150 umol) in anhydrous THF (8 mL) was added a THF solution (Aldrich, 1 M) of tert— butylmagnesium de (376 uL, 376 umol) dropwise. The mixture was stirred at room temperature for 15 min, then the THF on (0.5 M) of crude (2S)—isopropyl 2— (chloro(phenoxy)phosphorylamino)propanoate prepared in Example 1 Step A (751 uL, 376 umol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then ed by the addition of THF solution (Aldrich, l M) of tert-butylmagnesium chloride (188 uL, 188 umol) and THE solution (0.5 M) of crude (2S)—benzyl 2—(chloro(naphthalen~l— phosphorylamino)propanoate (376 uL, 188 umol) sequentially. The reaction mixture was stirred at room temperature for ght. MeOH (2 mL) was added. The solvent was removed.

The residue was purified by flash chromatography (silica gel, 0—1 8% MeOH in DCM) to give the title compound as a white solid (3 mg, 4%).

LC-MS (M+H)+= 556.0 Preparation 13 Preparation of intermediate chiral 4—amino—1—[(2R,38,48,5R)—5-azido—3—(tert-butyl— diphenyl~si1anyloxy)—4—fluoro-5~hydroxymethyl—tetrahydro—furan-2—yl]- l H—pyrimidin-2—one M.W. 524.63 CstngN604Si To a solution of chiral 4-amino-1—((2R,3S,4S,5R)—5—azido—4—fluoro-3—hydroxy-5~ ymethyl-tetrahydro-furan~2~yl)-lH—pyrimidin—Z—one prepared in Example 8 (50 mg, 175 umol) and imidazole (119 mg, 1.75 mmol) in anhydrous DMF (2.62 mL) was added tert— butylchlorodipheny]silane (Aldrich, 480 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 20 min. The mixture was diluted with ethyl acetate, washed with water several times and brine. The organic layer was separated, dried over MgSO4, and concentrated.

The residue was purified by flashy chromatography (0-18% MeOI—l in DCM) to give the title compound as a white solid (36 mg, 39%) Preparation 14 ation of intermediate (S)—2-[[(2R,38,48,5R)-5~(4—amino—2—ox0-2H—pyrimidin—1~yl)- 0—4—(tert-butyl—diphenyl—silanyloxy)-3 ~fluoro—tetrahydro—furan—2—ylmethoxy]—(naphthalen— l-yloxy)-phosphorylamino]-propionic acid isopropyl ester M.W. 843.93 C41H47FN7OSPSi To a solution of chiral 4-amino—l-[(2R,3S,4S,5R)-5—azido-3—(tert-butyl—diphenyl— silanyloxy)fluoro—5—hydroxymethyl—tetrahydro-furan-Z-yl]-lH-pyrimidin—Z-one (20 mg, 38.1 umol) in anhydrous THF (4 mL) was added a THF solution ch, l M) of tar:- butylmagnesium chloride (95.3 uL, 95.3 umol) se. The mixture was stirred at room temperature for 15 min, then the THF solution (0.5 M) of crude (2S)-isopropyl 2— (chloro(naphthalen—1—yloxy)ph0sphorylamino)propanoate prepared in Preparation 12 Step A (191 ML, 95.3 umol) was added dropwise. The reaction e was stirred at room temperature for l h, then followed by the addition of THF on (Aldrich, l M) of terZ-butylmagnesium de (48 uL, 48 nmol) and THF solution (0.5 M) of crude (2S)—isopropyl 2- (ch10ro(naphthalen—l-yloxy)phosphorylamino)propanoate prepared in Preparation 12 Step A (96 ML, 48 nmol) sequentially. The reaction mixture was stirred at room temperature for ght.

MeOH (2 mL) was added. The solvent was removed. The residue was purified by flash chromatography (silica gel, 40 g, 2~18% MeOH in DCM) to give the title compound as a white solid (22 mg, 68%).

LC-MS (M+H)+ = 844.2 Example 8 Preparation of chiral (S){[(2R,3S,4S,5R)—5—(4-amino—2—oxo-2H—pyrimidin—l—yl)—2- azido-3—fluoro—4—hydroxy—tetrahydro—furan—2—ylmethoxy]~hydroxy—phosphorylamino}-propionic acid isopropyl ester M.W. 479.36 C15H23FN708P To a solution of (S)—2-[[(2R,3S,4S,5R)~5-(4-aminooxo-2H-pyrimidin—1-yl)—2-azido (tert—butyl—diphenyl-silanyloxy)fluoro-tetrahydro~furanylmethoxy] -(naphthalen-l -yloxy)- phosphorylamino]—propionic acid isopropyl ester (1 8 mg, 21.3 nmol) in THF (2.88 mL) was added a THF solution (1 M) of TBAF (21.3 nL, 21.3 nmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was d, and the residue was purified by Prep- HPLC to give the title compound as a white solid (6 mg, 59%).

LC-MS (M+H)+ = 479.9 Example 9 Preparation of [[(2R,38,48,5R)-5—(4—amino—2—oxo—2H~pyrimidin— 1 —y1)—2—azido-3— fluoro—4-propiony1oxy—tetrahydro—fi1ran—2—ylmethoxy]—(naphthalen—1 -yloxy)-phosph0rylamino] - propionic acid isopropyl ester 1—9 M.W. 661.59 C28H33FN709P To a on of chiral propionic acid (2R,38,48,5R)~2~(4—amino—2—oxo—2H—pyrimidin—1— yl)—5—azido—4—fluoro—5~11ydroxymethyl—tetrahydro-furan-3~yl ester ration will be disclosed separately, 25 mg, 73.0 umol) in anhydrous THF (5 mL) was added a THF solution (Aldrich, l M) of tert—butylmagnesium chloride (183 uL, 183 umol) dropwise. The mixture was stirred at room ature for 15 min, then the THF solution (0.5 M) of crude sopr0pyl 2— (chloro(naphtha1en—1-yloxy)phosphorylamino)propanoate prepared in Preparation 12 Step A (365 uL, 183 umol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then followed by the addition of THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (92 pL, 92 umol) and THF solution (0.5 M) of crude (ZS)—isopropy1 2- (chloro(naphthalen—1—yloxy)phosphory1amino)propanoate prepared in Preparation 12 Step A (183 uL, 92 umol) sequentially. The reaction mixture was stirred at room temperature for 2 h.

MeOH (2 mL) was added. The solvent was removed. The residue was purified by flash chromatography (silica gel, 40 g, 2—18% MeOH in DCM), then Prep—HPLC to give the title compound as a white solid (28 mg, 58%).

LC—MS (M+H)+= 662.2 Biological Examples HCV Replicon assay This assay measures the ability of the compounds of formula I to inhibit HCV RNA replication, and therefore their potential utility for the treatment of HCV infections. The assay es a reporter as a simple readout for intracellular HCV replicon RNA level. The Renilla luciferase gene was uced into the first open g frame of a genotype lb replicon construct NK5.1 (N. Krieger et (11., J. Virol. 2001 :4614), immediately after the internal ribosome entry site (IRES) sequence, and fused with the neomycin phosphotransferase (NPTH) virus (MD. Ryan & J. Drew, gene Via a self—cleavage peptide 2A from foot and mouth disease EMBO 1994 l3(4):928-933). After in vitro transcription the RNA was electroporated into human hepatoma Huh7 cells, and G418-resistant colonies were isolated and expanded. Stably selected cell line 2209—23 contains ative HCV subgenomic RNA, and the activity of Renilla luciferase expressed by the replicon reflects its RNA level in the cells. The assay was carried out in duplicate plates, one in opaque white and one in transparent, in order to measure the anti-viral activity and cytotoxicity of a chemical compound in parallel ensuring the observed activity is not due to decreased cell proliferation or due to cell death.

HCV replicon cells (2209-23), which express Rem‘lla luciferase reporter, were cultured in Dulbecco’s MEM (Invitrogen cat no. 010) with 5% fetal bovine serum (FBS, Invitrogen cat. no. 10082—147) and plated onto a 96-well plate at 5000 cells per well, and incubated overnight. -four hours later, different dilutions of chemical compounds in the growth medium were added to the cells, which were then further incubated at 37°C for three days. At the end of the tion time, the cells in white plates were harvested and luciferase activity was measured by using the R. lucz’ferase Assay system (Promega cat no. E2820). All the ts described in the following aph were included in the manufacturer's kit, and the manufacturer’s instructions were ed for preparations of the reagents. The cells were washed once with 100 uL of phosphate buffered saline (pH 7.0) (PBS) per well and lysed with pl of 1x R. erase Assay lysis buffer prior to incubation at room ature for 20 min.

The plate was then inserted into the Centro LB 960 microplate luminometer (Berthold 3O Technologies), and 100 ul of R. lucz‘ferase Assay buffer was injected into each well and the signal measured using a 2—second delay, 2—second measurement program. leo, the concentration of the drug required for reducing replicon level by 50% in relation to the untreated cell control value, can be calculated from the plot of percentage reduction of the luciferase activity vs. drug concentration as described above.

WST—l reagent from Roche Diagnostic (cat no. 1644807) was used for the cytotoxicity assay. Ten microliter of WST-l reagent was added to each well of the transparent plates including wells that contain media alone as blanks. Cells were then incubated for 2 h at 37° C, and the OD value was measured using the MRX Revelation microtiter plate reader (Lab System) at 450 nm (reference filter at 650 nm). Again CCso, the concentration of the drug required for reducing cell proliferation by 50% in relation to the untreated cell control value, can be calculated from the plot of percentage reduction of the WST-l value vs. drug concentration as described above.

Representative biological data are shown in Table 11 below: TABLE H.

Compound (uM) CCso (uM) l—l >100 >100 1-2 39.805 >100 1-3 79.095 >100 [.4 >100 >100 1—5 1.53875 91.2 1—6 32 >100 1-7 56 >100 1-8 >100 >100 1—9 27 58 It will be tood that nces herein to ent extend to prophylaxis as well as to the treatment of existing conditions, and that the treatment of s includes the treatment of humans as well as other s. Furthermore, treatment of a Hepatitis C Virus (HCV) infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or ed by Hepatitis C Virus (HCV) infection, or the clinical symptoms thereof. —56— The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, sed in their specific forms or in terms of a means for perfonning the disclosed function, or a method or process for attaining the disclosed result, as appropriate, utilized for realizing the invention in may, separately, or in any combination of such features, be diverse forms thereof.

The foregoing ion has been described in some detail by way of illustration and e, for purposes of clarity and understanding. It will be obvious to one of skill in the an that changes and modifications may be practiced within the scope of the ed claims.

Therefore, it is to be understood that the above ption is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the hill scope of equivalents to which such claims are entitled.

A11 patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each dual patent, patent application or publication were so dually denoted.

Claims (19)

A compound of a I wherein: R] is H, lower haloalkyl, or aryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo, lower haloalkyl, )2, acylainino, ~SOgN(R1a)2, 4:011”), l°), - NHSOz(R‘°), nitro or cyano; each Rla is independently H or lower alkyl; 10 each Rlb is independently -ORla or —N(Rla)2; each R1c is lower alkyl; R221 and R21) are (1') independently H, lower alkyl, -(CH2)rN(R'a)2, lower hydroxyalkyl, —CH28H, -(CH2)S(O)pMe, -(CH2)3NHC(=NH)NH2, (lH—indol—B- yl)met11yl, (lH—indolyl)methyl, —(CH2)mC(=O)Rlb and aryl lower alkyl, wherein , aryl 15 aryl may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R2:11 is H and R21) and R4 together form (CH2)3; (iii) R221 and R2b together form (CH2)n; or, (iv) R2a and R21) both are lower alkyl; R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl; R4 is H, lower alkyl, or R2b and R4 together form (CH2)3; 20 R5 is H, C(=O)R‘C, C(=O)Rlb or P(=O)(OR1)(OR“‘); R6 is o NH2 HN N’

1.A | A l EN{NH\ N’ NH2 0 N O N l u | . 01‘ * a * 9: , in is 0 to 3; nis4or5; -58— p is 0 to 2; and r is 1 to 6; or a pharmacologically acceptable salt thereof. 5

2. The compound of claim 1, wherein R4 is H.

3. The compound of claim 2, wherein R6 is o NH2 HNJ] N2] 0 i}: 0 1? >‘.- 01’ ax: 10

4. The compound of claim 3, wherein R1 is naphthyl or phenyl.

5. The compound of claim 4, wherein R2a is H.

6. The compound of claim 5, wherein R21) is methyl.

7. The compound of claim 6, n R3 is isopropyl, ethyl, or benzyl.

8. The nd of claim 7, wherein R5 is H. 20

9. The compound of claim 7, wherein R5 is C(=O)Rlc.

10. The compound of claim 9, wherein R1C is ethyl.

11. The compound of claim 8, n R6 is HN/u] O N

12. The compound of claim 8, wherein R6 is

13. The compound of claim 2, wherein R6 is if“/ / N N NH2

14. A compound according to claim 1, selected from the group consisting of: (S)—2— {[(2R,3 S,4S,5R)—2-Azido~5-(2,4—dioxo—3,4~dihydro-2H—pyrimidinyl)—3-fluoro—4~hydroxy- tetrahydro-furan—2-ylmethoxy]—phenoxy—phosphory1amino } ~propionic acid isopropyl ester; (S)—2- { [(2R,3 S,4S,5R)—2-Azido—5-(2,4-dioxo-3 ,4—dihydro—2H—pyrimidin-1—yl)—3—fluoro—4—hydroxy— tetrahydro-furan-Z-ylmethoxy]-phenoxy—phosphory1amino}-propionic acid ethyl ester; (S)—2—[[(2R,3 R)—2—Azido—5-(2,4—dioxo~3 ,4-dihydro~2H~pyrimidiny1)~3-fluorohydroxy— tetrahydro-furan—2—ylmethoxy]~(naphthalen—1-yloxy)—phosphorylamino]—propionic acid ethyl ester; (S)~2-[[(2R,3S,4S,5R)—5-(4—Amino—2~oxo—2H~pyrimidin~1—y1)-2—azido—3-fluoro-4—hydroxy— tetrahydro—furan—2-y1methoxy]-(naphthalenyloxy)-phosphory1amino] —propionic acid isopropyl ester; (S)—2—[[(2R,3S,4S,5R)—5—(4-Amino-2~oxo—2H—pyrimidin—1—y1)—2-azido—3—fluoro-4—hydroxy— tetrahydro—furan—Z-ylmethoxy]-(naphthalen~1-yloxy)~phosphorylamino]—propionic acid benzyl ester; (S)—2—[[(2R,3S,4S,5R)-5—(4—Amino-2—oxo—2H-pyrimidin~1-yl)azido-3—fluoro—4~hydroxy— tetrahydro—furan—Z—ylmethoxy]—(naphthalen~1-yloxy)—phosphorylamino]—propionic acid ethyl ester; (S)—2— 3 S,4S,5R)—5—(4-Amino—Z-oxo—ZH—pyrimidin—1—yl)azidofluoro—4~hydroxy- tetrahydro-furan-2—y1methoxy]-phenoxy-phosphory1amino } -propionic acid pyl ester; (S)—2— {[(2R,3 S,4S,5R)(4-Amino0xo-2H—pyrimidin—1-yl)azid0-3 ~fluoro-4—hydroxy— tetrahydro—furan—Z—ylmethoxy]—hydroxy-phosphorylamino}—propionic acid isopropyl ester; and -60— [[(2R,3 S,4S,5R)—5—(4—Amino—2-0xo-2H—pyrimidin—1—yl)azido—3 —fluoro—4—propiony10xy— tetrahydro-furan—2—ylmethoxy]~(naphthalen—1—yloxy)—phosphory1amino]-propionic acid isopropyl ester.

15. The use of a compound ing to any one of claims 1—14 for the preparation of a medicament for the treatment or prophylaxis of Hepatitis C Virus (HCV) infection. 5

16. A compound according to any one of claims 1-14 for the treatment or prophylaxis of Hepatitis C Virus (HCV) infection.

17. A pharmaceutical composition comprising a compound of any one of claims 1-14 and therapeutically inert carriers.

18. A use according to claim 15 substantially as herein described with reference to any example thereof.

19. A pharmaceutical composition ing to claim 17 substantially as herein described 15 with reference to any example thereof.