NZ625342B2 - 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication - Google Patents

Abstract

Provided are 2',4'-difluoro-2'-methyl 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-{[(2S,3S,4R,SR)-S-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxyphosphorylamino}-propionic acid isopropyl ester and (S)-2-[[(2S,3S,4R,SR)-S-(S-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester. The compounds are inhibitors of hepatitis C virus (HCV) RNA replication. oxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxyphosphorylamino}-propionic acid isopropyl ester and (S)-2-[[(2S,3S,4R,SR)-S-(S-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester. The compounds are inhibitors of hepatitis C virus (HCV) RNA replication.

Description

Case 30770 2',4'-Difluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication FIELD OF THE INVENTION The invention relates to side derivatives as inhibitors ofHCV replicon RNA replication. In particular, the invention is concerned with the use of purine and pyrimidine side tives 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 e throughout the world.

Patients ed with HCV are at risk of developing cirrhosis of the liver and subsequent hepatocellular carcinoma and hence HCV is the major indication for liver transplantation.

Only two approved ies are currently available for the treatment ofHCV infection (R.

G. Gish, Sem. Liver. Dis., 1999, 19, 35). These are interferon-0t monotherapy and, more recently, combination therapy of the nucleoside analogue, ribavirin (Virazole), with interferon-0t.

Many of the drugs ed for the treatment of viral ions are nucleosides or nucleoside ues and most ofthese nucleoside analogue drugs inhibit viral replication, following conversion to the ponding triphosphates, through inhibition of the viral polymerase enzymes. This sion to the triphosphate is commonly mediated by cellular kinases and therefore the direct evaluation of sides as inhibitors ofHCV 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 ofprogeny RNA. It is believed that most of the non—structural proteins encoded by the HCV RNA genome are involved in RNA replication.

Lohmann et al. [V. Lohmann et al., Science, 1999, 285, 110—113] have described the construction of a Human Hepatoma (Huh7) cell line in which subgenomic HCV RNA JZ/3l.08.2012 les have been introduced and shown to replicate with high efficiency. It is believed that the mechanism ofRNA ation in these cell lines is identical to the replication of the full length HCV RNA genome in infected hepatocytes. The subgenomic HCV cDNA clones used for the ion of these cell lines have formed the basis for the development of a cell- based assay for identifying nucleoside analogue inhibitors ofHCV replication.

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

The ation provides a compound of Formula I 1 6 23R2b$ R . '5 "O A I R3/O NI \0 O N I4 0 RLO‘ ’F R1 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, acylamino, — SOzN(R‘a)2, -COR"’, ~SOz(R1C), —NHSOz(R1°), nitro or cyano; each RIa is independently H or lower alkyl; each Rlb is independently -OR1a or ~N(R‘a)2; each R1C is lower alkyl; R22‘ and R2b are (1') independently H, lower alkyl, —(CH2)rN(RIa)2, lower hydroxyalkyl, -CH2$H, ~(CH2)S(O)pMe, —(CH2)3NHC(=NH)NH2, (1H— indolyl)methyl, (lH—indolyl)methyl, -(Cl-I2)mC(=O)Rlb and aryl , aryl lower alkyl, wherein aryl may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R221 is H and R2b and R4 together form (CH2)3; (iii) R221 and R2b together form (CH2)n; or, (iv) R2a and R2b both are lower alkyl; R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl; R4 is H, lower alkyl, or sz and R4 together form (CH2)3; R5 is H, C(=O)R‘°, C(=O)R1b or , P(=O)(OR1)(ORla), P(=0)(0R1)(NR4R7); R6 is H, methyl, or halo; R7 is C(RZaRZb)c00R3 m is O to 3; n is 4 or 5; p is 0 to 2; and r is l to 6; or a pharmacologically acceptable salt thereof.

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

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

ED DESCRIPTION OF THE INVENTION The compounds ofFormula 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 ofHCV ions in human.

The term " as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms. Preferably, the term "alkyl" denotes a ht or branched chain hydrocarbon residue ning 1 to 7 carbon atoms. Most preferred are methyl, ethyl, propyl, isopropyl, n—butyl, yl, tert. ~buty1 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 cycloalkyl carbonyl.

The term "cycloalkyl" as used herein s an optionally substituted cyclo alkyl group containing 3 to 7 carbon atoms, e. g. ropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

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

The term "alkoxyalkyl" 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, methyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, xybutyl, tert. —butyloxybuty1, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers.

The term "alkenyl" 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 olefinic double bonds, preferably one olefinic double bond. Examples are vinyl, 1-propeny1, 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, ably 2 to 4 carbon atoms, and having one or where possible two triple bonds, preferably one triple bond. es are ethynyl, l— propynyl, ynyl, l-butynyl, 2«butynyl or 3—butynyl.

The term "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 hydroxymethyl, l-hydroxyethyl, 2—hydroxyethyl, 1—hydroxypropy1, 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 l, 2, 3 or more hydrogen atoms are substituted by a halogen.

Examples are l—fluoromethyl, l—chloromethyl, l-bromomethyl, 1—iod0methy1, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, l-fluoroethyl, l—chloroethyl, l—bromoethyl, l—iodoethyl, Z—fluoroethyl, 2-chloroethyl, 2—br0moethyl, 2—iodoethyl, 2,2- roethyl, 3-bromopropyl or 2,2,2-trifluoroethyl and the like.

The term "alkylthio" as used herein denotes a ht or branched chain (alkyl)S- group wherein the "alkyl" portion is as defined above. Examples are methylthio, ethylthio, n- propylthio, i—propylthio, mbutylthio, i-butylthio or tert.-buty1thio.

The term "aryl" as used herein denotes an optionally substituted phenyl and yl (e. be selected from g. thy1, thyl or 3-naphthyl). Suitable substituents for aryl can those named for alkyl, in addition however, halogen, hydroxy and optionally substituted alkyl, haloalkyl, l, alkynyl and aryloxy are substituents which can be added to the selection.

The term "heterocyclyl" as used herein denotes an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocyclic systems which contain one or more hetero atoms selected fi'om nitrogen, oxygen and sulfur which can also be fused to an optionally substituted ted, partially unsaturated or aromatic monocyclic carbocycle or heterocycle.

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

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

The term "acyl" lcarbonyl")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 ht chain or hydrocarbon residue containing 1 to 4 carbon atoms or a phenyl group.

The term halogen stands for fluorine, chlorine, bromine or iodine, able fluorine, chlorine, bromine.

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

Compounds of formula I exhibit stereoisomerism. These compounds can be any isomer ofthe compound of a 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 formula I exhibit 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 n two other atoms, to either ofwhich it forms a covalent bond. Tautomeric compounds exist in a mobile brium 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 al ties to be expected on the basis of the structures of the components.

The most common type of tautomerism is that involving carbonyl, or keto, nds and unsaturated hydroxyl compounds, or enols. The structural change is the shift of a hydrogen atom between atoms of carbon and oxygen, with the rearrangement ofbonds. 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.

Compounds of a 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, tartaric 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 carried out according to methods known in the art. tors ofHCV The application provides a compound of Formula I 115/0 F 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 l, lower alkoxy, halo, lower haloalkyl, ~N(RI")2, acylamino, - SOzN(Rla)2, ~COR1b, IC), —NHSOz(R]°), nitro or cyano; each Rla is independently H or lower alkyl; each R1b is independently -OR1a or —N(R"‘)2; each R1‘: is lower alkyl; R23 and R21) are (1') independently H, lower alkyl, -(CH2),-N(Rla)2, lower hydroxyalkyl, -CHzSH, -(CH2)S(O)pMe, —(CH2)3NHC(=NH)NH2, (1H- indol—3-yl)methyl, (lH—indol—4—yl)methyl, —(CH2)mC(=O)Rlb and aryl , aryl lower alkyl, wherein aryl may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R221 is H and R21) and R4 together form (CH2)3; (iii) R2a and R2b er form (CH2)n; or, (iv) R2"1 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)R1°, C(=O)R1b or , P(=O)(OR‘)(OR"‘), P(=O)(OR‘)(NR4R7); R6 is H, methyl, or halo; R7 is C(RZaRZb)COOR3 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 ation provides a compound of Formula I, wherein R4 is H.

The application provides a compound of Formula I, wherein R6 is H or Br.

The application provides a compound of Formula I, wherein R6 is H.

The application provides a nd of Formula I, wherein R6 is Br. 2O The application provides a compound of Formula I, wherein R4 is H and R6 is H or Br.

The ation provides a compound of Formula I, wherein R4 is H and R6 is Br.

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 compound of Formula I, wherein R1 is phenyl.

The application es a nd of Formula I, n R1 is phenyl and R4 is H.

The application provides a nd of Formula I, wherein R1 is phenyl, R6 is H, and R4 is H.

The ation provides a compound of Formula I, n R1 is naplithyl and R4 is H.

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

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

The application provides a compound of Formula 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, R6 is H, and R3 is pyl.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R221 is H, and R3 is isopropyl.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R23 is H, R2b is methyl, and R3 is isopropyl.

The application provides a compound of Formula I, n R5 is H.

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

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

The application provides a compound of Formula I, n R1 is naphthyl, R4 is H, R6 is H, and R5 is H.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R221 is H, and R5 is H.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R23 is H, R2b is , and R5 is H.

The application es a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R2‘1 is H, R2b is methyl, R3 is pyl, and R5 is H.

The application provides a compound of Formula I, wherein R5 is C(=O)R1°.

The application provides a compound of Fonnula I, wherein RI is naphthyl, R4 is H, R6 is H, R23 is H, sz is methyl, R3 is pyl, and R5 is C(=O)RIC.

The application provides a compound of Formula I, wherein RIc is ethyl.

The application provides a compound of Formula I, n R1 is naphthyl, R4 is H, R6 is H, R2101 is H, R213 is , R3 is isopropyl, and R5 is H2CH3.

The application provides a compound of Formula I, wherein R5 is P(=O)(OR1)(NR4R7).

The application provides a compound of Formula I, n R1 is naphthyl, R4 is H, R6 is H, R2a is H, R2b is methyl, R3 is isopropyl, and R5 is P(=O)(OR1)(NR4R7).

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

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R23 is H, R2b is methyl, R3 is isopropyl, R5 is P(=O)(OR‘)(NR4R7), and R1 is naphthyl.

The application provides a compound of Formula I, wherein R4 is H and R7 is CH(CH3)C(=O)OCH(CH3)2.

The application provides a compound of Formula I, wherein R1 is naphthyl, R4 is H, R6 is H, R261 is H, R2b is methyl, R3 is isopropyl, R5 is P(=O)(OR‘)(NR4R7), R] is naphthyl, R4 is H and is R? is CH(CH3)C(=O)OCH(CH3)2.

The application provides a compound selected from the group consisting of: (S) 3 S,4R,5R)(2,4-Dioxo-3 ,4-dihydro-2H—pyrirnidiny1)-2,4-difluoro-3 - hydroxymethy1-tetrahydro-furan—2-ylmethoxy]~phenoxy—phosphorylamino } ~pr0pionic acid pyl ester; (S)—2—[[(ZS,3S,4R,5R)—5-(2,4—Diox0—3 ,4-dihydro—2H-pyrimidin—1—y1)—2,4—difluoro—3 — hydroxy—4-1nethy1-tetrahydro—fiiran—Z—yhnethoxy]—(naphthalen— 1 -y10xy)— phosphorylamino]~pr0pionic acid isopropyl ester; (S)—2—[[(ZS,3S,4R,5R)—5—(2,4-Dioxo-3,4-dihydro-2H—pyrimidin—1—y1)—2,4-difluoro-3 — ymethyl-tetrahydro-furan-2—yhnethoxy]-(naphtha1en—2—y10xy)- orylamino]-pr0pionic acid isopropyl ester; (S)—2~[[(ZS,3S,4R,5R)—5-(2,4-dioxo-3 ,4—dihydro~2H—pyrimidin-1—y1)—2,4—difluoro-3 — [((S)— 1—isopr0poxycarbonyl-ethylainino)-(naphthalen—2—y10xy)-phosphorylo xy]—4-inethyl- tetrahydro—furan-2—y1methoxy]-(naphtha1en—2—y10xy)-phosphorylamino]—propionicacid isopropyl ester; (S)-2—[[(ZS,3 S,4R,5R)(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1—y1)—2,4-difluoro methylpropionyloxy-tetrahydro-fi1ran—2-y1methoxy]-(naphtha1en- l -y10xy)- phosphorylamino]-pr0pi0nic acid isopropyl ester; (S)~2-[(S)—[(2S,3S,4R,5R)-5~(2;4—Dioxo-3,4-dihydro-2H-pyrimidin—1—y1)-2,4— difluoro—3—hydr0xy—4—methyl-tetrahydro~fi1ran—2—yhnethoxy]—(naphtha1en—2—yloxy)— phosphorylamino]—propionic acid pyl ester; (S)-2—[(R)~[(.’ZS,3 S,4R,5R)—5—(2,4-Di0X0—3 ,4—dihydr0—2H—pyrimidin-1—yl)-2,4— diflu0r0~3—hydroxy—4~1nethy1~tetrahydro~fi1ran-2—y1methoxy]—(naphthalen—2—yloxy)~ phosphorylamino]—propionic acid isopropyl ester; (S)-2—[(R)—[(ZS,3 S,4R,5R)(2,4-Dioxo—3 ,4—dihydr0—2H-pyrimidin~1~y1)—2,4— difluoro—3-hydroxy1nethyl-tetrahydr0—furan—2—yhnethoxy]-(naphthalenyloxy)- phosphorylamino]~propionic acid pyl ester; (S)[(S)-[(ZS,3 S,4R,5R)—5-(2,4-Di0x0—3 ,4—dihydr0-2H—pyrimidiny1)-2,4- difluorohydroxyrnethyl-tetrahydro-furanylmethoxy]-(naphtha1en- 1 ~y10xy)— phosphorylamino]-propionic acid isopropyl ester; (S)-2— {(S)-[(ZS,3 S,4R,5R)—5—(2,4-Dioxo—3 ,4-dihydro-2H—pyrimidin— 1 -y1)—2,4- difluoro-3—hydr0xy—4—methy1—tetrahydro~furan—2—yhnethoxy]~phenoxy—phosphorylamino } — propionic acid isopropyl ester; (S) {(R)-[(ZS,3 R)—5-(2,4—Dioxo-3 ,4—dihydro—2H—pyrimidiny1)-2,4- difluoro—3—hydroxy—4—methyl—tetrahydro-furanylmeth0xy]~phenoxy-phosphorylamino } — nic acid isopropyl ester; (S)[(S)-[(2S,3 S,4R,5R)-5—(5-Bromo-2,4-dioxo-3,4—dihydro-2H—pyrimidiny1)- 2,4—difluoro—3—hydroxy-4—methyl—tetrahydro-fiiran—2-ylmethoxy]—(naphtha1en— 1 —yloKy)— phosphorylamino]-propionic acid pyl ester; (S)-2—[(S)—[(ZS,3 R)—5-(5~Bromo-2,4—dioxo—3 ,4—dihydro~2H—pyrimidin—1 —y1)- 2,4—difluoro-3—hydroxymethyl—tetrahydro~furan—2—ylmethoxy]~(naphthalen-2—yloxy)— phosphorylamino]—propionic acid isopropyl ester; (S)[(R)-[(ZS,3 S,4R,5R)(5-Bromo-2,4~dioxo—3,4-dihydro—2H-pyrimidin— l —yl)— 2,4—difluoro—3-hydroxy—4~methyl-tetrahydro-furan—2-ylmethoxy]—(naphthalen— 1 —yloxy)— phosphorylamino]-propionic acid isopropyl ester; (S)-2—[(R)—[(ZS,3 S,4R,5R)-5—(5—Bromo-2,4-dioxo-3,4-dihydro-ZH-pyrimidin— 1 -yl)- 2,4-difluorohydr0xy—4—methyl-tetrahydro—fiiranylmethoxy]-(naphthalen—2-yloxy)— orylamino]-propionic acid isopropyl ester; and (S)—2—[[(28,3S,4R,5R)(5-Bromo-2,4—dioxo-3 ,4-dihydro-2H—pyrimidin- l -y1)-2,4- difluoro—3~hydroxymethyl-tetrahydro—fi1ranylmethoxy]-(naphthalenyloxy)- phosphorylamino]—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 eutically effective amount of a compound 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 tized interferon.

In the above methods, the antiviral 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 combination thereof.

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

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

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

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

Compounds Examples ofrepresentative compounds encompassed by the present invention and within the scope of the invention are provided in the following Table. These es 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 rative and representative thereof.

In general, the nomenclature used in this Application is based on MTM v.4.0, a Beilstein Institute computerized system for the generation ofIUPAC systematic nomenclature. If there is a discrepancy between a ed structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

TABLE I depicts examples of compounds according to c Formula I. nd no. Structure Name J 0 0 (S){[(ZS,3S,4R,5R)—5-(2,4- Q’s/NR / NH Dioxo-3,4-dihydro-2H—pyrimidin- N-fl l-yl)-2,4-d1fluorohydroxy—4- I—l O methyl-tetrahydro—furan—2- ylmethoxy]—phenoxy— orylamino } —propionic acid isopropyl ester (S)—2—[[(28,3S,4R,5R)(2,4- Di0x0-3,4-dihydr0-2H-pyrimidin- Ii 1-y1)-2,4-difluoro-B—hydroxy 1-2 N 0 methyl-tetrahydro-furan-Z— C O F ylmethoxy]—(naphthalen— 1 -y10 xy)- 00‘ 9F phosphorylamino]—propi0nic acid isopropyl ester 4 0 0 H 9 (S)[[(23,3S,4R,5R)(2,4- 0 N‘ ~ (/4 NH 3,4—dihydro-2H—pyrimidin~ O N 0 1—y1)-2,4—diflu0ro—3—hydr0xy—4— 1-3 0 F" methyl-tetrahydro—furan~2— 0 Ho‘ ’F ylmethoxy]-(naphthalen~2—yloxy)— phosphorylamino]-propi0nic acid isopropyl ester )‘O’KrN‘g-o N1H (S)-2—[[(ZS,3S,4R,5R)—5-(2,4— d10x0-3,4—d1hydro—2H—pyr1m1d1n—1—. . . . . 0 O o' F" yl)-2,4-difluoro—3—[((S)-1— O 6 9F isoprop0xycarbonyl-ethylamino)— I H 0 1-4 Gag-NJ (napl1thalenyloxy)- O 0 g 01/ phosphoryloxy]—4-methy1— O tetrahydro-furan—Z-ylmethoxy]- O (naphthalen—Z—yloxy)— phos horylamino]—propionic acidP isopropyl ester 4 o (VS/N}? / «0 (S)—2—[[(23,3S,4R,5R)—5—(2,4— Ib’ko NH H Di0x0~3,4-dihydro-2H—pyrimidin- O ' O 1-y1)-2,4—d1flu01o~4—methy1—3~.

CO \ ,, propionyloxy~tetrahydro-fi1ran—2— F yhnethoxy]—(naphthalen- 1 —y10xy)— 0 phosphorylamino]~propionic acid isopropyl ester A 0 0 #N"9 fl (S)—2-[(S)—[(ZS,3S,4R,5R)—5-(2,4— 0 / ~ H Diox0—3,4—dihydr0~2H—pyrimidin— 0 2,4-difluoro—3-hydroxy—4- \ 0 1-6 0 F‘ -tetrahydro—furan—2- 0 Ho‘ ’17 yhnethoxy]-(naphthalenyloxy)- orylamino]-pr0pionic acid isopropyl ester /< O 9 (—(O (S)—2—[(R)-[(28,3S,4R,5R)(2,4- O 1%;P~ / H Dioxo-3,4-dihydro-2H—pyrimidin— O 1—y1)-2,4-diflu0ro—3-hydroxy 1-7 0 0 F" methyl-tetrahydro—fi1ran Q 1.10" I’F ylmethoxy]-(naphthalen—2—yloxy)— phosphorylamino]—pr0pionic acid pyl ester 4 0 0 (S)-2—[(R)-[(ZS,3S,4R,5R)-5—(2,4- oJkrNgiH (/4 H Dioxo—3,4—dihydro—2H—pyrimidin- 0" N 0 1~y1)-2,4—diflu0ro-3—hydroxy—4— 1-8 G F" Z 0 methyl-tetrahydro-fi1ran—2- OHO" "F oxy]~(naphthalen—1—y10xy)— phosphorylamino]—propionic acid isopropyl ester 4 0 0 (S)-2—[(S)-[(2S,3S,4R,5R)—5—(2,4- (rs/NEH (/41; Diox0-3,4-dihydro—2H-pyrimidin- 0 1—y1)-2,4-diflu0rohydroxy—4— [-9 O 0 F" methyl—tetrahydro-furan—2- 0HO" "F oxy]-(naphtha1en—1—y10xy)- phosphorylamino]—propionic acid isopropyl ester 4 0 0 (S){(8)-[(28,3S,4R,5R)(2,4- OJS/lffilnii‘ [(NH Di0x0—3,4—dihydro—2H—pyrimidin— 0 6 1—yl)-2,4—difluor0—3—hydroxy—4- 0 N4 I— 1 0 C; O \\ methyl-tetrahydro—furan—2— HO\ 9F ylmethoxy]-phenoxy— phosphorylamino } —propi0nic acid isopropyl ester 4 0 0 (S)~2—{(R)—[(ZS,3S,4R,5R)—5-(2,4- O/SflfqliiO flNH Dioxo-S,4-dihydr0~2H-pyrimidin- ; 1—y1)—2,4-diflu0r0-3—hydroxy-4— 0 N—< 1-1 1 0 O \\ methyl—tetrahydro~furan—2- HO‘ "F yhnethoxy]~phenoxy- phosphorylamino } —pr0pionic acid isopropyl ester 4 0 Br 0 W H 2,4—dioxo—3,4—dihydro—2H—(S)[(S)—[(ZS,3S,4R,5R)—5-(5- Q’s/N"?~ N 0 pyrimidin—l—y1)-2,4—difluoro [—12 O 0 F\\ hydroxy—4—methyl—tetrahydro—furan— OH0" 'IF 2-y1meth0xy]-(naphthalen yloxy)-phosphorylamino]-propionic acid isopropyl ester A 0 Br 0 [(S)-[(2S,3S,4R,5R)—5-(5- Ofigwfi'l 2/4 H Bromo-2,4-dioxo-3,4—dihydro—2H— 0 pyrimidin-l-yl)-2,4-difluoro-3— 1-13 F‘K' z 0 hydroxy—4—methyl—tetrahydro-furan- O o ,, 2—ylmethoxy]~(naphthalen yloxy)—phosphorylamino]—propionic acid isopropyl ester 4 0 Br 0 (S)—2—[(R)—[(2s,3s,4R,5R)-5—(5— 013m}; 2/ 2}, Bromo-2,4-diox0—3,4—dihydro—2H— N pyrimidin- l ~y1)—2,4—difluoro-3— 1-14 0 0 F" hydroxy—4-methyl-tetrahydro—fiiran— 0 ¢ ,, ethoxy]~(naphthalen— l — HO F yloxy)-phosphorylam1no]-prop10nic. . . acid isopropyl ester 4 0 8H0 (S)[(R)—[(ZS,3S,4R,5R)(5- 9 / H Bromo—2,4—dioxo—3,4—dihydro-2H— 0 N—{l pyrimidin—l-yl)—2,4—difluoro-3— 1-15 0 F" hydroxy—4—methyl—tetrahydro—furan— 0 e ,, thoxy]-(naphthalen—2- yloxy)—phosphorylamino]-propionic acid isopropyl ester 40 O B 0 H 9 >4 (S)‘2'[[(25,3534R,5R)-5—(5-Bromo- N‘ NE 2,4—dioxo—3,4-dihydro-2H— o din—l—yl)-2,4—difluoro l- 1 6 O " F hydroxy—4-1nethyl—tetrahydro-fi.1ran— Q 110° 9}? 2—ylmethoxy]-(naphthalen—2— yloxy)~phosphorylamino]-propionic acid isopropyl ester Synthesis General Schemes The methods discussed above are described in more details below: The starting material 1 can be prepared according to the procedures described by Sofia, M. J. et al, J. Med. Chem. (2010), 53(19),7202—7218 and Clark, J. L. et al, J. Med. Chem. (2005), 48(17),5504-5508. Iodination followed by elimination of iodide under basic condition can lead to intermediate 3, in which protection of 3 ’—liydroxy with benzoyl group leads to ediate 4. The stereospecific reaction of converting intermediate 4 to 5 is the key step, Similar transformation to install a e at 4’ oz position has been described previously by Ajmera, S. et al, J. Med. Chem. (1988), 31(6),lO94—1098 and Moffatt, J.G. et al, J. Am. Chem. Soc. (1971), 93(17), 4323—4324. Displacement of 5’ iodide with sodium benzoate afford intermediate 6. Finally, deprotection of 3’, 5’ benzoyl groups in intermediate 6 gives nucleoside ediate 7 (Scheme 1).

In the below l Schemes, R1 can be H, lower haloalkyl, or aryl, wherein aryl can be phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower alkynyl, lower afl Scheme 1. ~18— N O 12» PPhs THF, 15 DC MeOH, 65 °C Q 9 HO" 9F 18 h HO‘ ’F 4h HO F o 0 3 1 2 I NH ’g I A BzCl,DMAP N 0 IvaAgF PhCOONa - N 0 o ___> o __... ._ ..

, Xi DCM 25 0C \‘ ’ 0F DMSO 100 0C THEOOC 0 , c 9 3h \ , 0 o‘ 18h min F ’F o o 0%) ("3:1 the N 0 NH N o 0 3 F‘\ \\ 0 MeOH, rt HOW \ ’ \ , d ’F 13 11 HO F Nucleoside 7 can also be smoothly converted into 5’—halogen intermediate 8 by reaction with NCS, NBS, or NIS under appropriate conditions e 2).

Scheme 2. [l1 R6 NH INAO N 0 NBX Ho HO 0 o __.

F" DMF, microwave F ‘ , H6 ’1? 80 0C, 10 min Hd F 7 X, R6=C1, Br,I Phosphoramidate compounds of the present invention can be prepared by condensation eoside 7 or 8 with a suitably substituted phosphochloridate compound 11 in the ce of a strong base (Scheme 3). The condensation can be carried out on the unprotected nucleoside 7 or 8. The coupled product 12 in formula I can be further derivatized into product 13. Both compound 12 or 13 in formulal are obtained as a mixture of two diastereomers lly under the coupling reaction and can be separated into their corresponding chiral enantiomers by chiral column, chiral HPLC, or chiral SFC chromatography.

Scheme 3. 2!) R23 R43 0. 3 1N1 R RA) 2 a ‘3 RIOH R1\ 9 0 Cl"’I""Cl —————> O‘If-Cl _._... RKeroth 0 1') 0 Cl NtEI: leither C1 NEt3 R1, C1, :0 9 10 R O NH 1 6 I A R la R213 NH ; N 0 tert-BuMgCl R ‘-' 0‘ 50 I A R~Cl,DMAP O '——’ —-* R3’O N’P\0 N O F" 11, THF 0 1'14 0 ~‘ ’I rt, 3 h F" HO F ¢ ,, HO F R5=C(=O)C1-6alkyl 7 or 8 1 6 R R R : O\P..O l l R3/O Na \0 N 0 I4 0 RLO‘ ’F Dosaoe and Administration: As shown in above Table the compounds of formula I have the potential to be efficacious as ral drugs for the treatment ofHCV 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 CV activity according to the method described herein.

Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D) and may include oral, topical parenteral, uscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.

The 4'—F substituted nucleoside derivatives as well as their ceutically useable salts, can be used as medicaments in the form of any pharmaceutical formulation. The pharmaceutical ation can be administered enterally, either orally, e. g. in the form of tablets, coated s, dragées, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions, or rectally, e. g. in the form of suppositories. They can also be administered erally (intramuscularly, 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 cture ofpharmaceutical preparations, the 4'—substituted nucleoside derivatives, as well as their pharmaceutically useable salts, can be formulated with a eutically inert, nic or c excipient for the production of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.

The compounds of formula I can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally as pharmacologically 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). tional s such as ates, bicarbonates or citrates can be used for this purpose. Of course, 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 itions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present 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 ordinary 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 particular compound in order to manage the pharmacokinetics ofthe present compounds for maximum beneficial effect in patients.

For parenteral formulations, the carrier will y comprise sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may be ed. Of , where sterile water is to be used and maintained as sterile, the compositions and rs must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

Suitable excipients for tablets, coated tablets, dragées, and hard gelatin capsules are, for example, lactose, corn starch and derivatives thereof, talc, and stearic acid or its salts.

If desired, the s or capsules may be enteric-coated or sustained release by standard techniques. le excipients for sofi gelatine es are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols.

Suitable excipients for ion solutions are, for example, water, saline, alcohols, polyols, glycerin or vegetable oils.

Suitable ents for itories 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, polyols, 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 pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, fiers, sweeteners, colorants, flavorants, salts for adjustment of the osmotic pressure, 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 palticular case. For oral stration, a daily dosage ofbetween about 0.01 and about 100 mg/kg body weight per day should be riate in monotherapy and/or in ation y. A preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 100 mg/kg body weight per day. A typical preparation will n 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 forms, 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 present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient. One of ordinary skill in the art will also take advantage of ble pharmacokinetic ters ofthe pro-drug forms, where applicable, in delivering the present compounds to targeted site within the host organism or patient to ze the intended effect of the nd.

Indications and Method of Treatment The compounds of the invention and their isomeric forms and pharmaceutically acceptable salts thereof 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 inhibiting replication of HCV in a cell comprising administering a compound of any one of Formula 1.

Combination Therapy The compounds of the invention and their isomeric forms and pharmaceutically 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 ons 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 usefial when combined with the nds ofthe ion 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 al ribosomal entry site (IRES) and other medicaments that inhibit HCV cell attachment or Vilus entry, HCV RNA ation, HCV RNA transcription, replication or HCV maturation, assembly or virus release. Specific compounds in these classes and useful in the invention e, but are not limited to, macrocyclic, heterocyclic and linear HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH—9005 l8), ITMN— 191 (R-7227), TMC—435350 (a.k.a. TMC—435), MK— 7009, 81-201335, 1 (ciluprevir), EMS-650032, ACH-1625, ACH—1095 (HCV NS4A protease tor inhibitor), , VX-8 13, PHX— 1766, PHX2054, IDX— 136, IDX-3 16, ABT—450 EP—O 13420 (and congeners) and VBY-376; 3O the Nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, R7128, PSI-785 1, 4, lDX—102, R1479, UNX-08 189, PSI-6130, PSI-938 and PSI—879 and various other side and tide analogs and HCV tors 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 nucleos(t)ides. cleosidic HCV polymerase (replicase) inhibitors useful in the invention, include, but are not limited to, 6, HCV-371, 9, VCH-916, VCH- 222, ANA-598, MK-3281, 3, ABT—O72, PF-00868554, BI—207127, GS—9190, 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 compounds, NM-81 1 as well as cyclosporine 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, ~lambda or tic) such as Intron A, Roferon—A, Canferon—A300, Advaferon, Infergen, ron, Sumiferon MP, Alfaferone, IFN~B, Feron and the like; polyethylene glycol derivatized (pegylated) interferon nds, such as PEG interferori—Ot—2a (Pegasys), PEG interferon-oz-Zb (PEGIntron), pegylated IFN—oz —conl and the like; long acting ations and derivatizations of interferon compounds such as the albumin-fused interferon, Albuferon, Locteron, and the like; interferons with various types of controlled delivery systems (e.g., lTCA-638, 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—O7 and the like; TOLL-like receptor agonists such as CpG-lOl OI (actilon), isotorabine, ANA773 and the like; thymosin oz—l; ANA—245 and ANA—246; histamine dihydrochloride; propagermanium; hlorodecaoxide; ampligen; IMP—321; KRN~7000; antibodies, such as civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like. In addition, any of the above-described methods involving administering an NSSA inhibitor, a Type I interferon or agonist (e.g., an IFN—oz) and a Type II eron receptor agonist (e. g., an IFN~y) can be augmented by stration of an effective amount of a TNF—oz antagonist. ary, non—limiting TNF—oz antagonists that are suitable for use in such combination ies include ENBREL, REMICADE, and 3O HUMIRA.

In addition, compounds of the invention can be used in combination with antiprotozoans and other antivirals thought to be effective in the treatment ofHCV 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 erferon oz—2a and ribavirin.

Compounds of the invention can also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., tarabavarin, levoviron), microRNA, small interfering RNA nds (e. g., XN and the like), nucleotide or nucleoside analogs, irnmunoglobulins, hepatoprotectants, nflammatory agents and other tors ofNSSA. Inhibitors of other targets in the HCV lifecycle include NS3 helicase inhibitors; NS4A co-factor inhibitors; antisense oligonucleotide inhibitors, 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 tors such as celgosivir, UT-231B and the like; KPE—02003002 and BlVN 401 and IMPDH inhibitors. Other illustrative HCV inhibitor compounds include those disclosed in the following publications: US. Pat. Nos. 876; 178; 6,344,465; and 6,054,472; PCT Patent Application Publication Nos. 0028; WO98/4038 l; WOOO/56331, W002/04425; WOO3/007945; WOO3/010141; W003/000254; WOOl/32153; WOOO/06529; W000/18231; WOOO/10573; W000/13708; WOOl/85172; WOO3/037893; W003/037894; WOO3/037895; W002/100851; WOO2/100846; WO99/01582; WOOD/09543; W002/18369; WO98/l7679, 56331; WO98/22496; WO99/O7734; W005/073216, W005/073195 and WOO8/021927.

Additionally, combinations of, for e, ribavirin and interferon, may be administered as multiple combination therapy with at least one of the compounds of the invention. The present invention is not d to the aforementioned classes or compounds and plates known and new compounds and combinations ofbiologically active agents. It is intended that combination therapies of the present invention include any ally compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not ate the anti-viral activity of the compound of this inventive group or the anti-viral activity of the pharmaceutical composition itself. ~26- 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. ation therapy need not be limited to two agents and may include three or more agents. The s 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 ion to be alleviated. It is to be further understood that for any particular t, specific dosage regimens and schedules may be adjusted over time according to the individual‘s need and the judgment of the one skilled in the art administering or ising the administration of the combination therapy.

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

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

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

The application es the above methods, wherein the antiviral agent is ed from the group ting of a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor, a HCV fusion inhibitor, and a combination thereof.

EXAMPLES Abbreviations used in this application include: acetyl (Ac), acetic acid (HOAc), azo-bis— isobutyrylnitrile (AIBN), l-N~hydroxybenzotriazole (HOBt), atmospheres (Atm), high pressure liquid chromatography (HPLC), 9—borabicyclo[3.3.1]nonane (9-BBN or BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert—butyl pyrocarbonate or boc anhydride ), l-(3-dimethylaminopropyl)—3-ethylcarbodiimide hydrochloride (EDCI), l (Bz), benzyl (Bn), m—chloroperbenzoic acid (MCPBA), butyl (Bu), methanol , benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl diimidazol: (CD1), MeSOz— (mesyl or Ms), l,4—diazabicyclo[2.2.2]octane (DABCO), mass um (ms) diethylaminosulfur ride (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]undec—7—ene (DBU), N-methylmorpholine (NMM), N—methylpyrrolidone (NMP), 1,2—dichloroethane (DCE), pyridinium chlorochromate (PCC), icyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC), dichloromethane (DCM), propyl (Pr), diethyl arboxylate (DEAD), phenyl (Ph), di—1‘50~propylazodicarboxylate inch (psi), di-iso-propylethylamine , DIAD, pounds per square (DIPEA), pyridine (pyr), di-iso-butylaluminumhydride room temperature, It or , DIBAL-H, RT, N,N-dimethyl acetamide (DMA), tert—butyldimethylsilyl or zSi, (TBDMS), 4- N,N—dimethylaminopyridine (DMAP), triethylamine (Et3N or TEA), N,N— ylformamide (DMF), triflate or CF3802~ (Ti), yl sulfoxide (DMSO), trifluoroacetic acid (TFA), 1,1 ’—bis~(diphenylphosphino)ethane (dppe), 2,2,6,6- tetramethylheptane—Z,6~dione (TMHD), 1,1 (diphenylphosphino)ferrocene (dppf), thin layer chromatography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF), diethyl ether (EtzO), trimethylsilyl or Megsi (TMS), ethyl (Et), p-toluenesulfonic acid monohydrate (TsOH or stOH), lithium hexamethyl 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 (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J . Rigaudy and D. P.

Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford). 3O General Conditions Compounds of the invention can be made by a y of methods depicted in the illustrative synthetic reactions described below in the es section.

The starting materials and reagents used in preparing these compounds generally are either available from commercial ers, such as Aldrich Chemical Co., or are PTCPE}?§d*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 1—15; Rodd’s Chemistry of Carbon nds, Elsevier Science Publishers, 1989, s 1—5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. It should be appreciated that the synthetic reaction schemes shown in the Examples section are merely illustrative of some methods by which the compounds of the ion can be synthesized, and s modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure ned 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, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, ing physical constants and spectral data.

Unless specified to the contrary, the reactions described herein are typically conducted under an inert atmosphere at atmospheric pressure at a reaction 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 ion can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by known methods of tution or conversion reactions. If the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups are known in the art, and can be employed. Examples ofmany of the possible groups can be found in ctive Groups in Organic Synthesis" by Green 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 ofthe diazo group with halogen. Acyl groups can be added by Friedel—Crafis acylation. The acyl groups can then be ormed to the ponding alkyl groups by various methods, including the Wolff-Kishner ion and Clemmenson reduction. Amino groups can be alkylated to form mono— and di-alkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers. Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to fonn ketones. Thus, tution or alteration reactions can be employed to provide a variety of substituents hout the molecule of the starting material, intermediates, or the final product, including isolated products.

Preparative Examples Preparation 1.

Preparation of intermediate chiral l-((2R,3R,4R,SS)fluorohydroxy ethyl)—3-methyl—tetrahyd nyl)pyrimidine-2,4(1H,3H)—dione M.W 370.12 C10H12F1N204 Chiral 1 —((2R, 3 R)~3 -fluoro—4—hydroxyhydroxymetliyl~3 -methyl-tetrahydro— furan—2-yl)-1H—pyrimidine-2,4-dione (6.14 g, 23.6 mmol), PPh3 (9 g, 34.4 mmol), imidazole (2.4 g, 34.41rnnol) and dry THF (100 mL) were added into a 3—neck flask bottle (500 mL), 2O the mixture was stirred at 20 °C under nitrogen here for 20 min. Then 12 (6.6 g, 26 mmol) dissolved in dry THF (100 mL) was added into the mixture dropwise at 20 0C during min, after addition, the whole mixture was stirred at 20 °C under nitrogen atmosphere for 18 hrs. TLC showed that the SM was consumed, then water (50 mL) was added into it, the e was extracted by EA (150 mL><3), organic layer was washed with brine, dried over Na2804, removed solvent by reduced pressure, residue was purified by silica gel chromatography column (DCM : MeOH = 100 : l to 50 : l) to afford the title compound as a white solid (8.2 g, 94%).

LC—MS (M+H)+ = 371.0 Preparation 2. ation of intermediate chiral 1-((2R,3R,4R)fluorohydroxymethyl methylene—tetrahydrofuran yl)pyrimidine-2,4(1H,3H)—dione N 0 if)" H6 gF M.W 242.21 C10H11FN204 Chiral 1-((2R,3R,4R,SS)—3~fluorohydroxy—5-(iodomethyl)—3-methy1-tetrahyd r0furan—2—yl)pyrimidine-2,4(1H,3H)-dione (8.2 g, 22 mmol) was ved in MeOH (100 1nL) and NaOMe (3.73 g, 69 mmol) was added into it under nitrogen atmosphere, after addition, the mixture was heated to 65 OC and stirred under en atmosphere for 14 hrs, TLC showed that the SM was consumed, then the mixture cooled to r.t., IR—12O (H) ion exchange resin was added into it to adjust the pH to 8, filtered and removed solvent by reduced pressure, the crude product was purified by silica gel chromatography column (DCM : MeOH = 15 : 1) to afford the title compound as a white solid (3.3 g, 59%).

LC—MS (M+H)+= 243.1 Preparation 3.

Preparation of intermediate chiral benzoic acid (3R,4R,5R)-5—(2,4-dioxo-3,4- dihydro-ZH—pyrimidin-l-yl)fluoromethyl—2—methylene-tetrahydro-furanyl ester Oca311 M.W 346.32 C17H15FN205 To a e of chiral 1~((2R,3R,fi§j—5-fluoro—4—hydroxy—3—methy1—5-methy1ene- tetrahydrofuran —2—yl)pyrimidine—2,4(1H,3H)—dione (18.3 g, 75.6 mmol) and DMAP (27.7 g, 227 mmol) in anhydrous THF (900 mL) at 0°C was added BzCl (15.9 g, 113.4 mmol) dropwise. The reaction e was stirred at 0 0C for 0.5 h, then sat. NaHCO3 was added to quench the reaction. The mixture was extracted with EA (300 mLX3). The combined organic t was washed with H20, brine, dried over NazSO4, and concentrated. The residue was d by silica gel chromatography column (DCM : MeOH = 160 : 1 to 120 : l) to give the title compound as a white solid (17 g, 65%).

LC-MS (M+H)+= 347.1 Preparation 4.

Preparation of intermediate chiral (2R,3S,4R,5R)(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)—2,4—difluor—0—2-(iodomethyl)methyl-tetrahydrofuran yl benzoate OFc', O F M.W. 492.22 C17H15F21N205 To a mixture of chiral benzoic acid (3R,4R,5R)~5—(2,4-dioxo—3,4-dihydro-2H- pyrimidin—l—y1)-4—fluoromethyl-2—methylene—tetrahydro—furan-3—y1 ester (17 g, 49 mmol) and AgF (31 THF solution g, 245 mmol) in ous THF (600 mL) at 0 0C was added a (600 mL) of 12 (24.8 g, 98 mmol) se. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 3 h. TLC analysis indicated that the starting material was completely consumed and the formation of the desired product. The reaction was quenched by aqueous Na82O3 solution (5%, 300 mL). The mixture was extracted by EA (350 mL><3). The combined organic extract was washed with brine, dried over NazSO4, and concentrated. The residue was purified by silica gel chromatography column (DCM : MeOH = 120 : l) to give the title compound as a white solid (11 g, 45%).

LC—MS (M+H)Jr = 493.0 Preparation 5.

Preparation of ediate chiral (2R,3S,4R,5R)(2,4-di0xo-3,4- dihydropyrimidin-l(2H)-yl)—2,4—difluor2—benzoylmethyl—4-methyl—tetrahydrofuran- 3-yl benzoate ©‘(0 [‘1NH N 0 Och, o F M.W 486.46 C24H20F2N207 Chiral (2R,3 S,4R,5R)(2,4-diox0—3 ,4-dihydropyrimidin-l(2H)-y1)-2,4-difluor-O-2— (i0domethyl)—4—methyl—tetrahydrofuran—3-yl benzoate (0.56 g, 1.15 mmol), sodium benzoate (0.825 g, 5.73 mmol) and 18—crown—6 (0.03 g, 0.115 mmol) were suspended in DMSO (20 mL), the solution was heated to 100 CC and stirred under nitrogen atmosphere for 18 h, then cooled to r.t., water (30 mL) was added into it, the mixture was extracted by EA (30 mL>< 3), the organic layer was washed with H20, brine and H20, removed solvent by reduced pressure, the e was purified by silica gel column tography (PE : EA = 1 : 2) to afford the title compound as a colorless oil (0.34 g, 61%).

LC-MS (M+Na)+= 509.1 Preparation 6.

Preparation of intermediate chiral 1-((2R,3R,4S,SS)-3,5-difluoro—4-hydroxy (hydroxymethyl)methyl-tetrahydrofuran-Z—yl)pyrimidine-2,4(1H,3H)-dione M.W 278.21 CioHizeNZOS Chiral (2R,3S,4R,5R)—5—(2,4—dioxo-3,4—dihydropyrimidin—1(2H)-yl)—2,4—difluor—0-2— benzoylmethylmethyl-tetrahydrofuran—3-yl benzoate (0.34 g, 0.7 irnnol) was dissolved into methanol, and a solution of ammonia in methanol (7 N, 20 mL) was added. The reaction mixture was d at room temperature for overnight and . The e was concentrated, the residue was purified by silica gel column chromatography (DCM : MeOH = 20 : 1) and pre—HPLC to afford the title compound as a white solid (0.074 g, 38%).

LC-MS (M+H)+= 279.1; 1H NMR (300MHz, DMSO—ds) 5 11.575 (3, 1 H), 7666—7639 (d, 1 H, J= 8.1 Hz), 6324-6266 ((1, l H, J= 17.4 Hz), 6056—6037 (d, 1 H, J: 5.7 Hz), .821 (brs, l H), 5713-5686 (d, 1H, J= 8.1 Hz), 023 (in, 1H), 3.636 (s, 2 H), 1.313- 1.238 (d, 3H, J: 22.5 Hz) Preparation 7.

Preparation of intermediate chiral S-bromo((2R,3R,4S,5S)—3,5-difluoro—4— y-S-hydroxymethyl—3-methyl-tetrahydr0—furan—2-yl)—1H-pyrimidine—2,4-dione M.W. 357.11 CloHnBerNzOs In a 2 mL microwave vial, chiral 1-((2R,3R,4S,5S)-3,5-difluorohydr0xy—5- (hydroxymethyl)-3—methyl—te trahydrofiirany1)pyrimidine-2,4(1H,3H)—di0ne (70 mg, 0.252 nnnol), and NBS (67.2 mg, 0.377 mmol), were dissolved in DMF (0.7 ml). The mixture was capped and heated under microwave irradiation at 80°C for 10 min. LC/MS is indicated the starting material was completely consumed and the formation of the desired production as the only major product. The solvent was evaporated, and the residue was purified by a 2x4g silica gel cartridge, eluted with 0-70% EtOAc in hexanes to provide the title compound as a white solid (94 mg, 90%) MS (M)+= 358; 1H NMR (300 MHZ, CDsOD): 5(ppm) 8.41 (s, 40—6.35 (d, lH),4.28— 4.18 (m, 1H), 3.80—3.76 (d,2H), l.45—l.37(d, 3H) Example 1.

Preparation of {[(28,38,4R,5R)(2,4-dioxo—3,4—dihydro-2H-pyrimidinyl)- 2,4-difluorohydroxymethyl—tetrahydro-furan-Z-ylmethoxy]-phenoxy— phosphorylamino}—propionic acid isopropyl ester M.W 547.45 C22H23F2N309P Step A. opropyl 2—aminopropanoate hydrochloride (Oakwood, 500 mg, 2.98 mmol) and phenyl phosphorodichloridate (Aldrich, 662 mg, 2.98 mmol) was suspended in anhydrous DCM (25 mL). The reaction was cooled to ~78 oC. ylamine (604 mg, 830 pl, 5.97 2O 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 overnight. The solvent was removed, the residue was washed with dry ether. The filtrate was concentrated to give crude (28)- isopropyl oro(phenoxy)phosphorylamino)propanoate as a light yellow oil (0.8 g, 88%) and used without further purification.

Step B.

To a solution of chiral 1—((2R,3R,4S,SS)-3,5-difluorohydroxy—5-(hydroxymethyl)—3- methyltetrahydrofi1ran—2-yl)pyrimidine~2,4( 1H,3H)~dione (42 mg, 151 umol) prepared in Preparation 6 in THF (8.00 ml) was added a THF solution (Aldrich, 1 M) of tert- butylmagnesium chloride (377 pl, 377 umol) dropwise. The e was stirred at room temperature for 15 min. followed by the addition ofTHF solution (0.5 M) of (2S)-isopropyl 2—(chloro(phenoxy)phosphorylamino)propanoate (755 u], 377 umol). The reaction mixture was stirred at room temperature for 1 hr, followed by the addition of THF solution (Aldrich, 1 M) of tert—butylmagnesium chloride (189 ul, 189 umol) and THF solution (0.5 M) of (28)- isopropyl 2-(chloro(phenoxy)ph0sphorylamino)propanoate (378 pl, 189 mmol). The reaction mixture was then stirred at room temperature for 2 h. Methanol (2 mL) was added to quench the reaction, The mixture was purified by flash chromatography (silica gel, 0— 15% MeOH in DCM) and dried in vacuo to give the title compound as a light—yellow solid (18 mg, 22%).

LC—MS (M+H)+= 548.1 Preparation of (S)-2—[[(2S,3S,4R,5R)-5—(2,4—dioxo-3,4-dihydr0-2H—pyrimidin-1—yl)— fluoro-3—hydr0xymethyl-tetrahydro—furan-Z-ylmethoxy]—(naphthalenyloxy)- phosphorylamino]-propionicacid isopropyl ester M.W 597.51 C26H30F2N309P Step A.

Naphthalen-l—ol (Aldrich, 1.5 g, 10.4 mmol) and phosphorus(V) oxychloride (Aldrich, 1.6 g, 0.97 ml, 10.4 mmol) were ded in anhydrous ether (37.5 mL), and the temperature was cooled to —78 OC. Triethylamine (1.05 g, 1.45 ml, 10.4 mmol) was added dropwise and the reaction mixture was stirred at -78 0C for 1 h. The on mixture was warmed up to room ature 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 (2 g, 74%) and used for the next step t further purification. —36- Step B.

(S)-isopropyl 2-aminopropanoate hydrochloride (Oakwood, 1.28 g, 7.64 mmol) and naphthalen-l-yl phosphorodichloridate (2 g, 7.66 mmol) was suspended in anhydrous DCM (35 mL). The reaction was cooled to -78 OC. Triethylamine (1.55 g, 2.13 mL, 15.3 mmol) was added dropwise. The on mixture was stirred at -78 0C for 1 h, 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)—isopropy1 2—(chloro(naphthalen~1~lexy)phosphorylamino)propanoate as a light yellow oil (2.5 g, 92%) and used without further purification.

Step C.

To a solution of chiral 1—((2R,3R,4S,SS)—3,5-difluoro—4—hydroxy—5—(hydroxymethyl) tetrahydrofiiran—2—y1)pyrimidine~2,4(lH,3H)-dione (150 mg, 539 umol) prepared in Preparation 6 in THF (24 ml) was added a THF solution (Aldrich, 1 M) of tert— butylmagnesium chloride (1.35 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 15 min, followed by the addition ofTHF solution (0.5 M) of (28)-isopropyl or0(naphthalen—1—yloxy)phosphorylamino)propanoate (2.7 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for l h, then additional THF solution ch, l M) of tert—butylmagnesium chloride (0.68 mL, 0.68 mmol) and THF on (0.5 M) of (28)—isopropyl 2—(chloro(naphthalen—1—yloxy)phosphorylamino)propanoate (1.35 mL, 0.68 mmol) were added. The reaction mixture was then stirred at room temperature for 3 h.

Methanol (6 mL) was added to quench the reaction, The mixture was purified by flash chromatography (silica gel, 0—15% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (0.2 g, 62%).

LC—MS (M-H)+= 596.0 ation of (S)[[(2S,3S,4R,5R)(2,4-dioxo-3,4-dihydro-2H-pyrimidinyl)- 2,4-difluorohydroxymethyl-tetrahydro-furanylmethoxy]-(naphthalenyloxy)- phosphorylamino]-propi0nicacid isopropyl ester M.W 597.51 C26H30F2N309P Step A.

Naphthalen-Z—ol (Aldrich, 2 g, 13.9 mmol) and phosphorus(V) oxychloride (Aldrich, 2.13 g, 1.29 ml, 13.9 mmol) were suspended in anhydrous ether (50 mL), and the temperature was cooled to -78 0C. ylamine (1.4 g, 1.93 ml, 13.9 mmol) was added se and the reaction mixture was stirred at ~78 0C for 1 h. The reaction mixture was warmed up to room temperature and stirred for overnight. The e was filtered, and the filtrate was concentrated to give crude naphthalen-2~yl orodichloridate as a light yellow oil (2.5 g, 69%) and used for the next step without further purification.

Step B.

(S)—isopr0pyl 2—aminopropanoate hydrochloride (Oakwood, 500 mg, 2.98 mmol) and naphthalen—Z-yl orodichloridate (724 mg, 2.98 mmol) was suspended in anhydrous DCM (25 mL). The reaction was cooled to -78 OC. Triethylamine (604 mg, 830 pl, 5.97 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, and the residue was washed with dry ethyl ether and filtered. The filtrate was concentrated to give crude (2S)—isopropy1 2—(chloro(naphthalen—Z-yloxy)phosphorylamino)propanoate as a light yellow oil (0.8 g, 75%) and used without filrther purification.

Step C.

To a solution of chiral l-((2R,3R,4S,SS)—3,5~difluoro—4-hydroxy—5—(hydroxymethyl)—3- methyltetrahydrofilra11-2—y1)pyrimidine—2,4(lH,3H)-dione (60 mg, 216 umol) prepared in -38— Preparation 6 in THF (8 ml) was added a THF solution ch, 1 M) of tert- butylmagnesium de (539 pl, 539 umol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the on ofTHF solution (0.5 M) of (ZS)-isopropyl 2-(chlor0(naphthalen-Z—yloxy)phosphorylamino)propanoate (1.08 mL, 539 umol). The reaction mixture was stirred at room temperature for l h, then additional THF solution (Aldrich, 1 M) of Icrt—butylmagnesium chloride (270 pl, 270 umol) and THF on (0.5 M) of (28)~isopropyl 2-(chloro(naphthalen—2-yloxy)phosphorylamino)propanoate (0.54 1nL, 270 umol) were added. The reaction mixture was then stirred at room temperature for 18 h.

Methanol (2 1nL) was added to quench the reaction, The mixture was purified by flash chromatography (silica gel, 1- 18% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (75 mg, 58%).

LC—MS = 596.1 Example 4 Preparation of (S)[[(2S,3S,4R,5R)-5—(2,4-dioxo-3,4-dihydro-2H-pyrimidinyl)- l5 2,4-diflu0ro-3—[((S)—1-isopropoxycarbonyl—ethylamino)-(naphthalen-Z—yloxy)— phosphoryloxy]methyl-tetrahydro-furan-Z-ylmethoxy]-(naphthalenyloxy)- phosphorylamino]—propionicacid isopropyl ester all! —-0 F11 M.W 916.81 C42H48F2N4013P2 In the method described for the preparation of (S)—2—[[(28,3S,4R,5R)—5—(2,4—dioxo—3,4— dihydro-ZH—pyrimidin-1—yl)—2,4—difluoro-3~hydroxy-4—methyl-tetrahydro-furan ylmethoxy]—(naphthalen—2-yloxy)-phosphorylamino]—propionicacid isopropyl ester in Example 3 Step C, (S)—2-[[(ZS,38,4R,5R)—5-(2,4—dioxo—3,4—dihydro~2H-pyrimidin-l—yl)-2,4— difluoro-3 - [((S)- 1 —isopropoxycarbonyl-ethylamino hthalen—2—yloxy)-phosphorylo xy] ~4- methyl-tetrahydro-furan-Z-ylmethoxy]-(naphthalen-Z-yloxy)—phosphorylamino]— propionicacid isopropyl ester was obtained as the second product: white solid, 8 mg (4%).

LC-MS (M+H)+ = 917.2 Example 5 Preparation of (S)—2-[[(2S,3S,4R,5R)—5-(2,4-di0xo—3,4-dihydr0-2H-pyrimidin—l-yl)- 2,4-difluoro—4—methyl-3—propionyloxy-tetrahydro—furan—Z-ylmethoxy]-(naphthalen-1— yloxy)-phosphorylamino]—pr0pionic acid isopropyl ester (1NH 70 O gig/k0 OF ‘ ‘ ’F M.W. 653.58 C29H34F2N3O9P To a on of (S)-2—[[(ZS,3S,4R,5R)—5-(2,4~dioxo-3,4~dihydro-2H—pyrimidin—l—yl)~ 2,4—difluoro~3-hydroxy—4emethy1—tetrahydro-furan—2~ylmethoxy]~(naphthalen— 1 -yloxy)- phosphorylamino]~propionicacid isopropyl ester prepared in Example 2 (86 mg, 144 umol) in THF (10 mL) were added propionyl chloride (66.6 mg, 720 nmol) and DMAP (87.9 mg, 720 pmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 0— 15% MeOH in DCM) to give the title compound as white solid (45 mg, 48%).

LC—MS (M—H)+= 652.1 e 6 Preparation of chiral (S)—2-[(S)-[(2S,3S,4R,5R)(2,4-dioxo-3,4-dihydr0-2H- pyrimidinyl)-2,4—diflu0r0hydroxy-4—methyl-tetrahydro-furan-Z-ylmethoxy]- halen-Z-yloxy)—ph0sphorylamin0}-propionicacid isopropyl ester M.W. 597.51 C26H3OF2N309P (S)—2—[[(28,3S,4R,5R)-5—(2,4-dioxo~3 ,4—dihydr0ill—pyrimidin—1-yl)~2,4-difluoro~3— hydroxy—4-methyl-tetrahydro~fi1ran-2—y1methoxy]~(naphtha1en—2—yloxy)-phosphory1amino]— propionicacid isopropyl ester prepared in Example 3 (50 mg) was separated by chiral SFC chromatography to provide chiral (S)[(S)-[(ZS,3S,4R,5R)~5-(2,4—dioxo—3,4-dihydro—2H- pyrimidin- 1 ~yl)—2,4—difluoro—3 ~11ydroxy—4—methyl-tetrahydro—furan—2—ylmethoxy]— (naphthalen-Z-yloxy)~phosphory1amino]-propionicacid isopropyl ester as a white solid (27 mg, 54%) LC-MS (M-H)+= 596.1 Preparation of chiral (S)—2-[(R)-[(28,3S,4R,5R)(2,4—di0X0—3,4—dihydro—2H- pyrimidin-1—yl)-2,4-difluorohydroxymethyl—tetrahydro—furan-Z-ylmethoxy]— (naphthalen—Z-yloxy)-phosph0rylamin0]-propionicacid isopropyl ester M.W. 597.51 C26H30F2N309P (S)—2—[[(2S,3S,4R,5R)—5-(2,4—dioxo—3 ,4-dihydro—2H—pyrimidin- l -yl)—2,4-difluoro—3 — hydroxy—4-1nethyl-tetrahydro-fi1ran¢2-ylmethoxy]-(naphtha1en-2—yloxy)-phosphory1amino] nicacid pyl ester prepared in Example 3 (50 mg) was separated by chiral SFC chromatography to provide chiral (S)—2—[(R)—{(ZS,3S,4R,5R)—5-(2,4—dioxo—3,4-dihydro—2H— pyrimidin- l ,4—difluoro-3 —hydroxy—4—methyl-tetrahydro—furan—Z—ylmethoxy] — halen—Z—yloxy)-phosphorylamino]—propionicacid isopropyl ester as a white solid (12 mg, 24%).

LC—MS (M—H)+= 596.1 Example 8 Preparation of chiral (S)KR)-I(28,38,4R,5R)—5-(2,4-dioxo-3,4-dihydro-2H- pyrimidinyl)-2,4-difluoro-3—hydroxymethyl—tetrahydro-furan-Z-ylmethoxy]- (naphthalen-l-yloxy)—phosphorylamino]—propionicacid isopropyl ester M.W 597.51 C26H30F2N309P (S)[[(28,3S,4R,5R)-5—(2,4~dioxo—3,4-dihydro~2H-pyrimidin—1-yl)—2,4-difluoro hydroxy—4-methyl-tetrahydro~furan~2-ylmethoxy]—(naphthalen~ 1 —yloxy)—phosphorylamino]— propionicacid isopropyl ester prepared in Example 2 (100 mg) was separated by chiral SFC chromatography to provide chiral (S)—2—[(R)—[(ZS,3S,4R,5R)(2,4—dioxo—3,4-dihydro—2H— pyrimidin— l -yl)-2,4-difluorohydroxy—4—methy1—tetrahydro-fi1ran—2—ylmethoxy] - (naphthalen—l-yloxy)-phosphorylamino]~propionicacid isopropyl ester as a white solid (24 mg, 24%).

LC—MS (M—H)+= 596.1 Example 9 Preparation of chiral (S)[(S)—[(ZS,3S,4R,5R)(2,4-dioxo—3,4—dihydro-2H- pyrimidinyl)-2,4-difluorohydroxymethyl—tetrahydro-furan-Z-ylmethoxy]- (naphthalen-1—yloxy)-phosphorylamino]-propionicacid isopropyl ester M.W. 597.51 C26H30F2N3O9P (S)-2—[[(2S,3S,4R,5R)—5—(2,4-dioxo-3,4-dihydro—2H-pyrimidin—1-y1)—2,4-difluoro hydroxy—4-methyl-tetrahydro-furan—2—ylmethoxy]~(naphthalen- 1 ~yloxy)-phosphorylamino]— propionicacid pyl ester prepared in e 2 (100 mg) was separated by chiral SFC chromatography to provide chiral (S)[(S)-[(2S,3S,4R,5R)(2,4-dioxo-3,4—dihydro-2H- pyrimidiny1)-2,4—difluoro—3 -hydr0xy—4-methyl-tetrahydro-fi1ranylmethoxy] - (naphthalen—1—y10xy)-phosphorylamino]-propionicacid isopropyl ester as a white solid (53 mg, 53%) LC—MS (M-H)+= 596.1 Example 10 Preparation of chiral (S)-2—{(S)—[(ZS,3S,4R,5R)(2,4-dioxo-3,4—dihydro-2H- pyrimidin—1-yl)-2,4—difluorohydroxy—4-methyl-tetrahydro-furan-Z-ylmethoxy}- phenoxy-phosphorylamino}-pr0pionic acid isopropyl ester M.W. 547.45 C22H28F2N309P (S) {[(ZS,3 S,4R,5R)—5-(2,4-dioxo-3 ydro-2H—pyrimidiny1)-2,4-difluoro-3 - hydroxy—4—methyl—tetrahydro-fi1ran—2-ylmethoxy]-phenoxy-phosphorylamino } -propionic acid isopropyl ester prepared in Example 1 (0.18 g) was separated by chiral SFC chromatography to provide chiral (S)—2— {(S)—[(ZS,3 R)~5—(2,4—dioxo-3,4—dihydro—2H- pyrimidin- 1 —y1)—2,4—difluoro—3—hydroxy—4-methy1—tetrahydro—furan-Z-ylmethoxy]—phenoxy— phosphorylamino}—propionic acid isopropyl ester as a white solid (60 mg, 33%) .

LC—MS = 548.0 Example 11 Preparation of chiral (S){(R)—{(2S,3S,4R,5R)-5—(2,4-dioxo-3,4-dihydro—2H— pyrimidinyl)—2,4-difluoro—3-hydroxy—4-methyl-tetrahydro-furan-Z-ylmethoxy]- phenoxy-phosphorylamino}-propionic acid isopropyl ester l—ll M.W 547.45 C22H28F2N309P (S)—2-{[(ZS,3S,4R,5R)-5—(2,4-dioxo—3,4—dihydro-2H-pyrimidin—1—y1)-2,4~difluoro—3— hydroxy—4~methyl—tetrahydro—furan-2~ylmeth0xy]—phenoxy—phosphorylamino}—propionic acid isopropyl ester ed in Example 1 (0.18 g) was separated by chiral SFC chromatography to provide chiral (S)—2—{(R)—[(ZS,3S,4R,5R)—5—(2,4-di0xo-3,4-dihydro—2H— pyriinidin— l —y1)—2,4-difluoro—3 ~hydroxy—4—methyl—tetrahydro-fin‘an-2—ylmethoxy] —phenoxy- phosphorylamino}-propi0nic acid isopropyl ester as a White solid (28 mg, 16%) .

LC-MS (M+H)+= 548.0 Example 12 Preparation of chiral (S)-2—[(8)—[(28,3S,4R,5R)(5—br0m0-2,4-dioxo-3,4-dihydro- 2H-pyrimidinyl)-2,4-difluorohydr0xy-4—methyl-tetrahydro-furan-Z-ylmethoxy]- (naphthalen-1—yloxy)—phosphorylamin0]-propionic acid pyl ester : NH a .0 \rm/‘go0 3"\ ON 0 H6 ’F 1—12 M.W 676.41 C26H39Bl‘2N309P Step A.

To a on of chiral 5—bromo-l—((2R,3R,4S,SS)-3,5—difluoro-4—hydroxy—5- hydroxymethyl—3—methyl—tetrahydro~furan-2—yl)-1H—pyrimidine-2,4—dione (50 mg, 0‘ 14 mmol) prepared in Preparation 7 in THF (3 ml) at 0 °C was added a THF solution (Aldrich, l M) of tert-butylmagnesium chloride (0.35 mL, 0.35 mmol) dropwise. The mixture was stirred at 0 0C for 15 min, followed by the addition ofTHF solution (0.5 M) of (2S)- isopropyl 2—(chloro(naphthalen—l—yloxy)phosphorylamino)propano ate prepared in Example 2 Step B (0.7 mL, 035 rnmol). The reaction mixture was warmed to room temperature and d for 2 11. ol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5—lO% MeOH in DCM) to give (S)-2~[[(2S,3S,4R,5R)—5—(5— bromo—2,4-dioxo-3 ,4-dihydro-ZH-pyrimidin— l —yl)~2,4—difluoro—3-hydroxy-4—methyl~ tetrahydro—furan—2-ylmethoxy]—(naphthalen~ l ~yloxy)~phosphorylamino]—propionic acid isopropyl ester as a white solid (50 mg, 52%).

Step B.

(S)-2—[[(28,3S,4R,5R)(5-bromo~2,4-dioxo—3 ydro—2H-pyrimidin- l ~y1)—2,4— difluoro—3—hydroxy—4—methyl—tetrahydro—furanylmethoxy]—(naphtha1en—1 —yloxy)— phosphorylamino]~propionic acid isopropyl ester (50 mg) was separated by chiral SFC chromatography to provide chiral (S)[(S)—[(2S,3S,4R,5R)-5—(5—bromo-2,4-dioxo-3,4- dihydro—ZH-pyrimidin- l —yl)—2,4—difluoro—3—hydroxy—4—methyl—tetrahydro—furan—2— ylmethoxy]—(naphthalen-l—yloxy)-phosphorylamino]-propionic acid isopropyl ester as a white solid (11 mg, 22%).

LC-MS (M)+= 6760 Example 13 Preparation of chiral (S)[(S)-[(ZS,3S,4R,5R)(5-bromo-2,4-dioxo-3,4-dihydro- 2H—pyrimidin-1—yl)-2,4—difluoro—3-hydroxymethyl-tetrahydro—furan-Z-ylmethoxy]- (naphthalen—Z-yloxy)-phosphorylamino]-pr0pionic acid isopropyl ester 1-13 M.W 676.41 C26H39Br2N309P (S)—2—[[(ZS,3S,4R,5R)—5—(5-bromo—2,4-dioxo—3,4—dihydro-2H-pyrimidin-1 ,4- difluoro—3—hydr0xy—4—methyl—tetrahydro—fi1ran-2—ylmethoxy]—(naphtha1en—2~yloxy)— phosphorylamino]—pr0pionic acid isopropyl ester prepared in Example 16 (50 mg) was separated by Chiral SFC chromatography to provide chiral (S)~2-[(S)—[(ZS,3S,4R,5R)—5-(5— broinc—2,4-di0xo—3 ,4—dihydro~2H—pyrimidin- l -yl)—2,4*difluoro-3—hydroxy1nethyl— tetrahydro-fiiran-Z-ylmethoxy]-(naphthalen-Z-yloxy)—phosphory1amino]~propi0nic acid isopropyl ester as a white solid (27 mg, 54%).

LC—MS (MY: 676.0 Example 14 Preparation of chiral (S)[(R)—[(28,3S,4R,5R)(5-brom0—2,4-dioxo—3,4-dihydro— 2H-pyrimidinyl)-2,4-difluoro—3-hydroxymethyl—tetrahydro-furan-Z-ylmethoxy]— halenyloxy)-phosphorylamino]—propionic acid isopropyl ester H6 ’1? l—14 M.W. 676.41 C26H39Br2N3O9P During the separation of (S)—2—[[(28,3S,4R,5R)—5—(5-bromo-2,4~dioxo—3,4—dihydro—2H~ pyrimidin— 1 ~y1)-2,4—difluoro—3-hydroxymethyl-tetrahydro~furan—2—ylmethoxy] ~ (naphthalen-1—yloxy)-phosphorylamino]-propionic acid isopropyl ester (50 mg) by chiral SFC chromatography in Example 12 Step B, chiral (S)[(R)—[(ZS,3S,4R,5R)-5—(5-bromo- 2,4-dioxo-3 ydro—2H—pyrimidin- l -yl)-2,4-difluoro—3-hydroxy—4-methyl—tetrahydro— furan—Z-ylmethoxy]—(naphthalen— l —yloxy)-phosphorylamino]—propionic acid isopropyl ester was obtained as the second product: White solid (8 mg, 16%).

LC-MS (M)+= 676.0 Example 15 Preparation of chiral (S)—2-[(R)-[(28,3S,4R,5R)—5-(5-brom0-2,4-di0x0-3,4—dihydr0- 2H-pyrimidinyl)-2,4—difluorohydroxy-4—methyl—tetrahydro—furan-Z-ylmethoxy]- (naphthalen—Z—yloxy)—phosphorylamino]-propionic acid isopropyl ester I-lS M.W. 676.41 C26H39Br2N309P During the separation of (S)[[(2S,3S,4R,5R)~5-(5—bromo—2,4—dioxo—3,4—dihydro-2H— pyrimidin— l ,4~difluoro-3 —hydroxy—4—methyl-tetrahydro~furan—2—ylmethoxy] - (naphthalen—Z—yloxy)—phosphory1amino]—propionic acid isopropyl ester ed in Example 16 (50 mg) by chiral SFC chromatography, chiral (S)[(R)-[(2S,3S,4R,5R)—5-(5-bromo— 2 XO-3 ,4-dihydr0 -2H-pyrimidin- l -yl)-2,4—difluoro-3 -hydroxymethyl-tetrahydro — furan—2—ylmethoxy]—(naphthalen—Z-yloxy)-phosphory1amino]-pr0pionic acid isopropyl ester was obtained as the second product: white solid (16 mg, 32%).

LC—MS (M)+= 675.9 Example 16 Preparation of chiral {[(2S,3S,4R,5R)(5-bromo—2,4—dioxo-3,4-dihydro-2H- pyrimidin—1-yl)—2,4-difluor0—3—hydroxy-4—methyl—tetrahydr0-furanylmeth0xy]- (naphthalen-Z-yloxy)-phosphorylamino]-propionic acid isopropyl ester 1—16 M.W. 676.41 C26H39BT2N309P To a solution of chiral 5~br0mo-1~((2R,3R,4S,5S)—3,5-difluoro—4—hydroxy-5— hydroxymethyl-3—methyl-tetrahydro—furan—2-yl)-1H~pyrimidine—2,4-dione (92 mg, 0.26 mmol) prepared in Preparation 7 in THF (3 ml) at 0 0C was added a THF solution (Aldrich, 1 M) of Zert—butylmagnesium chloride (0.64 mL, 0.64 mmol) se. The mixture was stirred at 0 °C for 15 min, followed by the addition ofTHF solution (0.5 M) of (2S)— isopropyl 0ro(naphthalen—2—yloxy)phosphorylamino)propanoate prepared in Example 3 Step B (1.29 mL, 0.64 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give the title compound as a white solid (56 mg, 32%).

LC—MS (M)+= 676.0 ~48- 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 RNA level. The assay es a reporter as a simple readout for ellular HCV replicon Rem’lla luciferase gene was introduced into the first open reading frame of a genotype lb replicon construct NKS .1 (N. Krieger et (11., J. Virol. 2001 75(10):4614), immediately after the internal ribosome entry site (IRES) sequence, and fused with the neomycin phosphotransferase (NPTII) gene via a leavage peptide 2A from foot and mouth disease virus (M.D. Ryan & J. Drew, EMBO 1994 l3(4):928—933). After in vitro transcription the RNA was electroporated into human hepatoma lluh7 cells, and G418-resistant colonies were isolated and expanded. Stably selected cell line 2209-23 contains replicative HCV subgenomic RNA, and the activity ofRenilla luciferase expressed by the replicon s its RNA level in the cells. The assay was carried out in duplicate , one in opaque white and one in transparent, in order to measure the anti-viral activity and xicity of a chemical compound in parallel ensuring the observed activity is not due to decreased cell proliferation or due to cell death.

HCV on cells (2209—23), which express Rem‘lla luciferase reporter, were cultured in Dulbecco’s MEM (Invitrogen cat no. 10569-010) 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. Twenty—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 incubation time, the cells in white plates were harvested and luciferase activity was measured by using the R. luciferase Assay system (Promega cat no.

E2820). All the reagents bed in the following paragraph were included in the manufacturer's kit, and the manufacturer’s instructions were followed for preparations of the ts. The cells were washed once with 100 uL ofphosphate buffered saline (pH 7.0) (PBS) per well and lysed with 20 ul of IX R. luczferase Assay lysis buffer prior to incubation at room temperature for 20 min. The plate was then inserted into the Centro LB 960 microplate luminometer (Berthold Technologies), and 100 pl ofR. lucg’erase Assay buffer was injected into each well and the signal measured using a nd delay, 2—second measurement program. lC50, the tration 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 ofWST—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 tion microtiter plate reader (Lab ) at 450 nm (reference filter at 650 nm). Again CCso, the concentration ofthe drug required for reducing cell proliferation by 50% in relation to the untreated cell control value, can be calculated from the plot of percentage ion of the WST-l value vs. drug concentration as described above.

Representative biological data is shown below in Table II.

TABLE II.

HCVReplic WS.T.'1 Compound Cytotox1c1ty on ICso (uM) CCso (uM) 1—1 0.424 >100 1—2 0.1149 >100 1—3 0.15768 >100 1-4 7.19 >100 I-5 0.1515 67.8 1—6 0.05374 >100 I-7 0.20155 >100 1—8 1.02945 >100 1—9 0.06016 >100 I—10 0.17082 >100 I—11 1.30888 95.6 1—12 17.365 34.8 1-13 38.465 >100 1—14 9.641 50.8 1-15 13.175 38.5 1—16 77.61 >100 It will be understood that references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions, and that the treatment of animals es the treatment of humans as well as other mammals. rmore, treatment of an Hepatitis C Virus (HCV) infection, as used herein, also includes ent or prophylaxis of a disease or a condition associated with or mediated by Hepatitis C Virus (HCV) infection, or the clinical symptoms thereof.

The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their c forms or in terms of a means for ming the sed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in e forms thereof.

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope ofthe appended claims.

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

All patents, patent applications and publications cited in this application are hereby incomorated by nce in their entirety for all purposes to the same extent as if each individual , patent application or publication were so individually denoted.

Claims (20)

Claims

1. A compound of formula I 1 6 2a 1121;1'1 R R a ..0 A l R3/O NI \0 O N RS/o‘ ’F wherein: R1 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, ~N(Rla)2, acylamino, -SOzN(Rl“)2, -COR“’, I°), -NHSOz(R‘°), nitro or cyano; 10 each R18 is independently H or lower alkyl; each Rlb is independently —ORla or —N(Rla)2; each R1C is lower alkyl; R2a and R2b are (1') independently H, lower alkyl, rN(R1a)2, lower hydroxyalkyl, ~ CstH, -(CH2)S(O)pMe, —(CH2)3NHC(=NH)NH2, (lH—indol—3—yl)methyl, (lH—indol—4- 15 yl)methyl, -(CH2)mC(=O)R1b , aryl and aryl lower alkyl, wherein aryl may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo, nitro or cyano; (ii) R2a is H and R2b and R4 together form ; (iii) R2“ and R21) together form (CH2)n; or, (iv) R221 and sz both are lower alkyl; R3 is H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl; 20 R4 is H, lower alkyl, or R2b and R4 together form (CH2)3; R5 is H, C(=0)R‘°, lb , OR1)(OR”), 0rP(=O)(OR1)(NR4R?); R6 is H, methyl, or halo; R7 is C(Rzasz)COOR3 m is 0 to 3; 25 nis4or5; p is 0 to 2; and r is 1 to 6; or a pharmacologically acceptable salt thereof.

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

3. The compound of claim 2, wherein R6 is H or Br.

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

5. The compound of claim 4, wherein R”1 is H.

6. The compound of claim 5, wherein sz is methyl. 15

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

8. The compound of claim 7, wherein R5 is H.

9. The compound of claim 7, wherein R5 is C(=O)R1°.

10. The compound of claim 9, wherein R10 is ethyl.

11. The compound of claim 7, wherein R5 is P(=O)(ORI)(NR4R7). 25

12. The compound of claim 11, wherein R1 is naphthyl.

13. The compound of claim 12, wherein R4 is H and is R7 is CH(CH3)C(=O)OCH(CH3)2.

14. A compound of claim 1, selected from the group consisting of: (S)—2- 3 S,4R,5R)(2,4—Dioxo-3 ydro-2H—pyrimidin-1—y1)—2,4-difluoro-3 — hydroxy—4—methyl—tetrahydro—furan—2—ylmethoxy]-phenoxy—phosphorylamino } -propionic acid isopropyl ester; (S)—2-[[(28,3S,4R,5R)—5—(2,4-Dioxo—3 ,4—dihydr0—2H—pyrimidin—1—y1)—2,4-difluoro—3 - hydroxy1nethy1—tetrahydro-fi1ran—2—y1methoxy]-(naphtha1en— 1 ~ylo xy)- phosphorylamino]-p1'0pionic acid isopropyl ester; [[(283S,4R,5R)(2,4-Di0x0—3 ,4-dihydro-2H—pyrimidin—1-y1)-2,4-diflu0ro hydroxy-4—methy1-tetrahydro~furan-2—y1meth0xy]—(naphthalen-2—yloxy)- phosphorylamino]—pr0pi0nic acid isopropyl ester; (S)—2-[[(ZS,3 S,4R,5R)~5—(2,4-dioxo-3 ,4-dihydro~2H-pyrimidin—1-y1)-2,4—difluoro—3—[((S)isopropoxycarbonyl-ethylamino)-(naphtha1eny10xy)—phosphoryloxy]—4—methyl- tetrahydro~furany1methoxy]~(naphtha1en~2-y10xy)~ph0sphorylamino]-pr0pionicacid pyl ester; (S)—2~[[(28,3S,4R,5R)—5-(2,4—Di0x0-3,4-dihydro—2H-pyrimidin—1—yl)—2,4-difluoro—4— methylpropiony10xy—tetrahydro—furan-2—y1methoxy]-(naphtha1en— 1 -y10xy)- phosphorylamino]-pr0pionic acid isopropyl ester; (S)—2—[(S)—[(ZS,3 S,4R,5R)—5—(2,4-Diox0—3 ,4-dihydro-ZH-pyrimidin—1-y1)—2,4-diflu0ro hydroxymethyl-tetrahydro—furan—2—ylmethoxy]—(naphthalen—2—y10xy)- phosphorylamino]-propionic acid isopropyl ester; (S) [(R)-[(ZS,3 S,4R,5R)(2,4-Dioxo-3 ,4—dihydr0-2H—pyrimidiny1)-2,4—difluoro—3- hydroxy—4—methy1—tetrahydro-fi1ran—2—ylmethoxy]~(naphtha1en—2-y10 xy)— phosphorylamino]—propi0nic acid isopropyl ester; (S)—2~[(R)-[(ZS,3 S,4R,5R)—5—(2,4-Dioxo—3 ydro—2H—pyrimidin— 1 ,4—diflu0r0~3— hydroxy-4—methy1—tetrahydro-fi1ran—2~y1methoxy]—(naphtha1en— 1 -y10 xy)— phosphorylamino]-p1'opi0nic acid pyl ester; (S)—2- [(S)-[(ZS,3S,4R,5R)~5—(2,4—Di0xo—3 ,4~dihydro—2H—pyrimidin—1-y1)—2,4—difluor0—3~ 1iydroxy—4—methy1-tetrahydro—furan—2~y1meth0xy]—(naphtha1en— 1 —y10 xy)— phosphorylamino]-pr0pionic acid isopropyl ester; (S)—2— {(S)—[(ZS,3 S,4R,5R)—5—(2,4-Di0x0—3,4-dihydro—2H—pyrimidin—1—y1)—2,4—difluoro hydroxy—4—methyl-tetrahydro—furany1methoxy]-phenoxy—phosphorylamino } —propionic acid isopropyl ester; (S) {(R)~[(ZS,3 S,4R,5R)—5-(2,4-Di0x0~3,4-dihydro-2H—pyrimidin—1-y1)-2,4-difluoro-3— hydroxy—4-methy1—tetrahydro—fiiran-Z-ylmethoxy]~phenoxy-phosphorylamino } onic acid isopropyl ester; (S)[(S)—[(ZS,3 S,4R,5R)-5~(5—B1'0m0—2,4—di0x0-3 ,4-dihydro—2H—pyrimidin— 1 -y1)—2,4— difluoro-3~hydr0xymethyl-tetrahydro~fu1'any1methoxy]~(naphthalcn— 1 -y10xy)— phosphorylamino]-propionic acid isopropyl ester; (S)-2—[(S)—[(ZS,3 S,4R,5R)—5-(5—Bromo-2,4—dioxo-3 ,4-dihydro-ZH-pyrimidinyl)—2,4— difluorohydroxy—4—methyl-tetrahydro-furan—2-ylmethoxy]—(naphthalenyloxy)- phosphorylamino]-propionic acid isopropyl ester; (S)—2— [(R)—[(ZS,3 R)(5—Brorno-2,4—dioxo-3 ,4-dihydro—2H—pyrimidin-1—yl)—2,4- difluoro—3—hydroxy—4—methyl-tetrahydro-fi1ran-2~ylmethoxy]~(naphthalen— 1 —yloxy)- phosphorylamino]-propionic acid isopropyl ester; (S)~2-[(R)—[(ZS,3 S,4R,5R)-5—(5-Bromo-2,4-dioxo—3 ydro~2H—pyrimidin—1-yl)—2,4— difluoro~3—hydr0xy—4—methyl-tetrahydro—furan—2-ylmethoxy]—(naphthalen—2-yloxy)- orylamino]-propionic acid isopropyl ester; and (S)—2—[[(28,3S,4R,5R)~5-(5-Bromo-2,4—dioxo—3 ,4—dihydro-2H—pyrimidin—1-yl)-2,4— difluoro—3-hydroxymethy1—tetrahydro—furair2—ylmethoxy]-(naphthalen~2-yloxy)- phosphorylamino]-propionic acid isopropyl ester.

15. A nd according to any one of claims 1 to 14 for use as therapeutically active substance.

16. A pharmaceutical composition comprising a compound in ance with any one of claims 1 to 14 and a therapeutically inert carrier.

17. The use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or laxis of Hepatitis C Virus (HCV) infection.

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

19. A pharmaceutical composition according to claim 16 substantially as herein described with reference to any example thereof.

20. A use according to claim 17 substantially as herein described with reference to any example thereof.