VIRA L POLYMERASE INHIBITORS

RELATED APPLICATION

This application claim s benefit of U.S. Serial No, 61/102,593 filed October 3« 3008, which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to com pounds, com positions and m ethods for the treatm ent of hepatitis C virus (HCV) infection, in particular, the present invention provides novel ϊnhibttors of the hepatrtts C vtrus NS5B polym erase, pharm aceutical com positions containing such com pounds and m ethods for using these com pounds in the treatm ent of HCV infection.

BACKGROUND OF THE INVENTION It Is estim ated that at least 170 m illion persons worldwide are infected with the hepatitis C virus (HCV). Acute HCV infection progresses to chronic infection in a high num ber of cases, and, in som e infected individuals, chronic infection leads to serious liver diseases such as cirrhosis and hepatocellular carcinom a,

Currently, standard treatm ent of chronic hepatotϊs C infection involves adm inistration of pegytated interferon-alpha in com bination with ribavirin, However, this therapy is not effective in reducing HCV RNA to undetectable levels in m any infected patients and is associated with often intolerable side effects such as fever and other influenza- 1 ike sym ptom s, depression, throm bocytopenia and hem olytic anem ia. Furtherm ore, som e HCV- infected patients have co-existing conditions which coπtraindicate this treatm ent

Therefore, a need exists for alternative treatm ents for hepatitis C viral infection. One possible strategy to address this need is the developm ent of effective antiviral agents which inactivate viral or host cell factors which are essential for viral replication,

HCV is an enveloped positive strand RNA virus in the genus Hepacivirϋs in the Flaviviπdae fam ily. The single strand HCV RNA genom e is approxim ately 9500 nucleotides in length and has a single open reading fram e (ORF), flanked by 5' and 3' nαn-traosiated regions. The HCV 5" non -translated region is 341 nucleotides in length and functions as an internal nbosom e entry site for cap-independent translation initiation. The open reading fram e encodes a single large polyprotein of about 3000 am m o acids whrch is cleaved at m ultiple srtes by cellular and viral proteases to produce the m ature structural and non-structural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins. The viral IMS2/3 protease cleaves at the NS2- N S3 junction, while the viral NS3 protease m ediates the cleavages downstream of WS3 _» at the NS3-NS4A, NS4A-NS4B, NS4B- NS5A and NS5A-NS5B cleavage sites, The NS3 protein also exhibis nucleoside triphosphatase and RNA helicase activities. The NS4A protein acts as a cefaclor for the W53 protease and m ay also assist in the m em brane localization of NS3 and other virai replicase com ponents, Although NS4B and the NSSA phosphoproteiπ are also likely com ponents of the replicase, their specific roles are unknown. Trie NSSB protein is the elongation subunrt of the HCV re picas© possessing RNA-dependent RNA polym erase (RdRp) activity,

The developm ent of new and specific anti-HCV treatm ents is a high priority, and virus-specific functions essential for replication are the m ost attractive targets for drug developm ent. Trie absence of RNA dependent RiMA polym erases in non- hum ao m am m als, and the fact that this enzym e appears to be essential to viral replication, would suggest that the NS5B polym erase is an ideal target for anti-HCV therapeutics. It has been recently dem onstrated that m utations destroying MS5B activity abolish infeetivity of RNA in a chim p m odel |KolykhaIov, A. A.; Mihalik, K,; Feinstone, BM ; Rice, CM., 2000; J, WoL ?4: 2046-20S1).

WO 2007/087717 and WO 2008/0019477 disclose com pounds of the general form ula (A):

wherein R ^s is an optionally sub inssttiittuutteedd a arryyll o orr H Heett wwhhiicclh are useful for the treatm ent of Hepatitis C virus infections SUMMARY OF THE INVENTION

The present invention provides a novel series of com pounds hawing inhibitory activity against HCV polym erase. In particular com pounds according to this invention inhibit RNA synthesis by the RNA dependent RNA polym erase of HGV ₁ especially the enzym e NS5B encoded by HCV. A further advantage of com pounds provided by this invention ts their low to very low or eveo noπ-signicant activity against other polym erases. Further objects of this invention arise for the one skilled in the art from the following description and the exam ples.

One aspect of the invention provides com pounds of form ula (I):

where rn: either X is absent and ¥ is O; or Y is absent and X is O; n is O to 4; R ² ϊs selected from : a) halo, cyaπo, nϊtro or SO ₃ H; b) R ⁷ , -CI=O)-R ⁷ , -C(=Q)-Q~R ⁷ , -O- R ⁷ , - S-R ⁷ , -SO-R ⁷ , - SO ₂ -R ⁷ , -(C ₁ Jalkyiene-IR ⁷ , -(C _{1 6} )aikyiene-C(=O)- R ⁷ » -(C _t4 )aikyien§-C(=O}- O-R ⁷ , -(Cjalkylerie-O- R ⁷ , HC ₁ . ,j]aikyIene- S- R ⁷ _» - (Ci, ₆ )alkylene-SO-R ⁷ or - (C,. _s )ali<yiene~SQj~R ⁷ ; wherein R ⁷ is in each instance independently selected from H, (Ct ejalkyl (C _{2 €} «)alkeiiyl, (C _{2 β} )alkynyl» (Ct _# )haloatkyi, {C* r)cycioalkyl, -^Ci^alkyl-tC^cycloaikyi, aryt and Hit; wherein the (C, _-β )alkyl, (C ₂ <a)a:ikeny1, (C^)alkynyl, (C^haloalkyf, (Ga.i)cycloalkyl, -(Ci, ₆ )alkyl-(C ₃ .?}cydoalkyI, and (C _t ejalkyiene are optionally substituted with 1 or 2 substituents each independently selected from -OH ₍ -(C, _β )alNyl optionally substituted with -O-(Ci. ₆ )aikyl, halo, -(d. _β )haloalkyl _t (Ca.jjcycloafcyl, -O-(C«)allyl« cyano, COOH , - NH ₂ , -NH(C _{1 -4} )aSkyf, - NH(C _M )cycloalkyl, -N((C _1-4 )alkyl)(C _{3 -7} )cycloalkyl. - N((C _M )alkyl) _a -N({C _{S 4} )alkyl)<aryl), aryl, -(C^Jalkyl-aryl, -0-(C _{1 6} )alkyi- aryl, -S-(C _1-6 )akyl-aryl, Het, -(Ci _β )alkyl- Het, -0-(C _{1 6} )alkyl-Het; and wherein each of the aryl and Met is optønaliy substituted with 1 to 3 substituents each independently selected from ,

\) halo, cyaπo, oxo, thϊoxo. im rno, -OH, - 0- (Ci e)alkyl. -O-(d «)haloalkyl. -{C^eyctoa-Ikyf, - (C^^haloalkyl. -C(-O)- (C _1-6 )alkyl. COOH, -SOj(C _{1 β} )alkyi, -CC=O)-NH ₃ , -C(^Q)- NH(C _1-4 )alkyl, - C(=Oj-N((C, ₄ )alkyl) _2< -C(=G}- NH(C _M )eyctoaikyl, -C(=OJ- N((C _1-4 )afcylKCw )cydoaikyI, - NH ₂ , -NH(C _{1 4} )alkyl, -N((C _M )atkyl) _2> -NH(C3.7)cycloatkyl _r - N((C _M )alkyIKC _H )cycl03lkyl or -NH-C(=θχC _M )alkyl; it) (C _1-6 )alky! Qptionalfy sybstrlut€d with -OH, -O- (C _1-6 )hatoafcyi, or -O-(C _1-6 )alkyl; and iiϊ) aryl, -(C _1-6 )alkyl-aryl. Het Or-(C ₁ «)alkyl- Het, wherein each of the aryl and Het te optionally substituted with halo, (C _1-6 )alkyl or NH ₂ , and c) - N(R ^s )R ^f , -C(=O)- N(R ^e )R ^s , -O-C(=O) _' N(R ⁸ }R ^f , -SO _r N(R ^B )R ⁹ , -(C _1-6 )atkyfene-N{R*)R ^s , - (C _1-6 )alkylene -C(=O|-N(R ^s )R ^l , -(C _1-6 )aIkyieoe-0-C(=0)- N(R ⁱ )R ⁹ , or -(C _{1 6} }sIhylene-SO ₂ -N(R ^a )R ^B ; wherein the (C _i4 )alkylene is optionally substituted with 1 or 2 substituents each independently selected from -OH, - (d ejalkyl, halo, -(C _1-6 )hatoallyi, (C ₃ 7>cycioalkyi , -0-(C _1-6 )alkyl, cyano. COOM ₁ -NH ₂ , - NH(Ct-i)alkyl _r -NHfCs-Tlcycloafeyi, -NC(C, j,)alkyl)(Ca τ)cycbalkyf and ^■ N((Ci.*)alkyl b: R ^J is in each instance independently seieded from H, (C«)alkyl and (Cj. _τ )cycloa!kyl; and R ^β is in each instance independently selected from R ¹ , -O-(C _1-6 )alkyl, -(C , sjai kylene-R ⁷ , -SO?- R ⁷ , -C(=O)- R ⁷ , -C ( =0)0R ⁷ and -C( ^S O)Np ⁸ IR ¹ ; wherein R ⁷ and R* are as defined above; or R* and R ⁹ , together with the N to which they are attached, are linked to form a 4- to T-m em bered heterocycle optionally further containing 1 to 3 heteroatom s each independently selected from N , O and S, wherein each S heteroatom m ay, independently and where possible, exist in an oxidized state such that it is farther bended to one or two oxygen atom s to form the groups SO or SO ₁ ; wheretn the heteracyeie is optionally substituted with 1 to 3 substituents each independently selected from (Ci _© )alkyl, (d «)haloalkyl. halo, oxo, -OH, -SH, -0(C _{1 B} )alkyl. -S(C _{1 β} )alkyl, (Cj jjcycloaikyi , -NH ₂ , - NH(C ₁ ,JaIKyI ₁ - N((Ci ₆ )alkyl) _? , - NH|C ₃ ,)cycfoalkyi, -M((C, ₄ )a!hyI3{C _{3 /} Jcyeloafcyl, -CI=O)(C _{1 9} )alkyl and -NHC(=O)-(Ci ejalkyl, R ⁵ is H, (Ci^)alkyl. (C ₃ i)cyetøalkyi, -(C, ₆ )3lkyl-(Cj _τ )cycloalkyl, aryl, -(C _{1 6} )alkyl-aryi, H et or -IC ₁ §)alkyl- Het; each being optionally substituted with 1 to 4 sybstttuents each Independently selected from (Chalky I, (C ^) ha tea I kyi, {C^rjcycloalkyl, Het. -OH, - COOH, -C(-QHC»-β}afkyI, -C(^G)- Q-(C _{1 β} )alkyl _f -SCyC^alkyl. -C(=O)-M(R ⁵ⁱ )R ^s and -O- R ^Θ ; wherein R ^5Ϊ is <C _t «)alkyl, (C _{3 -7} )cycloalkyl, -(C _{1 c} )alkyl- (Cuϊcyeioalkyl, aryl, -(C _{1 β} )alkyl-aryl, Hit or - (Cι «)atkyl-H6t, said aryl and Het being optionally substituted with (C _{1 6} )afkyl or -0- (Ci c)alkyl; wherein R ⁵¹ is H, (C _{1 &} )aikyl or (C _{3 /} )cycloalhyi; and R ⁵¹ is H, (C ₁ B)alkyϊ. (C ₃ . ₇ )cycloalkyl» aryi, HeI, -(C _f j)alkyl-aryl or -(C _{1 3} )aikyϊ-Het, wherein eaeft of the (Ci-e)aikyl, |C3-7)cycloaIity1 ₍ aryl, Het, -(C _{1 3} )alkyl-aryl and - (C _{1 3} )a!kyl-Het are optrønally substriuied with 1 to 3 substituents each independently selected from (C ₁ §)alkyl, (Ci ₄ )haloalkyl. halo, oxo, -OH, -Q(C ₁ «)alkyl. -NH ₂ , -NH(C _{1 e} )aikyl _r - N((Ct i}alkyl) _2> -NH(C _{3 -7} )cydoalkyI, -N((Ci^)alkyl)(C ₃ . _r )cyclo3lkyl. -C(=O)(Cn)alkyl and -NHC(=O)-(C ₁ «)alkyl; wherein the (C^ _-6 )alkyl is optionalfy substituted with OH; or R ⁵¹ and R ⁵² , together with the N to which they are attached, are Im ked to form a 4- to 7-m em bered heterocycle optionally further contaϊm ng 1 to 3 heteroatom s each independently selected from N, O and S, wherein each S heteroatom m ay, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atom s to form the groups SO or SO>: wherein the heterocyeie is optionally substituted with 1 to 3 substituents each independently selected from (C ₁ §)alkyl, (Ci ₆ )haloalkyl. Halo, oxo, -OH, -OfC _{1 &} )aftyϊ, -NH?, -NH(C ₁ «)alkyt, -H((Cf e)alkyl) _2l -NH(C, _r )cycloalkyl, -N(CC ₁ 4JaIRyIMC ₃ ,)cycloalkyl. -Cf=O)(C, «)alkyl and -NHC(=OMCi «)alkyl; R ⁶ is (C ₃ /|<eyefoaikyI, -(Ci^)atkyl-(Ci, _/ }cycioalkyl, aryi, -(Ci g)alkyt-aryl, HeI Or -(C ₁ §)alkyl-ttet; being optionally substituted with 1 to 5 substituents each independently selected from halo, (Chalky I, (C^haloalkyl, {C ₃ . ₇ )εycloaBcyl, -OH, -SH, -O-fC _M jalkyl, -S-(C ₄ JaIKyI and -N|R ^B )R ⁹ ; wherein R ^B and R ⁹ are as defined above; and Het Is a 4- to 7-membered saturated, unsaturated or aromatte heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S , or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O ₁ N and S; wherein each N fieteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form in N-oxide group and wherein each S heteroatom may, independently and wfiere possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO ₂ ; or a salt or ester thereof, Another aspect of this invention provides a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as a medicament

Still another aspect of this invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (IJ or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutical Iy acceptable carriers.

According to an embodiment of this aspect, the pharmaceutical composition according to this invention additionally comprises at least one other antiviral agent,

The invention also provides the use of a pharm aceutical composition as described hereinabove for the treatment of a hepatitis C viral infection in a mammal having or at risk of having the Infection.

A further aspect of the invention involves a method of treating a hepatitis C viral infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, or a composition thereof as described hereinabove.

Another aspect of the invention Involves a method of treating a hepatitis C viral infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula (I) or a pharm aceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof.

Also within the scope of this invention is the use of a compound of formula (I} as described herein, or a pharm aceutically acceptable salt or ester thereof, for the treatment of a hepatitis C viral infection in a mammal having or at risk of having the infection,

Another aspect of this invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for tie treatment of a hepatitis C viral infection in a mammal having or at risk of having the infection.

An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat a hepatitis C vfral infection; and packaging material comprising a label which indicates that the composition can be used to treat infection bv the hepatitis C virus; wherein the composition comprises a compound of form ula (I) according to this invention or a pharmaceutically acceptable salt or ester thereof,

Still another aspect of this invention relates to a method of inhibiting the replication of hepatitis C virus comprising exposing the virus to an effective amount of the compound of formula (I), or a salt or ester thereof , under conditions where replication of hepatitis C virus is inhibited,

Further included in the scope of the invention is the ust of a compound of formula (I), or a salt or ester thereof, to inhibit the replication of hepatitis C virus.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the following definitions apply unless otherwise noted;

The term "substituenf, as used herein and unit as specified otherwise, is intended to m ean an atom , radical or group which m ay be bonded to a carbon atom , a heteroatom or any other atom which m ay form part of a m olecule or fragm ent thereof, which would otherwise be bonded to at least one hydrogen atom Substjtuents contem plated in the context of a specific m olecule or fragm ent thereof are those which give rise Io chem ically stable com pounds, such as are recognized by those skilled in the art

The term "(G _{1 n} )alkyl" as used herein, wherein n is an integer, either alone or in com bination with another radical, is intended to m ean acyclic, straight or branched cham alkyl radicals containing from 1 to n carδon atom s and includes, but is not lim ited to, m ethyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-m ethylethyl (isø-prøpyl), 1-m ethyIprøpyl (see- butyl), 2-m ethy I propyl (/sσ- butyl), 1 , 1-dfm ethylethyl (teit-butyl), peotyl and hexyl The abbreviation Me denotes a m ethyl group; Et denotes an ethyl group, Pr denotes a propyl group, tPr denotes a 1-m ethylethyl group, Bu denotes a butyl group and tBu denotes a 1 _t 1-dϊm ethyleihyl group.

The term "(C _{1 π} )alkyleπe" as used herein, wherein π is an integer, either alone or in com bination with another radical, is intended to m ean acyclic, straight or branched chain divalent alkyl radicals containing from 1 to n carbon atom s and includes, but is

not lim ited to, -CH ₂ - , -CH ₂ CH ₂ - ,

The term "(Cj _n )alkenyl", as used herein, wherein n is an integer, either alone or in com bination with another radical, is intended to m ean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atom s, at least two of which are bonded to each other by a double bond Exam ples of such radicals include, but are not lim ited to, etftenyl (vinyl), 1-ρropenyl, 2- ρropenyl, and 1-butenyl.

Unless specified otherwise, the term ^β {C ₂ ,,jalkeπyi ^™ is understood to encom pass Individual stereoisom ers where possible, including but not lim ited to (E) and (Z) isom ers, and m ixtures thereof. When a (Cj _n ) alkenyϊ group is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom , unless specified otherwise, such that the substitution would give rise to a chem ically stable com pound, such as are recognized by those skilled in the art,

The term "(C _{7 π} )alkynyl ^π . as used herein, wherein n is an integer, either atone or in com bination with another radical, is intended to m ean an unsaty rated, acyclic straight or branched chain radical containing two to n carbon atom s, at least two of which are bonded to each other by a triple bond Exam ples of such radicals include, but are not lim ited to, ethynyl, 1-ρrapynyl, 2-ρrapynyl, and 1-butynyl. When a (Ciβ)alkynyi groyp is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom , unless specified otherwise, such that the substitution #ould give rise to a chem ically stable com pound, such as are recognized by those skilled in the art.

The term ^■" (Gj. _m jcycloalkyl" as used herein, wherein m is an integer, either alone or in com bination with another radical, is intended to m ean a cycloalkyl substituent containing from 3 to m carbon atom s and includes, but is not lim ited to, cycloprσpyl, cydobutyi, cyεϊopentyl, cyclohexyl and cydoheptyl.

The term "- (Cf «)alkyl-{C ₃ .m)cydoalkyr as used herein, wherein n and m are both integers, either alone or in com bination with another radical, is intended to m ean an alkyl radical having 1 to n carbon atom s as defined above which is itself substituted with a cyctoalkyl radical containing from 3 to m carbon atom s as defined above, and includes, but is not lim ited to, cyclopropylrπethyl, cyclobutylm ethyl. cydopenty I m ethyl, cydohexylm ethyl. 1-cyclopropylethyl, 2-cydcpropyl ethyl. 1- cyclobutylethyl, 2-cyciobutylethyl, 1-cyefopentylethyi, 2-cydopentylethyl. 1- cyelohexylethyl and 2-cy do hexy (ethyl When a |C _{3 H1} ,jcycIoai KyI-IC _{1 n} )alkyt- group is substituted, it is understood that substϊuents m ay be attached Io either the Cf cioalkyt or the alkyl portion thereof or both, unless speciied otherwise. The term "aryt" as used herein, either alone or in com bination with another radical, is intended to m ean a eartecycic arom atic m onocyclic §roup containing 6 cartoon atom s which m ay be further fused to a second 5- or S- m em bered carbocycic group which m ay be arom atic, saturated or unsaturated, Aryl includes, but is not lim ited to, pnenyl, iπdanyl, iπdenyl, 1-naphthyl, 2-naμhthyl, tetrahydroπaphthyl and dihydroπaphthyl.

The term "- (Ci _Λ )atkyi-aryl" as used herein, wherein n is an integer, either alone or in com bination with another radical, is intended to m ean an alkyl radical having 1 to π carbon atom s as defined above which is itself substituted with an aryi radical as defined above. Exam ples of aryl-(C| _n )alkyl- include, but are not lim ited to, phenylm el hyi (benzyl), 1-phenylethyl, 2-phenylethyl and phenyipropyl When an aryi-{Cι _n )alkyl- group is substituted, tt is understood that substituents m ay be attached to either the aryl or the alkyl portion thereof or both, uniess specified otherwise.

The term "Met" as used herein, either atone or in com bination with another radical, is intended to m ean a 4- to 7-m em bered saturated, unsaturated or arom atic rieterocycle having 1 to 4 heteroatom s each independently selected from O, N and S, or a 7- to 14-m em bered saturated, unsaturated or arom atic heteropolycyde having wherever possible 1 to 5 heteroatom s, each independently selected from O, N and S; wherein each N iieteraatom m ay, independently and where possible, exist in an oxidized slate such that it is further bonded to an oxygen atom to form an N- oxide group and wherein each S heterøatom m ay, independently and where possible, exist in an oxidized state sueh that it is further bonded to one or two oxygen atom s to form the groups SO or SCb, unless specified otherwise. When a Het group is substituted, it is understood that substituents m ay be attached to any cartoon atom or heteroatom thereof which would otherwise bear a hydrogen atom , unless specified otherwise.

The term "- (Ci _n )alkyl-Het" as used herein and unless specified otherwise, wherein n is an integer, either alone or in com bination with another radical, is intended to m ean an alkyl radical having 1 to n carton atom s as defined above which is itself substituted with a Het substituent as defined above. Examples of inclode, but are not limned to, thienyl methyl, fϋrylmethyl. piperidioylethyl, 2- pyndinylmethyl.3-ρyridiny (methyl, 4-ρyrtctinylmethyl, quinolinylpropyl, and the like.

When a Het-(Ci. _π )aikyl- group is substituted, it is understood that substituents may be attached to either the Het or the alkyl portion thereof or both, unless specified otherwise

The term "heteroatom" as used herein is intended to mean O, S or N,

The term "heterocyde ^1* as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a 4- to 7-membered saturated, unsaturated or aromatic heterocycfe containing from 11o 4 heteroatoms each independently selected from O, N and S; or a monovalent radical derived by removal of a hydrogen atom therefrom. Examples of such heterocycles include, but are not limited to, azetidϊπe, pyrrolidine, tetrahydrofuran, tetrahydrathtophsne, tniazoicJiπe, oxazolidine, pyrrole, thiophene, furan, pyrazole, tmidaiole, isoxazole, oxazole, ϊsothsazote, thϊazole, Iriazote, tetrazole, pϊpeπdme, piperazine, azepine, diazepine, pyrsn, 1,4-dιoxane, 4-morpholιne, 4-th iomorp hoi tne, pyridine, ppdιne~N-o»de, pyridazine, pyraane, pyrimidine, and the following heterocycles:

and saturated, ynsaturated and aromatic derivatives thereof,

The term "heteropolycycte ¹¹ as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a fieterøcyele as defined above fused to one or more other cycle, including a carbocycle, a heterocycte or any other cycle; or a monovalent radical derived by removal of a hydrogen atom therefrom. Examples of such fieteropoiycycles include, out are not limited to, indole, iso Indole, benzimidaiole, benzothiophene, benzofuraπ, benzodroxoie, beozottiazole, quϊnoline, isoquirtoline, naphthyridme, and the following heteropoly cycles; and saturated, ynsaiu rated and aromatic derivatives thereof

The term "halo" as used herein is intended to mean a halogen substituerit selected from fluoro, chloro, bromo or ιodo.

The term "(Ci _n )haloalkyr as used herein, wherein n is an integer, either atone αr in combination with another radical, is intended to mean an aikyl radical having 1 to π carbon atoms as defined above wherein one or more hydrogen atoms are each replaced by a halo substitueπt. Examples of (C _{1 n} )haloaikyl include but are not limited to chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bramoethyl, ciibromoetftyl, fluoromethyl, diuorømetliyi tπfiuoromethyl, fluoroethyl and diffuoroethyl,

The term s " ^■ -O-(Cn,)atkyr or "(G^aikoxy" as used herein interchangeably, wherein n is an integer, either alone or in combination with another radical, is intended to mean an oxygen atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above, Examples of -O-(Ci _n )afcyl include but are not limited to methoxy (CH ₃ O-), eth∞cy fCHjCHjO-), propoxy ICH ₃ CHJCHZO-), 1 -methyl ethoxy {iso- propoxy; (CH ₃ ) _Ϊ CH-O-) and 1,1-dιmethylethoxy (ferf-butoxy; (CHh) jC-O). When an -O-(Ci njaiHyl radical is substituted, it ts understood to be substituted on the (C _{1 n} )alkyi portion thereof.

The terms "--S-(C _{1 π} )aikyl" or "(C _{1 n} )aikylttiiθ" as use-d herein interchangeably, wherein n is an integer, either alone or in combination with another radical, is intended to mean an sulfur atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above, Examples of -S-IC _{1 π} )aiyi include but are not limited Io methylthio (CH ₃ S-), ethylthto (CH ₃ CH _? S-), propyithio (CH ₃ CHjCH ₃ S-), i-methyletriylthio (isopropylthto, (CHj) ₃ CH-S-) and 1,1-dιmethylethytthιo (tert-birtylthio; (CH,) ₃ C-S-) When -S-(C ₁ ^aI kyl radical, or an oxidized derivative thereof, such as an -SO-(C _{1 n} )aikyl radical or an -SOr(C _{1 n} Jalfcyi radical, is substituted, each is understood to be substituted on the (Ci _n )alkyl portion thereof. The term "oxo" as used herein is intended to m ean an oxygen atom attached to a cartoon atom as a sybstiuent by a double bond {=O}.

The term "thioxe" as used herein is intended to m ean a sulfur atom attached to a carbon atom as a substftuent by a double bond (=S).

The term Im ino" as used herein is intended to m ean a NH group attached to a cartoon atom as a substituent by a double bond (=NH).

The term "cyano" or ⁴¹ CN" as used herein is intended to m ean a nitrogen atom attached to a carbon atom by a tπple bond (C=N).

The term "COOH ^* as used herein is intended to m ean a carboxyl group (-C(=O)-OH), It is welt known to one skilled in tie art that cartjoxyl groups m ay be substituted by functional group equivalents. Exam ples of such functional group equivalents contem plated in this in vent ton include, but are not lim ited to, esters, am ides, ϊm ϊdes, bofonic acids, pluosphortic acids, phosphoric acids, tetraaoies, tπaioles, N-acylsulfem ides (RCONHSOaNRj) ₁ and N-acyfsulfbnam ides (RCONHSOaR).

The term "functional group equivalent" as used herein is intended to m ean an atom or group that m ay replace another atom or group which has sim ilar electronic, hybridization or bonding properties,

The term "protecting group" as used herein is intended to m ean protecting groups that can be used during synthetic transformation, including but not lim ited to exam ples which are listed in Greene, "Protective Groups in Organic Chem istry", John Wiley & Sons, New York (1981 ), and m ore recent editions thereof, herein incorporated by reference,

The following designation is used in siΛ-form ulas to indicate the bond wπich is connected to the rest of the m olecule as defined. The term "salt thereof ^* as used herein is intended to m ean any acid and/or base addition salt of a com pound according to the invention, including but not lim ited to a pharm aceutically acceptable salt thereof.

The term "pharm aceutically acceptable salt" as used herein is intended to m ean a salt of a com pound according to the invention which is, within the scope of sound m edical Judgm ent, suitable for use in contact with the tissues of hum ans and lower anim als without undue toxicity, irritation, allergic response, and the like, com m ensurate with a reasonable benefit/risk ratio-, generally water or oil-soluble or dispersible, and effecfce for their intended use. The term includes pharm aceutical Iy- acceptable acid addition salts and pharm aceutics I ly-aceeptab Ie base addition salts. Lists of suitable salts are found in, for exam ple, SM, Berg e et al. _r J. Phamn. Sd., 197?, 66, pp 1- 19, herein incorporated by reference

The term "pharm aceuticaiy-aeceptable acid addition salt" as used herein is intended: to m ean those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, form ed with inorganic acids including but not lim ited to hydrochloric acid, hydrobrom ic acid, sulfuric scid, sulfam ic acid, nitric acid, phosphoric acid and trie like, and organic actds including but not lim ited to acetic scud, trifluoroacete acid, adipic scud, ascorbic acid, as pa rtic acid, benzenes u If onic acid, benzoic acid, butyric acid, cam phoric acid, cam phorsulfonrc acid, αnnam ic acid, ctlrtc acid, digluconϊc acid, ethanesulfonic add, glutam ic add, glycolic acid, glycerophosphoric acid, riem isutfic acid, hexanoϊc acid, form ic acid, fum aric acid, 2-hydroxyethanesulfoπic acid (isetriionϊc acid), lactic acid, hydrexym aleϊc acid, m alic add, m atonϊc acid, m andelϊc acid, m esitylenesulfonic acid, m ethanesulfoπic acid, naphthaϊenesulfonic acid, nicotinic acid, 2-πaphthafenesuIfcπic acid, oxalic acid, pam oic acid, pectinic acid, phenylacetic acid, 3~ phenyl prop ionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfam ic acid, tartaric acid, p- taiuenesutfenic actd, uπdecaπoic actd and the like

The term "pharm aα≥utieaily-acceptable base addition salt as used herein is intended to m ean those sals which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, form ed with inorganic bases including but not limited to ammonia or the hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium , lithium , calcium , magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly preferred are the ammonium, potassium, sodium , calcium, and magnesium salts, Salts derived from pharmaceutical ly-acceptable organic nontoxic bases include but are not limited to salts of primary, secondary, and tertiary amines, quaternary amine com pounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamiπe, dϊmethylamine, trimethylamine, ethy famine, diethylamfne, triethylamine, ϊsopropylamiπe. tri propylamine, tributylamine, ettianoiamiπe, diethaπolamine, 2-dimethylaminύethanoL 2-diethylamfnαethanol, dicyclσhexylamiπe, lysine, arginine, hisiidϊne, caffeine, hydrabamine, choline, betaine, ethyfeπediamϊne, glucosamine, methylglueamine, theobromine, purines, piperazine, piperidine, N- ethylprpendin-e, tetramethyiammonϊum compounds, tetraethylammonium compounds, pyndine, N,N-dtm#thyIani!iπe, M-m#thyIpiρeridine, N-rπethylmorpholine, dicyclohexytamirte, dibenzytamine, N.N-dibenzylphenethylamine, 1-epfienarτiine, N.N'-dibenzytethylenediamine, polyamϊne resins and the like. Particularly preferred organic nontoxic bases are isop ropy Ia mine, diethylamine, elhanolamine, trimethylamine, dicycloiiexyiamine, choline, and caffeine,

The term "ester thereof as used herein is intended to mean any ester of a compound according to the invention in which any of the -COOH substituents of the molecule ϊs replaced by a -COOR substituent, in which the R moiety of the ester is any carbon-contain ing group which form s a stable ester moiety, including but not limited to alkyf, alkenyl, alkynyl, cycloalkyl, cycJoalkylaikyl, aryl, arylalkyϊ, heterocyclyl, heterocyclylalkyi, each of which being optionally further substituted, The term "ester thereof includes but is not limited to pharmaceutically acceptable esters thereof.

The term "pharmaceutically acceptable ester" as used herein is intended to mean esters of the compound according to the invention in which any of the COOH substiuents of the molecule are replaced by a -COOR subsituent, in which the R moiety of the ester is selected from alkyl (including, but not limited to, methyl, ethyl, propyl.1-mettiylethyl, 1,1-dimethyletfiyl, butyl): altoxyalkyl (including, but not limited to metfioxymethyt); acyioxyalkyi (including, but not limited to aoetQJsymethyi); aryiatkyl (including, but not limited to, benzyl); aryloxyalkyl (Including, but not limited to, ptieoσxymethyi); and aryl {including, but not limited to phenyl) optionally substituted with halogen, (Chalky! or (C _M )alkoxy. Other suitable esters can be found in Design of Prodrugs, BuπcJgaard, H, Ed, Elsevier (1385), herein incorporated toy reference. Such pharmaceutical Iy acceptable esters are usually hydrolyzed in wvo when injected into a mammal and transformed into the acid form of the compound according to the invention, With regard to the esters described above, unless otherwise specified, any alky I moiety present preferably contains 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group. In particular the esters may be a (Ci iβ)alkyl ester, an unsybstituted benzyl ester or a benzyl ester substituted with at least one halogen, fG^slalkyl, (C ₁ ^aIkOXy ₁ niro or tπfluoromethyl.

The term "mammal" ^* as used herein is intended to encompass humans, as wefi as non-human mammals which are susceptible to infection by hepatitis C virus, Non- riuman mammals tnclude but are not limited to domestic animals, such as eows, pigs, horses, dogs, cats, rabbits, rats and mice, and norKtomestϊe animals.

Trie term "treatment" as ysed herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/of to prevent the virus from reaching detectible levels in the blood.

The term "antiviral agent" as used herein is intended to mean an agent that is effective to inhibit the form ation and/or replication of a virus in a mammal,, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.

The term "therapeutically effective amount" means an amount of a compound according to the Invention, whtcn when adm inistered to a patient in need thereof, is sufficient to effect treatm ent for disease-states, conditions, or disorders for which the com pounds have utility. Such an am ount would be sufficient to elicit the biological or m edical response of a tissue system , or patient that is sought by a researcher or clinician, The am ount of a com pound according to the invention which constitutes a therapeutically effective am ount will vary depending on syeh factors as the com pound and its biological activity, the com position used for adm inistration, the tim e of adm inistration, the route of adm inistration, the rate of excretion of the com pound, the duration of the treatm ent, the type of disease-state or disorder being treated and its severity, drugs used in com bination with or coincidental^ with the com pounds of the invention, and the age, bodv weight, general health, sex and diet of the patient. Such a therapeutical Iv effective am ount can be determ ined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure,

Preferred embodiments

In the following preferred em bodim ents, groups and substituents of the com pounds of form ula (I):

are described in detail.

Core: Core-A: In one em bodim ent, the Core is:

wherein R ² , n , R ⁵ and R ⁶ are as defined herein; and wherein X and Y are defined as; X, Y-AiIn one embodiment X is G and Y is absent X, Y-BJn one embodiment, Y is O and X is absent.

Any and each individual definition of X, Y as set out herein may be combined with any and each individual definition of n, R ² , R ^s and R ⁴ as set out herein.

Core-β: In another embodiment, the Core ΪS ¹

wherein R ^J , n, R ^a and R* are as defined herein.

Core-G: In another embodiment the Core ss ¹

wtierein R ² , R and R ^s are as defined herein.

Core-D: In another embodiment, the Core is;

wherein R ml , _O R5 and R are as defined herein.

Core-E; i n a nother embodiment , the Core is :

wherein R , R and R are as defined herein. Cort-F; In another embodiment, the Core is;

wherein R ² , m, R ^s and R ^s are as defined herein. Cαre-6: In another embodiment, the Core is:

wherern w si, D RS and R are as defined herein.

Core-H: In one embodiment, the Core is: wherein R sϊ*, R I ₃ S* and R ⁶ are as defined herein. Core-I; in one embodiment, the Core is;

wherein R ² _F R ⁵ and R ⁶ are as defined herein. Any and each individual definition of the Core as set out herein may be combined with any and each individual definition of n, R ² , R ⁵ and R ⁶ as set out herein.

R ² : R ² -A: In one embodiment, R ² is selected from: a) halo, cyano, nϊtro or SO ₃ H; b) R ⁷ -C(=O)-R ⁷ , -C(=O)-O-R ⁷ , -O-R ^f , -S-R ⁷ , -SO-R ⁷ , -SO ₂ -R ⁷ , -(C _1-6 )alkylene-R ⁷ , -(C 1 ₆ )alkyIene-C(=O)-R ⁷ , -(C _1-6 )aIkyIene-C(=O)-O-R ⁷ ,-(C _1-6 )aIkylene -O-R ⁷ ,-(C _1,

₆ )alkylene-S-R ⁷ , -(C _1-6 )alkyIene-SO-R ⁷ or -(C _1-6 )alkylene-SO ₂ -R ⁷ ; wherein R ⁷ is in each instance independently selected from H, (C _1-6 )alkyl _r (C _2-6 )alkenyl, (C _2-6 )alkynyi, (C _1-6 )haloalkyl, (C _3-7 )cycloalkyl, -(C _1-6 )alkyl-(C _3-7 )cycloalkyl, aryl and Het; wherein the(C _1-6 )alkyl. (C _2-6 )alkenyl (C _2-6 )alkynyl, (C _1-6 )haloalkyl, (C _3-7 )cycloalkyl, -(C _1-6 )alky-(C _3-7 )cycloalkyl, and(C _1-6 )alkylene are optionally sybsirtuted with 1 or 2 substituents each independently selected from -OH, -(C _1-6 )alky I optionally sybstituted with -O-(C _1-6 )alkyl, halo, -(C _1-6 )haloalkyl, (C _3-7 )cycloalkyl, -O-(C _1-6 )alkyl. cyano, COOH, -NH ₂ , -NH(C _1-4 )aIkyl, -NH(C _3-7 )cycioaϊkyl, -N((C _1-4 )alkyl)(C _3-7 )cycloalkyl, -N((C _1-4 )alkyl) ₃ -N((C _1-4 )alkyI)(aryl), aryl, -(C _1-6 )alkyl-aryl, -O-(C _1-6 )alkyl-aryl, -S-(C _1-6 )alkyl-aryl. Het. -(C _1-6 )alkyl- Het. -O-(C _1-6 )alkyl-Het. and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, cyano, oxo, thioxo imino, -OH, -O-(C _1-6 )alkyl, -0-(C _1-6 )haloalkyl, (C _3-7 )cycloalkyl, (C _1-6 )haloalkyl, -C(=O)-((C _1-6 )alkyl, COOH, -SO ₂ (C _1-6 )alkyl, -C(=O)-NH ₂ , -C(=O)-NH(C _1-4 )alkyl, -C(=O)-N((C _1-4 )alkyl) ₂ , -C(=O)-NH(C _3-7 )cycIoaIkyl, -C(=O)-N((C _1-4 )aIkyl(C _3-7 )cycloalkyI, -NH ₂ , -NH(C _1-4 )alkyI, -N((C _1-4 )alkyI) ₂ , -NH(C _3-7 )cycloalkyl. -N((C _1-4 )alkyI)(C _3-7 )cycIoalkyl or -NH-C(=O)(C _1-4 )alkyl; ii) (C _1-6 )alkyl optionally substituted with -OH, -O-(C _1-6 )haloalkyl, or -O-(C ₁ β)alkyl; and Hi) aryl, '(Ci.β)alkyl-aryl, Het or -(C _{1 -6} )alkyl-Het, wherein each of the aryl and Het ts optionally substituted with haio _t (Ci _# )alkyl or NH ₂ ; and c) -N(R ⁸ }R ^fl , -C(=O)-N(R ⁸ )R ^β . -0-CC=O)- N(R ⁸ JR', -SO ₇ - NIR ¹ JR ⁹ , -(C _{1 §} )aIkyIene-N(R ⁸ )R ^s , - (G, ₆ )alkytene-C(=O)-N(R ⁱ )R ⁹ _r -(C _14j jaikyiene-O-C(=O)-N(R ^β )R ^fl , or - (C, ^)aikyiene-SO _? -N{R ⁸ )R*; wherein the (Cr.)alkyfene is optionally substituted with 1 or 2 substituents each independently selected from -OH, - (Ci «)arkyl. halo, (C, e)haloalky1, (C ₃ 7)cyclαalkyl , -O-CC^ialkyi, cyano, COOH, -NHj, - NH(C _M )alkyi, -NHIC _{3 τ} )cyctoalkyl. -N((C _M )a«ιyl)(C _{3 ?} )cyctoalkyl and - NI(C _{1 -4} )afcy1} ₂ ; R* ΪS in each instance independently selected from H, (C _t «)alS<yl and (C^^ycloalkyl; and R ⁹ is in each instance independently selected from R ^τ , -O-(Cμ ₆ )alkyl, -{d^alkylene-R ⁷ , -SO _r R ⁷ , -Cf=Q)- R ¹ , -C(=0)0R ⁷ and -C(=θ)N(R ^β )R ⁷ ; where m R ^τ and R* are as defined above; or R ¹ and R ⁹ , together with the N to which they are attached, are linked to form a 4~ to 7-m em bered heterocycle optionally further containing 1 to 3 heteroatom s each independently selected from N , O and S, wherein each S heteroatom m ay, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atom s to form the groups SO or SO ₂ , wherein the heterocycle is optionally substituted with 1 to 3 substituents each independently selected from (Ci ₆ )alkyl _r (C«)haloalkyl» halo, oxo, -OH, -SH ₁ -CXC^alkyl, - S(C _{1 f} Oalkyl, (C _M )cycloalkyl . -NH ₂ , - NH(C _{1 6} )aikyl, -N(fC«)alkyl) ₃ , -NHξC _{3 7} )cycloaikyl, -N((C _{1 4} )alkyiχC ₁ . _? }cycIoaIkyl ₁ -CI=OHC _{1 §} )alkyi and -NHC(=O)- (Cκ)alkyI. R ² -B: In another em bodim ent, R ³ is selected from : a) halo, nttro or SO ₃ H; b) R ^τ , -CC=Q)-R ¹ , -D-K', -S-R ⁷ , - SO-R ⁷ , - SO _r R ⁷ , -(C, _ft )alkyϊene-R ⁷ . ~{Cι,φikyiene-C{=QyR ^l , - (C _t ejalkyϊene-O-R ¹ , -H;C _{l 6} }alkylene-S- R ⁷ , -(C ₁ Jalkyieπe-SD-R ⁷ or -(C _{1 6} )alkyIene-SOi.-R ⁷ ; wherein R ⁷ is in each instance independently selected from H, (C _1-6 )alkyl _r (Cjejalkenyl, (Cj«)atkyπyl, (C _1-6 )haioa(kyl. (C _M )cycIoaikyi _r -(C _1-6 )alkyl-(C _{3 ?} )cyctoalkyl. aryl and HeI; wherein the (C _1-6 )alKyl. (C ₂₆ )afcenyl« (C _M )alky?iyl» (C _1-6 )haloalkyl, (Ci ijcycloalkyl -(C _1-6 )afcyl-(C _{3 7} )eycfoalkyl, and (C _1-6 )aikyiene are optionally substituted with 1 or 2 sobsirtuents each independently selected from -OH, - (C _1-6 )alkyl optionally substituted with -O-(C _1-6 )alkyi, halo, -(C _{1 6} )haloalkyl, (C _{3 7} )cycloalkyl, -O-(C _1-6 )alkyl , cyano, CQQH, - NH ₂ , - NH(C _{1 4} )alkyl, - NH(C ₃ , _? jcycloalkyl, - N((C, ₄ )alkyl)(C ₃ . ₇ ]cycbaikyl. - N(CC ₁ ^aIKyI) ₅ - N((C _{t 4} )alkyI)(aryI), aryI, -(C _1-6 )alkyl-aryl, -O-(C _1-6 )alkyl-aryl. -S-(C _1-6 )alkyl-aryl, HeI, -(C _1-6 )alkyl- Het. -O-(C _1-6 )alkyl-Het; and wherein each of the aryl and Het ϊs optionally substituted with 1 to 3 substituents each independently selected from ι) halo, eyano, oxo, -OH, -O-(C _1-6 )aikyi, -0-(C _1-6 )haioaikyi, (C _3-7 )cyctoaikyI, (C _1-6 )haiøalkyl, -C(=O)-(C _1-6 )alkyl, COOH, -SO ₇ (C _1-6 )alkyl, -Cf=O)-NH ₂ , -C(=O)-NH(C _M )«alkyl _i -C(=O)- N((C _M }aIkyi) _af -C(^Q)-NH(C _{3 7} )cycl03lkyl, -C(=O)- N((C _{3 -7} )akyi)(Ci _? )cyeioaikyi, -NH ₂ , - NH(C _M )alkyl, -N((C , ^ JaIHyI) ₂ , -NH(C _{3 r} )εydoafHyI ₍ - Nf(C ₁ ^ )alkyl)(Cj. ₇ )cycloalkyf or -NH- C(=Q)(C _{t 4} )aikyl; ii) (C _1-6 )alkyl optionally substituted with -GK - O- fCi.eJhafoalkyl. or -0-(C ₁ a)alkyl; and iii) aryl, -(C _t .e)alkyl-aryl, Het or -(Ci, ₆ )alkyl- Het, wherein each of the aryl and Het is optionally substituted with halo, (Ci ^alkyl or NH ₂ ; and c) -N(R ⁶ )R ⁹ , -C(=Q)- N(R ⁸ )R ^β , -O-C(=Qj- N(R*)R ^β , ^SO _r N|R ⁶ )R ^g , -(C _1-6 )alkyϊene-N(ft ^a )R ^β « - (C, _§ )alkylene-C(=O)-N(R ⁱ }i ^a , -(C _{1 β} )alkyiene-O-C(=O)- N(R*)R ^β , or -(C _{1 6} )aIkylene- SO ₂ -N(R ⁸ )R ^β , wherein the (Cdalkylene is optionally substityted with 1 or 2 sutetituents eadi independently selected from -OH, - (C _{1 β} )alkyl, halo, (Ci^)hsloalkyl. (C _{3 7} )cycloalkyl , -0- (C ₁ e)alkyl, cyano, COOH, -NH ₂ , - NH(C _M )atkyl, - HH(G ₃ ^)eydoaIky1, -N((Cn)a)kyl)(C ₃ . ₇ )cycbalkyl and - N((Ci^)alkyl) ₂ ; R8 is in each instance independently selected from H, (C _1-6 )alkyl and (C3, τ)cycloalkyl; and R ⁸ is in each instance independently selected from R ¹ , -O-(C _1-6 )alkyl _> -(C _1-6 )alkylene-R ⁷ , -SO ₂ - R ⁷ , -C{=O)- R ⁷ , -C(=G)GR ⁷ and ~G(=O)N(R ⁸ )R ⁷ ; wherein R ⁷ and R8 are as defined above, R ² -C: In another em bodim ent, R ² is selected from ¹ a) halo, nttro or SO ₃ H; b) R ^f . -C( =0 )-R ⁷ , -O-K ¹ . -S-Ff, -SO-R ⁷ , - SO ₃ -R ⁷ , -(C _1-6 )alkylene-R ¹ « -(C _{1 -6} )alkyfene-O-R ⁷ , -(C ₁ <,)alkylefie-S- R ⁷ , -(C _1-6 )alkylene-SG-R: ⁷ or -(C _1-6 )alkylene-SCt>~R ^3r , wherern R ⁷ is in each instance tndependenily selected from H , (C _1-6 )alkyl, (C _2-6 )alkenyl, (C ₇₄ )alkyπyl _r (C _t «)haloalkyl. (C _{3 ;} )cycloalkyl _r -(C _1-6 )alkyl-(Ci ^cyrfoalkyi, aryl and Het; wherein the (C _1-6 )alkyl, (C ₂ ^)alkenyl, (C _? «)alkynyl, (C^lhaloalkyt, (Ca, /)cycloalkyl, -(C _1-6 )alkyl-(C; _< τ)cycloalkyl, and (Ct tjalkyiene are optionally sybstiluted with 1 or 2 sybslrluente each independently selected from -OH, -(C _{1 d} )alkyl optionally substituted wrth -O-(C ₁ t)alkyl, halo, - (C _{1 6} jhaloaikyl, (C _{3 ?} )cycloalkyl, -O-(Ci^)alkyl. cyano, COOH ₁ -NH ₇ , -NH(C _{1 4} )alkyl. - NH(C _{3 -7} )cycloalkyt, -N((C _t ^)alkyl)(C _{3 7} )cycloalkyl, - N((C _M )alkyl)2 -N((C _M )alkyl)(aryI), afyI, -(C _t -cjalkyl-aryl, - O-fCi^Jalkyl- aryl, -S- (C _{1 -6} )afcyl-aryl, Het. -(C _{1 G} )alkyl* Het, -0-(Ci φ\k≠-Het: and wherein each of the aryl and Het is optionally substituted wrth 1 to 3 subsϊituents each independently selected from , i) halo, cyano, oxo, -OH, -0-(C i _R )aikyi, -O-(Ci _c )haloaikyl ₄ (C _{3 T} )cycloalkyl ₍ (C, _β )haloalkyl» -C(=OHC, e)alkyl _t COOH ₁ -SO ₂ (C,. ₆ )alkyl, -C(^O)-NH ₂₁ - C(=O)- NH(C _1-4 )alkyl _t -Cf=O)- NI(C _{1 4} >alkyl} _{3 r} -C(=O)-NH(C _{3 J} )cyctoaϊkyl, -C(=O)- N((C _{3 -7} )aIhyiXC ₁₇ )cycioaI(<yI, -NH _?( -NH(C _{1 4} )alkyl ₄ -Nt(C _M >alkyl)j. -NH(C ₃ . ₇ )cycloalkyl, -Ni(Ci 4)alkylKC ₃ . _? jcycloaikyl or - NH-C(=oχCi Oalkyl; ii) (C«)alkyl optionally sybstrtuted with -OH, -O- (C, «)haloalkyl. or -O-(Ci a)alkyl, and iii) aryl, -(C _{1 -6} )alkyl-aryl, Het or-(C ₍ eJalkyl-Het, wherein each of the aryl and Het is optionally substituted with halo, (C _1-6 )alkyl or NH ₂ ; and c) -M(R ⁸ )R ⁹ , -C^Q)- N(R ⁸ PVSQrMIR ¹ P ⁹ . -(C _1-6 )alky IeOe-N(R ¹ )R ^f , -(C _1-6 )aIkyϊene- C(=O)- N(R ⁸ )R ⁱ or - (C _1-6 )alkylene-SOrN{R')R*; wherein the (C _1-6 )alkyte πe is optionally substituted with 1 or 2 substituents each independently selected from -OH, '(C _1-6 )alkyl, halo , (C _1-6 )haloalkyl. (C _3-7 )cycloalkyl , -O-(C _1-6 )alkyl, cyano, CQOH, -NH ₂ , -NH(C _1-4 )alkyl, -NH(C _3-7 )cycloalkyl. -N((C _1-4 )alkyl)(C _{3 -7} )cyclc>alky'l and - N((C _1-4 )aIkyl) ₂ ; R ⁸ is in each instance independently selected from H and (C _1-6 )alkyl; and R ⁹ is in tach instance independently selected from R ⁷ , -O-(C _1-6 )alkyl, -(C _1-6 )alkylene-R ⁷ ₁ -SQ ₂ -R ⁷ , -C(=O)- R ⁷ ; wherein R ⁷ and R ⁸ are as defined above. R ² -D: In another em bodim ent, R ² is selected from : a) halo, nitro or SO ₃ H; b) R ⁷ , C(=O)OH, C(=O)(C _1-6 )alkyl, -0-R ⁷ , -S- R ⁷ , -SO- R ⁷ , -SO _Z -R ⁷ , -(C _1-6 )alkylene-R ⁷ . -(C _1-6 )alkylene- O-R ^τ , -(C _{1 S} )alkyiene-S- R ⁷ , -(C _1-6 )aikyIene-SO- R ⁷ or -(C _1-6 )alkylene-SO ₂ - R ⁷ ; wherein R ⁷ is in each instance independently selected from H, (C _1-6 )alkyi. (Cj-iialkenyi, (C2.β)alhynyl, (C _1-6 )haloalkyl. (C _{3 -7} )cydoa!kyl, -(C _1-6 )aIkyl-|C _{3 -?} )cycfoaIkyi aryl and Het; wherein the (C ₁ c)alkyl, (Cj e)alkeπyl. (Cj-^Jalkynyf, (Ci ^)haloalkyl, (Cv7)cycloalkyl, -(Ci. ₆ )alkyt-(C ₃ 7)cycloaH<yl, and {C _t «)atkylene are optionally substituted with 1 or 2 substituents each independently selected from -OH, -(C ₁ ^)SlKyI optionally substituted with -O-(C _{1 6} )alkyl, halo, -(d^Jhaloalkyi, (C ₃ . _/ )cyc!oaIkyl, -Q~(C _{t e} }a\k≠, cyaro, COOH, -NH ₂ , -NH(C ₁₄ )Si^I, - NH(C ₃ .?)eyctoΛyl, - N((C» J ₁ JaIKyI)(C _{3 -7} Jcycloalkyl, - N((C _M )aKyi) ₂ - Nf(C,^ )alkyl)( aryl), aryi, -(C _1-6 )alkyl-sryl, O-(C _1-6 )alkyl-aryl, -S-(C _1-6 )aISϊyl-ary1, Het, -(C _1-6 )alkyl- Het, -0-(C _{1 6} )alkyϊ-Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from , i) halo, cyano, oxo, -OH, -G-(Ci. _Λ )afcyi, -O-(C, -s)haloalkyl, (C _3-7 )cycloalkyl _r (C _1-6 )haloafhyl _r - C(=O)-(C _1-6 )alk yl, COOH, -SO ₂ (C _1-6 )alkyf, -Cf=Gl-MH ₂ , - CI=G)- MH(C _1-4 )atkyl, -C(=0)- N((C _1-4 )alkyl)a ₁ -C(=0>NH(C3.,)cycloalkyl ₁ -C(=O)- N((C i ₄ )alkyiχCi ,)cycloalkyl, - NH ₃ , - NH(C _M )alkyl, - N((Ct <)alkyl)z> -NH(C _{3 r} )cycloalkyl, -N((C _M )alkylKC3.7)cyctoalkvl or -NH-C(=Oχc _M )alkyl; it) (C _1-6 )alkyl optionally substituted with -OH, -O-(C _1-6 )haloalky1, or -O-(C _1-6 )alkyl; and

IH) aryl, -(C _1-6 )alkyl-aryl, Het or-(C _1-6 )alkyl- Het, wherein each of the aryl and Het is optionally substituted with halo, (C _1-6 )alkyl or NH _? ; and c) -N(R ⁴ JR*, -Ct=Q)- N(R ⁸ JRVSQ ₂ -NfR ⁶ IR ¹ , -{Chalky IeHe-N(R ¹ JR*, -(C _{1 6} )alkylene- C(==O)- N(R ^β )R* or - (C,. ₆ )alkylene-5G _r N(R ^s )R ^s ; wherein the (Ci-β)slkylene is optionally substituted with 1 or 2 substϊtuents each independently seiected from -OH, - (C,^)alkyi, halo, (C^ejhaioaikyl, (C ₃ . _r )cycloalkyl , -O-(C _1-6 )a lkyl, cyano, CQOH, -NH ₂ , -NH(C _M )alkyl aod -N((C _M )a!kyi) ₂ ; R* is in each instance independently selected from H and (C _1-6 )alkyl; and R ^s is in each tnstance indep€fidenly seiected from R ^τ , -O-{Ci.β)alkyl _r -(C _t - ₆ )aIkyIene-R ⁷ , -SO ₂ - R ⁷ , -C{-O)- R ⁷ ; wherein R ⁷ is as defined above, R ² -E; In another em bodim ent, R ^z is selected from : a) halo, nttro or SO3H; t>) R ^f , C{=O)OH, Ct=O)(C _{1 β} )aikyl ₍ -0-R ⁷ , -SQ ₂ -R ⁷ , - (C _{1 6} )aftylene- R ^f , -(C 1 e,)alkyϊene- O- R ⁷ , -<Ci ^atkyieoe-S- R ⁷ or -(Ct β}alkyIene-SQ _? -R ⁷ ; wherein R ⁷ is in each instance independently selected from H, (C, β)alkyl, (C _{2 6} )atkenyi, {C ₂ , ₆ )aikynyi, (C _t4 )haloatkyl, (C _v r)cycloalkyl _r ^C _t .β)alkyl-(C ₃ . ₇ )cycloalkyl _I aryl and Het; wherein the (C _{1 6} )alky1. (Cj^)alkenyt. (Cj^)alkynyl, (C^habalkyl, (C ₃ ι)cycloalkyi, -(Ci _θ )aikyl-{C _{ϊ r} >cycloalkyl, and (C _t «)alkylene are optionally substituted with 1 or 2 substftuents each independently selected from -QH, -(Ci.β)alkyl optionally substituted with -O-(C ₁₄ )alkyl, halo, -(d.βjhaloalkyl. (C^^cycioalkyl, -O-(C«)atkyI, COOH, - NHj, - N((C _I θalkyt)(aryl), aιyl, -(Ci ₉ >alkyl-aryl. -O-(C _M )afcyl- aryl, -S-(C _{1 c} )aftyl-aryl, Het, -(C ₁ β)alkyUHet, -O- (C«)atkyi-Het« and wherein each of the aryi and Met is optionally substituted wilh 1 to 3 substituerts each independently selected from ι) halo, cyano, oxo, -OH ₁ -0-(C ₁ sjalkyl, -O-(C _{1 β} )haloalkyl, (C _{1 7} )cycloalkyl, (C _{1 fi} )haloalkyl, -C(=OHCi *)alkyl. COOH, -Cf=O)- NH ₂ , -C(=O)- NH(Ci ₄ )alKyt. -C|=0)- N(|Ci j)alkyf) _2i -NH ₂ , - NH(C _{1 -} i)alkyl, - N((C _{t J} .)alkyl) ₂ or - NH-C(=0)(C, _-4 )alky1, tt) (Ci«β)atkyl optionally substituted with -OH, -O- (Ct «)haloalkyl, or -G-IC ₁ alalttyl, and

HI) aryl, -(Ct _« )alkyl-aryl, Het or -(Cf «)alkyl-Het _F wherein each of the aryf and Het is optionally substrtute-d with halo, (C _{1 w} )alhyl or NH ₂ , and c) 'N(R ⁸ JR*, -C(=O)- N(R ¹ )R ⁹ ,-Sθ ₂ -N|R ⁸ )R ⁱ , -(C _{1 §} )alkyϊerte- N(R ⁸ )R ^s , -(C _{1 6} )aikifIene- C{=O)- N(R ⁱ )R ⁹ or -(C, ₄ )aH<ylene-S0j- N(R ^a )R ⁹ _» wherein the (C^alkylene is optionalfy substituted with 1 or 2 substituents each independently selected from -OH, - (Ci «>alkyl, hato, -(Ct eJhatoalkyl, -0-(C _{1 δ} )aikyl» R ^β is in each instance independently selected from H and (C _lJt ,}alkyl _r and R ^β ΪS in each instance independently selected from R', -Cs-(C _t j _» )a Iky I ₁ -(C ₁ *5aIkyieπe-R ⁷ , -C(=Q)-R ^f , wfierBin R ^τ is as defined above R ^J -F; In another em bodim ent, R ² is selected from a) halo, nttro or SO ₃ H, h) R ⁷ , OH, C(-0)0H, C(O)(C _{1 c} )alkyl , -SO ₂ -R ⁷ , -(G _{1 f} )aIkyIene- R ⁷ , -(C, ₆ )aIkyϊene- O-R ⁷ , -(Ci ₆ )alkyiene-S-R ⁷ or -(C _t eJalk^iene-SOj- R ⁷ , wherein R ⁷ is in each instance independently selected from H, (Ci β)alkyl _> (C _2C )alkeπyi ₍ (C _{3 ε} }alkyrtyl ₍ {C _{t β} )haloalkyl, (C _{3 7} )cycloalkyl _f -(C 1 ₆ )alkyl-(C _{? τ} )cycloalky1, aryl and Het, wherein the |Ci _e )alkyl, (C ₇ «)aJkeny1. (C-? ₆ )alkynyl, (C _{1 e} JhaIoalkyl, (Ci rjfcycloalkyl, -(C, ₆ )aihyl- (Ci ₇ )cydoalky!, and (C, _g )alkylene are optionally substituted with 1 or 2 substituents each independently selected from -OH, -(C^alkyl optionally substituted with -O-(C ₁₄ )alkyl, halo, -(C _{1 6} )ha!oalkyi, (C _{3 7} )cycioalkyl, - O- (C, *)atkyl. COOH, - NH _j , - N((Ci ₄ )alkyt)(aryl), arøi -(Ci ₉ >alkyl-aryl. -G-(C _M )afcyl- aryl, -S-(C _{1 G} )alkyl-aryl, Het. -(C ₁ ^alkyUHet, 0- (C _{1 C} )alkyl- Het; and wherein each of the aryi and Met is optionally substituted wilh 1 to 3 substituerts each independently selected from ι) halo, cyano, oxo, -OH ₁ -0-(C ₁ sjalkyl, -O-(C _{1 β} )haloalkyl, (C _{1 7} )cycloalkyl, (C _{1 6} )hatøalkyl, -C(=OHCi *)alkyl. COOH, -Cf=O)- NH ₂ , -C(=Q3- NH|Ci ₄ )alKyt. -C|=0)- N(|Ci j)alkyf) _2i -NH ₂ , - NH(C _{1 -} i)alkyl, - N((C _{t J} .)alkyl) ₂ or - NH-C(=O)(C _i4 }aityl; tt) (Ci«β)atkyl optionally substituted with -OH, -O- (Ct «)haloalkyl, or -G-IC ₁ alalttyl, and

HI) aryi, -(Ct _« )alkyl-aryl, Het or -(Cf «)alkyl-Het _F wherein each of the aryf and Het is optionally substituted with halo, (C ₁ ^)alhyl or NH ₂ , and c) -N(R ⁸ JFf, -C(=O)- N(R ¹ )R ⁹ ,-Sθ ₂ -N|R ⁸ )R ⁱ , -(C _{1 §} )alkyϊerte- N(R ⁸ )R ⁹ or -(C _{1 6} )aikyIene- C(=O)- N(R ⁱ )R ⁹ , wherein the (C _{1 s} )alkyler»e is optionally substituted with 1 or 2 substrtuents each independently selected from -OH, -(C _{1 6} )alkyl, halo, -(C _{1 6} )haloalhyl, - Q-(C _{1 t} >alkyl, R ^β is in each instance independently seϊeeted from H and (C«)alkyl, and R ^fl is in each Instance independently selected torn H ¹ , -O-(Ci *)alkyl, -(C _{1 6} )alkylene-l ⁷ , -C(=O)-R ⁷ , wherein H ⁷ is as defined above R ² -G; in another em bodim ent, R ¹ is selected from a) halo, nrtrø or SO ₃ H. b) R ⁷ , OH, C(-0)0H, C(O)(Ci β)alkyl. ^« SO?-R ⁷ _r -(C _{τ 6} 3aikyIene-R ⁷ , -(C _{1 9} )alkyIene- O- R ⁷ ₍ -(Ci _β )alkyiene-S-R ^7' or -(C ₁ , _β )alkyiene-SO _? -R ¹ ', wherein R ⁷ is in each instance independently selected from H ₁ (C,.«}atl<yi, (C _{2 (} s)alkenyl( (C ₂ i)alks/nyl, (C^) ha balky I, (Cj ₇ )cyeioalkyl, -(C ₁ fejaikyl-fCj ?)cycloaikyi, aryl and Het, wherein the (Ci _B )alhyl, (C _? «)alkenyl, (C _{? &} )alkynyl, (Ci^)haloalkyl, (C _{3 7} |cyeloalkyl, -(C _{1 β} )aikyl-(C _{3 F} )eycioalkyl, and (C _t <Oalkylene are optonaliy sybsiituted with 1 or 2 substrtuents each independently selected from -OH, halo, (C, _§ )halαatkyl, -G-(Ci _e )alkyl _> COOH -N((C _TJ |)alkyl)(aryl), aryi, -(C _i4 )alkyl-aryl, -O-(Ci _g )alkyl-aryl, -S-(C, _β )alkyi-aryi, Het. - (Ci _B )alkyl-Het, O-(C _{1 6} )atkyl-Het. and wherein each of the aryl and Met is optionally substituted with 1 to 3 substϊtnents each independently selected from '

I) halo, cyano, oxo, - OH, -0-(C _{1 6} }alkyl, (C _{1 6} )haloalkyl, -NH _/ . -N((C _M )alkyl) ₂ or -MH-C(=O)(C _i4 )afcy1; if) (C _t ^)alkyl optionally sybsliiut&d with -O-(C _{1 &} )alkyl; and in) aryl, -(C i «)alkyl-aryl, Het Qr-(C _f .sJalkyl- Het, wherein each of the aryl and Hit is optionally substituted with halo, (C ₁ ϋ)aikyi or NH ₂ ; and c) -N(R ^β )R ^β , -C(=O5- N(R ^e )R ^s ,-SO _r N|R ^e )R ⁹ or -(C,^aikytene- N(K ⁸ )K ⁵ ; R ⁸ is H; and R ⁹ is in each instance independently selected torn R ¹ , -(G _{1 β} )alkylene-R ^τ or -C(=O)- R ⁷ , wherein R ⁷ is as defined above. R ^z -H: In another em bodim ent, R ² is selected from . a) halo, nitro or SO ₃ H; b) R ^τ , OH, C(O)OH ₁ C(O)(Ci _β )alkyl. -SO ₃ - R', - (Ci ₆ )aIkylene- R ^τ , -(C ₁ s)alkyiene- O-R ⁷ ₍ -(C ₁ ^Ja I kyIene-S-R ^f or -(C, _lB )alkyIene-SQ _r R ^!' ; wherein R ⁷ is in each instance independently selected from H, (C, .β)alkyl, (C _M JalkeπyI, (C ₂₆ )alkyπyl, (C _{t β} )haloalkyl. (Cu^ycloalkyl, -(C _{1 6} )aIkyi-(C _{3 7} |cycloalkyi, aryl and Het; wherein the (Ci^)alKyt. (C _M )aIhenyl, (C ₇ o)atkynyl, (C^Jhabalkyl, (Cwjcydoalkyi, -(C _{1 6} )alkyl-(C _{3 7} )cycloafkyl, and (C _{t f} jalkytene are optional Iy sybstttufed with 1 or 2 substrluents each independently selected from -OH, halo, (Cm)haloalhyi -O-(C ₁ ^alkyl. COOH, -N((C _M 1alkyl)(aryl). aryl, -(C«)afcyl-aryl, -0-(C, jalkyl-aryl, -S-(C _{1 -6} )alkyl-aryl _a Het, -fCi^)aIkyf- Hef, - O- (C _t <»)alkyϊ-H©ι _r and wherein each of the aryl and Het is optional Iy substituted with 1 to 3 substituenfs each independently selected from . i) halo, cyano, oxo, - OH, -0-(C, &Jalkyl, (C _{1 e} )haloaikyl, - NH? _» -N ((Cι ₄ >alkyl) ₂ or -NH-Ci=O)(Ci ₄ )alkyl; li) (Ci e)alkyl optionally substituted with -0-(C _{1 8} ]ιalkyl; and

IH) aryl, -(Cnjjalkyi-aryl, Het or-{Ci «)alkyi- Het, wherein each cat the aryt and Het is optionally substituted with halo, (C _{1 e} )alkyl or NHj; and: c) -N(R ⁸ )R ⁹ , -C(=O)- N(R*)R*,-SO _Ϊ - N(R ⁸ P ⁵ or -(C _{1 6} laIkylene- N(R ^β )R ^f , R ⁸ is H; and R ⁹ is in each instance independently selected from R ⁷ , -(C _1-6 )alkylene-R ⁷ or -C(=O)-R7, wherein R ⁷ is as defined above: wherein Het is defined as;

R ² -l; in another embodiment, R ² is; H, F, SOjH, NO ₂ ,C(=0)OH, C(=O)CH ₃ , NH ₂ , CH ₁ , CF ₁ , OH, -OCH, -CH ₂ OCH ₃ , -

CH ₂ OCH ₂ CH ₃ , -CH ₂ OCH(CH ₃ ) ₂ , -C H ₂ OCH ₂ C H (CH ₃ ) ₂ , -CH ₂ OH

Any and each individual definition of R ^a as set out herein may be combined wilh any and each individual definition the Core, π, R ⁵ and R ⁶ as set out herein.

It n-A: In one embodiment, n is 0, 1 _» 2, 3 or 4, n-B: In another embodiment, n is O ₁ 1 , 2 or 3. n-C: In another embodiment, n is O ₁ 1 or 2, n-0 In another embodiment, n is 0 or 1.

Any and each individual definition of n as set out herein may be combined with any and each individual definition of the Core, R ² , R ^s and R ^s as set out herein.

Bf: R ⁵ -A; In one embodiment, R ⁵ is H, (Ci. _o )alky1, (Cj./)cycloalkyi, -(Ci ₆ )alkyl-(C ₃ 7}cycloalKyl, aryi, -(Ci efclkyl-aryl, Hetor-{Ct fjaikyl-Het; eaeri being optionally sybstituted with 1 to 4 substituerts each independently selected from (Cejalkyl, (C ₁₄ )haloalkyl, (C _3-7 )cycloalkyf, Met, -OH, -COOH, -Cf=O)-(C ₁ ejalkyl, -C(=O}-O-{C, ₈ )aIkyI, -SO ₂ (C ₁ . _β )alkyl. -C(=O)-N|R ⁵¹ )R ⁵² and -O- R ⁵³ ; wherein R ⁵³ is (C _1-6 )alkyl, (C^Jcycloatkyl, -(C _1-6 )alkyi- (C ₃ /jcycloalkyl aryl, -(C _1-6 )alkyl-aryl, Het or - (C _1-6 )aikyI- Het, said aryl and Het being optronaiy substituted with (C _1-6 )alkyl or -O-(C _1-6 )alkyl; wherein R ⁵¹ is H, (C _1-6 )alkyl or (C^Jcycloalkyl; and R ⁵² is H, (C _1-6 )alkyl, (C ₃ ^)Cy cloa I kyi» aryi, Het, -(Ci ₃ )alkyl-aryi or -|C, ₃ )aikyI-Het; wherein each of the (C _1-6 )alkyl, (C ₃ ^cydoalkyl. aryi, Het, -(Ct ₃ )alkyl-aryl and - (Ci ₃ )aIkyl~Het are optionally substituted wtth 1 to 3 subsiϊtuents each independently selected from (C _1-6 )alkyl _r (C _1-6 )haroalkyl. hato, oxo, -OH, -O{C, $)alkyl, - NH ₂ , - NH(C _1-6 )alkyl _r -N((C _1-6 )alkyl) ₂ , -NH(C _3-7 )cydoatkyϊ, -N^Ct ^alkyl^C^Jcydoalkyt, -C(=O)(C _1-6 )alkyl and - NHC( ^» O-(C _1-6 )alkyl; wherein the (C _1-6 )alkyl is optionally sybstiluted with OH; or R ⁵¹ and R ⁵² , together with the N to which they are attached, are linked to form a 4- to 7-m em bered heterocyde optionally further containing 1 to 3 heteroatom s each independently selected from N, O and S, wherein each S heteroatom m ay, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atom s to form the groups SO or SO ₂ ; wherein the heterocycle is optionally substituted with 1 to 3 substituents each independently selected from {C _{t #} )alkyl, (C,^)hato3lkyl, halo, oxo, -OH, -0{C _f e5alkyI, -NH ₂ , -NH(Ct _β )alkyl, -N((C _{1 -6} )atkyl)a, -NH(C ₃ . ₇ )eycieatkyi, -N((Ci^)alkyl)(C3.τ)cycloalkyl, -C(- 0)(Ci4)slKyl and - NHC(-O)-{Ct*)aikyl. R ^s -B, in another em bodim ent, R ⁵ is H, {C^Jalkyl, (C ₃ ?)cycloalkyl, - fCi ^JaIfCyI- (C _{3 7} )cycloalkyl, aryi, -{C^ϊalkyl-aryl, Het or -{G,^}alkyl-Het; each being optionally substituted with 1 to 4 substituents each independently selected from (Cwdelkyl, (Ci. _β )haloalkyl, {Cj ₇ )cyclogϊhyl, HeI ₁ OH, -COOH, -C(=O)- (C _iJ6 ^lkyi, -C(=Oj- O-{C _{t 6} )aikyi, -SQ ₃ (C ₁ ^ ₈ )aittyl, -C(=O)-N(R ^β1 )R ^H and -0- R": wherein R ^H is (C _{1 β} )alkyl, (C^cydαalkyl, -{C«)alkyi- (C ₃ /)cycloalkyi, aryi, -(C _{1 β} )aikyt-aryf, Het or - (Cn;)afcyl- Het, said aryf and Het being optionally substituted with (C-,, ₆ )alltyl or -O-{ Chalky I; wherein R ⁵¹ is H, (C _{1 d} )alkyl or (C ₃ . _? )cyctoallyi; and R" is H, (C ₁ olalkyi, (C _{3 7} )cydoalkyl aryi, Het, -(C ₁ Jaikyi-aryl or -(C _{t 3} )alkyi-ttet; wherein each of the (C _1-6 )alkyl, (C _{3 7} )cycloalky1. aryf, Het, -{d^alkyl-aryl anct - (C ₁ ^aIkIy I -Het are optional Iy substituted with 1 to 3 substituents each independently selected from (C _1-6 )alkyl _r (Ci ₄ )haloalkyl. hate, oxo, -OH, -O(C _1-6 )alkyl, -NH ₂ , - NH(C _1-6 )alkyl, -N((C _1-6 )alkyl) ₂ , -NH(d-7)cycloalkyl, -N((C _t ^alkylKC-^lcycloalkyl, -C(=O)(C _1-6 )aiKyl and - NHC(=O)(C _1-6 )alkyl; wherein the (C _1-6 )alkyl ts optionally substituted with OH, R ⁵ -C, In another em bodim ent, R ⁵ is (C _1-6 )alkyl, (C^cycloalkyl, -(C _1-6 )alkyl-(C _{3- 7} )cycloalkyl, aryl, - (C^alkyl-aryi. Het or -(C _1-6 )alky met; each being optionally substituted with 1 to 4 substituents each independently selected from (C _{1 -6} )alkyl, (C _1-6 )haloalkyl. (Cj,?)cycϊoalhyi, Het, -OH, -COOH, ~C(=O)- (C _1-6 )alkyl, -C(=O)-O-(C _1-6 )alkyl, -SO ₂ (C _1-6 )aikyl« ^C(=OhN{R ^5f )R ^fl and -0- R"; wherein R ⁵³ is (Ci _β )alkyf, (C, _τ )cycloalkyl. -(Ci _β )alkyl- (C ₃ . _? )cycloa!kyϊ, aryϊ, -(C _1-6 )alkyl-aryl, Met or - (C _M )alkyl-Het, said aryl and Het being optionally substituted with (Chalky! or -0-(C _1-6 )aikyl; wherein R ⁵¹ is H, (Ci ₆ )alkyi or (C _{3 ?} )cyclαalkyl; and R ⁵² is H, (d^Jaikyt, (C _{3 -7} )cycloalkyl, aryl, Het, -(C, Jalkyi-aryl car -(Ct ,Jalkyl-Het, wherein each of the (d β)alHyt, (Ca j)cycloalhyl, aryl, Het, -(C _{t s} )aikyi-aryl and -(C _{1 3} )alkyl-Het are optionally substituted with 1 to 3 substiuerts each independently selected from (C _t .β>alkyl, (d _H s)haloalkyl. halo, oxo, -OH, -O(C _t . _t )alkyI _r -NHs, - NH(C ₁ «)alkyl, -N f(C ₁ β)alkyl) _9r -NH(C> ₇ )cydoa(kyl, -N((C _t 4)aikyIHC ₃ ,ι)cycloaIl<yl, -C(-OKC,-e)aSlcyl and - NHC(-OHC«)aIkyI; wherein the (d ^Jalkyl ts optionally subsituted wrth OH. R ⁵ -D: In anottier em bodim ent, R ⁵ is (d^alkyl, (C ₃ . ₇ )cycloalkyl, -(C «)a I KyI-(C ₃ , 7)cycloalkyl; each being optionally substituted with 1 to 4 substituents each independently selected from (d β)alkyl, (C i _c JhaIoalkyl, (C ₃ j)cyeloalkyl, Het, -OH, -COOH, -C(=OJ- (C«)alkyI, -G(=O)-O-(Ci. _f jalkyI, -SO ₂ (C ₁ . ₆ )alkyt, -C(=O>N(R ⁵¹ )R ⁵³ artd -O-R ⁵² ; wherein R ^B is (C, «)alkyl (Ci rjcyctoaikyi, - (Ci«>alkyl {C»7>cycloalkyl, aryl, -(Ci^)alkyf aryl, Het or (Ct^alkyl-Het, said aryl and Het being optionally substituted with (C _1-6 )alky[ or -O-(C,. ₆ )aIkyϊ; wherein R ⁵¹ is H, (C, _-β )alkyl or (C^^yctoalkyl; and R ⁵² is H, (C-i^alkyl. (C ₃ . _τ )eycioalkyi, aryl, Het, -(C _{1 3} )alkyl-aryl or -(Ct ₃ )alkyi-Het; wherein each of the (Cv$)alkyt, fC ₃ ,?)eyclσaIlkyl» aryl, Het, -(Cv?)alkyl-afyl and - (C^Jalkyt-Het are optionally substituted with 1 to 3 substituents each independently selected from (C _1-6 )alkyl, (C^)hatoalkyl, hato, oxo, -OH, -O(C _1-6 )alkyl, -NH ₂ , -NH(C _1-6 )alkyl. -Nl(C ₁ e)alfcyi)a, -NHCC^cycloalkyl, -N((C _t ,, JaIKyI)(C ₃ .? )cycloalky I ₁ -C(=O)(C _1-6 )alkyl and - NHC(=OH(C _1-6 )alkyl; wnerein the (C _1-6 )alkyl is optionally substituted with OH. R ⁵ -E; in one em bodim ent, R ⁵ is (C^jalkyl, (C^cycloalkyl, -(C _1-6 )alkyl-(C ₃ ,

₇ )cycloalkyl; each being optionally substituted with 1 to 2 substituents each independently selected from (C _1-6 )alkyl, -OH, -C(^O)- (C ₁ «)alkyl, -C(=O)-O-{C, ^)alkyI, -C(=O)-N(R ⁵¹ )R ⁵² and -O-R ⁵³ ; wherein R ⁵³ is (C _1-6 )alkyl _t (C ₃ . ₇ )cycloalkyl or -(C _1-6 )alkyl-(C _3-7 )cycloalkyl; R ⁵¹ is H, (C _1-6 )alkyl Or (C ₃ . 7)cycloalkyl; and R ⁵¹ is H ₁ (C _1-6 )alkyl or (C _{3 7} )cycloalkyl. R ⁵ -F; In one embodiment, R ⁵ is (C _1-6 )alkyl or (CvJcycloalKyf; each being optionally substituted with 1 to 2 substituents each independently selected from (C _1-4 )alkyl -OH, -C(=O)-(C, 4alkyl, -C(«O>O- (C _1-4 )alkyl _r - C(=O)-N (R ⁵¹ )R ⁵² and -O-(C ₁ ^aI kyi; R ⁵¹ is H or (C^)alkyl; and R ⁵² is H or (C^)alkyl. R ⁵ -G; In another em bodim ent, R ⁵ is (C _1-4 )alkyl or (Ca. _? )cycloalkyl; each being optionally substituted with 1 to 2 substituents each independently selected from (C _{1 -4} )alkyl, - C(=O)- N(R ⁵¹ )R ⁵² and -O-(C, «)alkyl; R ⁵¹ is (Ci ^)aikyi; and R ⁵² is (C _{1 -4} )alkyl. R ⁵ -H: In another em bodim ent, R ⁵ is:

Any and each individual definition of R ⁵ as set out herein may be com bined with any and each individual definition of the Core, n, R ² and R ⁶ as set out herein. R ⁶ : R ⁶ -A; In one embodiment R ⁶ is (C _3-7 )cycloalkyl, -(C _1-6 )StIkVt-(C _{3 7} }cyetøalkyi, aryl, -(C _1-6 )alkyl-aryl, Het or - (C _1-6 )alkyl- Het; being optionally substituted with 1 to 5 substituents each independently selected from halo, (C ₁ «)athyl, (C _1-6 )haloalkyl. (C _{3 f} )cycloalkyl, -OH, -SH, -O-(Ci ₄ )alkyf. -S-(C, ₄ )alkyl and - N(R*)R ⁵ ; wherein R* is in each instance independently selected from H, (C _{1- 6} )alkyl and (C _3-7 )cycloalkyl; and R* is in each instance independently selected from R ^τ , -O-(C _1-6 )alkyl, -(C _1-6 )alkylene-R ⁷ , -SO ₂ -R ¹ , -Ct=O)- R ⁷ . ~C(=G)GR ⁷ and ^C(=O)N|R ⁸ )R ⁷ ; wherein R ⁷ and R ^s are as defined above, or R* and R ⁹ , together with the N to which they are attached, are linked to form a 4- to 7- membered heterocycle optionally further containing 1 to 3 heteroatom s each independently selected from N , O and S, wherein each S heteroatom m ay, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO ₂ ; wherein the heterocycle is optionally substituted with 1 to 3 substityents each independently selected from (C _1-6 )alkyl, (C _1-6 )haloalkyl, halo, oxo, -OH, SH, -O(C _1-6 )alkyI, -S(C _1-6 )alkyl, (C-, ₇ )cycloalkyl , -NH ₂ , - NH(C _1-6 )alkyl, - N((C _1-6 )alkyl) _2r -NH(C ₃ , ₇ )cyeioaikyI, -N^C _M ΪalkylMC^Jcycloslkyl, -C(^O)(C ₁ sjalkyl and - NHCf^OHC^Jalkyl. R ⁶ -B- In yet another alternative em bodim ent, R* is (C ₃ ?)cycloalky!, -(C i u)alkyl- (Cj ι)cycloalkyi, aryl, -(C ₁ e)alkyl-aryl, Hit or - (d «)alkyl- Het, being optionally substituted with 1 to 3 substϊtuerits each independently selected from halo, (Ci _β )atkyi and (C _1-6 )haloalkyl, R ⁶ -C: In still another em bodim ent, R ⁶ is (C _3-7 )cycloalkyl, -(Ci ₄ )alkyi-fCa. _? )cycIoalkyl, phenyl or Het, optionally substiyted with 1 to 3 substituents each independently selected from halo, (Ci ₄ )BlIyI and {C _M )haløalKyi; wherein the Het is selected from -

R ^s -D ^" In another alternative em bodim ent, R* is {C _M )cydoaikyI, -(C _1-3 JaSkVl- (C^ cjcycloalkyl, phenyl or Met optionally substituted with 1 to 3 substituents each Independently selected from halo, (Chalky! and (C _1-4 ) ha tea I ley I; whereto Met

Is a 4- to 7-m em bered saturated, unsaturated or arom atic hete recycle having 1 to 3 nitrogen lieteroatom s. R ^f -E: In still another em bodim ent, R ⁶ is phenyl, cydohexyl, -CHj-cydopentyf or pyridine optionally substituted wrth 1 to 3 substituents each independently selected from halo, (Ci ₄ )alkyl and (Ci ₄ )haloalkyl. R ⁶ -F: In still another em bodim ent, R ⁶ is phenyl, optionally substituted with 1 to 3 sufctstϊfuents each independently selected from halo and {Cn)alkyl, R ^β -G: In still another em bodim ent, R ⁶ is pyridine, optionally substituted with 1 to 3 substitϋ€frts each Independently selected from halo and (C ₁₄ JaIKyL R ^β -H: In sttll another em bodim ent, R ^β is cyclonexyl or - CHj- cydopentyl, optionally substituted with 1 to 3 subslituents each independently selected from halo, (Ci _-4 >alkyl and {G _M )hafoalϊ<yl R'-l: In still another em bodim ent , R ^s is:

Any and each individual definition of R ⁸ as set out herein m ay be com bined with any and each m dividual definition of the Core, n, R ² , and R ^s as set out herein. Exam ples of preferred subgeneric em bGdirmente of the present invention are set forth in the following table, wherein each substrtuent group of each em bodim ent is defined accord tng to the definitions set forth above

Examples of most preferred compounds according to this invention are each single compound listed in the following Tables 1 to 3.

to general, all tautomeric and isomeric form s and mixtures thereof, for example, individual geometric isomers, stereoisomers, atropisomers, enantjomers, diastereomers, race mates, racemic or noπ-racemϊε mixtures of stereoisomers, mixtures of diastereomers, or mixtures of any of the foregoing forms of a chemical structure or compound is intended, unless the specific stereochemistry or fsomene form is specifically indicated in the compound name or structure. Compounds of the invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemie forms.

It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to me stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one emamtiαmer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of trie present invention from this disclosure and the knowledge in the art

Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or more of the many methods of fa) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof Tnese resolution methods generally rely on cΛirai recognition and include, for example, chromatography using chiral stationary phases, enaπtioseiective host- guesi complexatioru resolution or synthesis using ehirai auxiltaπes, enantϊoselective synthesis, enzymatic and nonenzymatϊc kinetic resolution, or spontaneous enantjσeeϊective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed,), G, Subramanian (ed,), Wiey-VCH, 2000; T-E. Beesley and RP W. Scott, Cbiral Chromatography, John Wiley & Sons, 1999, and Satmder Ahuja, Chiral Separations by Chromatography, Am . Cfiem Soc, 2000, herein incorporated by reference. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conform atton _t for example, CD, ORD, X-ray crystallography, or NMR.

The compounds according to the present invention are inhibitors of the hepatitis C virus MS5B RNA-dependent RNA polymerase and thus may be used to inhibit replication of hepatitis C viral RNA.

A compound according to the present invention may also be used as a laboratory reagent or 3 research reagent For example, a compound of the present invention may be used as positive control to validate assays, including but not limited to surrogate cell-based ¹ assays and in vitro or in vim viral replication assays.

Compounds according to the present invention may aϊso be used as probes to study the hepatitis C virus NS5B polymerase, including but not limited to the mechanism of action of the polymerase, conform ational changes undergone by the polymerase under various conditions and interactions with entities which bind to or otherwise interact with the polymerase.

Compounds of the invention used as probes may be labelled with a ϊabei which allows recognition either directly or indirectly of the compound such that it can be detected, measured and quantified, Labels eontempiated for use with the compounds of Ihe indention include, but are not limited to _f fluorescent labels, chemiluminescent labels, coloπmetnc labels, enzymatic markers, radioactive isotopes, affinity tags and photo reactive groups.

Compounds of the invention used as probes may also be labelled with an affinity tag whose strong affinity for a receptor can be used to extract from a solution the entity to which the Iigamd is attached. Affinity tags include but are not limited to biotln or a derivative thereof, a histidine polypeptide, a polyarginϊoe. an amylose sugar moiety or a defined epitope recognizable by a specific antibody.

Furthermore, compounds of the invention used as probes may be labelled with a photoreactive group which is transformed, upon activation by light, from an inert group to a reactive species, such as a free radical. Photoreactive groups include but are not limited to photoafftnity labels such as benzophenone and azϊde groups,

Furthermore, a compound according to the present invention may be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials),

Pharmaceutical composition Compounds of the present invention may be administered to a mammal in need of treatm ent for hepatitis C viral infection as a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or ester thereof; and one or more conventional non-toxic pharmaeeutreafy-aceeptabie earners, adjuvants or vehicles. The specific formulation of the composition is determ ined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. The pharmaceutical composition according to the present invention may be administered orally or systemicatly.

For oral administration, the compound, or a pharm aceutically acceptable salt or ester thereof, can be form ulated in any orally acceptable dosage form including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets. For systemic administration, including but not limited to administration by subcutaneous, intracutaneous, intravenous, Intramuscular, ϊntra-artlcular, intrasynovial, intrasternal, intrathecal, and intraiesional injection or infusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable sterile aqueous vehicle.

Pharmaceutically acceptable carriers, adjuvants, vehicles, exdpients and additives as well as methods of formulating pharmaceutical compositions for various modes of administration are well-known to those of skill in the art and are described in pttarrmaceutilcal texts such as Remington; The Science and Practice of Pharmacy, 21st Edition, Lrppincott Wtliams & WilWns, 2005; and L, V. Allen, N.G. Popovish and H. C, Ansel, Pharmaceutical Dosage Form s and Drug Delivery Systems, 8th ed., ϋppincett Williams & WHkins, 2004, herein incorporated by reference,

The dosage administered will vary depending ypon known factors, including but not limited to the activity and pharmacodynamic characteristics of the specific compound employed and its mode, time and royte of administration; the age, diet, gender, body weight and general health status of the recipient; the nature and extent of the symptoms; the severity and course of the infection; the Sand of concurrent treatment; the frequency of treatment; the effect desired; and the judgment of the treating physician. In general, the compound is most desirably administered at a dosage level that will generaiiy afford antiviralty effective results without causing any harmful or deleterious side effects,

A daily dosage of active ingredient can be expected to be about 001 to about 200 milligrams per kilogram of body weight, with the preferred dose being about 0,1 to about 50 mg/kg. Typically, the pharm aceutical composition of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be ysed as a chronic or aeute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration, A typical preparation will contain from about 5% to about 95% active compound (wfw ¹ }. Preferably, such preparations contain from about 20% to about 80% active compound.

Combination therapy Combination therapy is contemplated wherein a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, is co-administered with at least one additional antiviral agent The additional agents may be combined with compounds of this invention to create a single dosage form . Alternatively these additional agents may be separately administered, concurrently or sequentially, as part of a multiple dosage form.

When the pharmaceutical composition of this invention comprises a combination of a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, and one or more additional antiviral agent, both the compound and the additional agent should be present at dosage levels of between about 10 to 100% ₍ and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. In the ease of a synergistic interaction between the compound of the invention and the additional antiviral agent or agents, the dosage of any or all of the active agents in the combination may be reduced compared to the dosage normally administered in a monotherapy regimen.

Antiviral agents contemplated for use in sych combination therapy include agents {compounds or biologtcals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from another anti-HCV agent; an HiV inhibitor; an HAV inhibitor; and an HBV inhibitor

Other anti-HCV agents include those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms or disease. Such agents include but are not limited to immunomodulatory agents, inhibitors of HCV WS3 protease, other inhibitors of HCV polymerase, inhibitors of another target in the HCV life cycle and other anti-HCV agents, including but not limited to ribavirin, amantadine, tevovirin and viramidine,

Immunomodulatory agents include those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal. Immunomodulatory agents include, but are not limited to, iπosine monophosphate dehydrogenase inhibitors such as VX-49T {merimepodib, Vertex Pharmaceuticals), class I interferons, class Jl interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not lim ited to interferons conjugated with other proteins including but not lim ited to hum an album in. Class I interferons are a group of interferons that all bind to receptor type I ₁ including both naturally and synthetically produced class I tnterferons, while class it interferons all bind to receptor type II, Exam ples of class I tnterferons include, but are riot lim ited to, α- , β- , 6-, ω- , and τ-ϊoterferons, while exam ples of class 11 interferons include, but are not lim ited to, ^interferons, in one preferred aspect, the other anti- HCV agent is an interferon. Preferably, the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A and lym phobisstoid interferon, In one preferred aspect, the com position com prises a com pound of the invention, an interferon and ribavirin.

Inhibitors of HCV NS3 protease include agents (com pounds or b ^' robgicals) that are effective to inhibit the function of HCV NS3 protease in a mammal, inhibitors of HCV NS3 protease include, for exam ple, those com pounds described in WO 99/07733, WO 99/07734, WO 00/09553, WO 00/09543, WO 00/59329, WO 03/064416, WO 03/064455, WO 03/064456, WQ.2004/039970, WO 2004/037855, WO 200*039833, WO 2004/10160Z ₁ WO 2004/101605 _« WO 2004/103996, WO 2005/028501 _r WO 2005/070955, WO 2006/000085, WO 2006/007700, WO 2006/007708, WO 2007/009227, WO 2004/09391 S, WO 2004/009121 (ail by Boehringer Iπgelheϊm J, WO 2006/122188, WO 2006/086381, WO 20O7/044S33, WO 2007/056120, WO 2008/057B75, US 2004/077551, WO 2007/008657, WO 2008/064061 ₍ WO 2008/064057, WO2006/008776, US 2004/0048802, WO 2008/064086, WO 2008/060927, WO 2008/057871 , WO 2008/057873, US 2002/0177725, WO 02/48157, WO 02/48116, WO 2007/001406, WO 2006/101538, WO 02/08251, WO01/02424, WO 01/40262, WO 01/07407, WO 01/64678, WO 02/183Si, WO 98/46597, US 2005/0153877, WO 02/0<6Oδ26, WO 03/053349, WO 03/099274, WO 03/039316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410 _« WO 2005/054430 {all by BMS), US 2008/0032936, WO 2008/021360, WO 2000/002024, WO 2007/146695, WO 2007/143694, WO 2008/021733, WO 2008/01 t28f, WO 2008/022006, WO 2008/021956, WO 2008/013266, WO 2008/019303, WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2006/010029 fall by Enanta), WO 2005/095403, WO 2008/005511, WO 2007/015S24, WO 20Q7/Q44S93, WO 2005/037214 (Irterm une). WO 01/58929» US 5990276, WO 97/43310, WO 01/77113 _» WO 2008/130628, US 2003/0216325, US 2005/0176648« US 2005/0209164, WO 01/77113, WO 01/81325, WO 02/08187, WO 02/08198, WO 02/08244, WO 02/08256, WO 02/48172, WO 03/062228, WO 03/062265, WO 2005/021584, WO 2005/030796, WO 2005/058821, WO 2005/051980, WO 2005/085197, WO 2005/085242, WO 2005/035275 _» WO 2005/087721 , WO 2005/087725, WO 2005/087730, WO 2005/087731« WO 2005/107745 and WO 2005/113581 (all by Schering) _r WO 200S/057209, WO 2008/05147S, WO 2006/119061 , WO 2007/016441 , WO 2007/015855, WO 2007/015787 {all by yerck), WO 2006/043145 (Pfizer), all of which are herein incorporated by reference; and the candidates VX-95Q, SCH-9B034, ITMN-191, TMC 435350, and MK7QQ9.

Inhibitors of HGV polym erase include agents {com pounds or bϊologicats) that are effective to inhibit the function of an HCV polym erase. Such inhibitors include, but are not lim ited to, non- nucleoside and nucleoside inhibitors of NS4A, NS5A, NS5B polym erase. Exam ples of inhibitors of HCV polym erase include but are not lim ited to those com pounds described in; WO 03/007945, WO 03/010140, WO 03/010141 , US 6,441 » 281 , WO 02/04425, WO 2006/019477, WO 2007/067717, WO 2006/007693, WO 2005/080388, WO 2QO4/0S9241 , WO 2004/065367, WO Z004/06492S (all by Boehfϊnger Ingelheϊm ), WO 2006/093801 , US 2005/0107384, WO 2005/019191, US 2004/0187123,WO 2004/041818, WO 2008/011337 (ail by Abbott Laboratories), WO 01/32153 (BiO€hem Pharm a Inc.), WO 01/60315 {Bϊochem Pharm a Inc.}, US 2004/0138170, WO 2004/106350, WO 2006/050161. WO 2006/104945, WO 2006/002231 , US 2005/080053, US 2004/0242599, US 2004/0229839, WO 03/087298 _» WO 02/069903 fall by Bϊocryst Pharm aceuticals, Inc.), WO 2008/094347 (Biota, Inc.), WO 2005/021568 (Biota, Inc.), WO 2008/051637. WO 2007/150001 , WO 2006/066073 fail by AfJϋdys Pharm aceuticals }, WO 2007/033032, WO 2007/033175, WO 03/026587, WO 2007/143521, WO 2007/140109 _« WO 2007/140200, WO 2007/140254, WO 2007/136982, WO 2007/092000, WO 2007/092888, WO 2006/020082, US 2005/011931 S, WO 2005/034850 (all by Bristol-Myers Squibb), WO 2007/034127 (Arrow Therapeutics Lim ited), WO 200S/063734 (Bayer), WO 03/093290, WO 2005/Q1228S. WO 2008/011521 ₁ WO 2008/008907, WO 200S/008312, WO 2007/084157, WO 2007/019397, WO 2006/138744, WO 20061121468, WO 2006/116557, WO 2006/102594, WO 2006/076529, WO 2006/075993, US 2006/0111311, WO 2005/054268, WO 2005/042558, US 2005/0090463, WO 2004/108687, WO 2004/028481 , WO 2006/093986, WO 2006/093987 (all by Genelabs Technologies), WO 2006/117306, WO 2004/046159, WO 2007/113159, WO 2007/093541 , WO 2007/068615, WO 2007/065829, WO 2007/020193, WO 2006/021341, WO 2006/021340, WO 02/100415, WO 02/094289, WO 02/18404 (ail by F. Hoffmann- La Roche), WO 2007/039142, WO 2007/039145, WO 2007/033144, WO 2006/045613, WO 2006/045615, WO 2005/103045, WO 2005/092863, WO 2005/079799, WO 2004/096774, WO 2004/096210, WO 2004/0764 IS, WO 2004/060889, WO 2004/037818, WO 2004/009543, WO 03/097646, WO 03/037393, WO 03/037894, WO 03/037895, WO 03/000713 (all by Glaxo Group), WO 2007/144686, WO 2006/000922, WO 2004/046331, WO 2004/002422, WO 2004/002999, WO 2004/003000, WO 2005/009418, WO 03/026675, WO 03/026519, WO 2007/025043 (all by Idem x), US 03/050320, WO 2007/119883, WO 2006/052013, WO 2005/080399, WO 2005/049822, WO 2005/014543, EP 1 162 196, WO 01/47883 (all by Japan Tobacco), WO 2007/095269, WO 2007/054741 , WO 03/062211, WO 00/06529, WO 99/64442, WO 2006/119975, WO 2006/046030, WO 2006/046039, WO 2005/034941, WO 2005/023819. WO 2004/110442, WO 2004/087714, WO 2007/06S883, WO 02/06246, WO 2007/129119, WO 2007/029029, WO 2007/028789, WO 2006/029912, WO 2006/027628, WO 2006/008556 (all by Istituto Di Richerche Di Biologia Molecolare P Angeletti SPA), WO 2008/005542, WO 20Q6/Q91905, WO 2005/063751, WO 2004/005286 (ail by Gilead Sciences), WO 2008/043704 (Medivir). WO 2005/123087, WO 2007/021610, WO 2006/065335, WO 2006/012078, WO 2004/00313S« WO 2004/000858, WO 03/105770, WO 03/020222, WO 2005/084192, WO 2004/009020, WO 2004/007512 _« WO 02/057425, WO 02/057287, WO 2007/022073, US 2004/0229840 (ail by Merck and CO ). WO 2006/018725, WO 2004/073599, WO 2004/074270, WO 03/095441, WO 03/082848 (all by Pfizer), US 2005/00154056, WO 2004/002S77, WO 2004/002944, WO 2004/002940 (all by Pharmacia & Upjohn Company), WO 00/04141 (Ribozyme), WO 2006/050035 (Scherm g), WO 2006/050034 (Schering), US 2003/0203948 (Shionogi), WO 02/20497 (Shionogi), WO 2005/121132 (Shiooogi) EP 1321463 (Shire Biochem ), WO 02/100851 (Shire Biochem ), WO 02/100846 (Shire Biochim ), WO 03/061385, WO 03/062256, WO 03/062255, US 6,906,190, WO 2004/080468 {all by Rtbapϊwm ), WO 2007/026024 (TibQtec), WO 2006/065590 (XTL Bϊopharm aceuticafs), WO 2008/051244, WO 2007/092558, WO 2006/034337« WO 03/099275, WO 03/099824 (all by Wyeth), WO 03/059358, WO 01/85172» WO 01/85720, WO 03/037262, WO 2008/059042, WO 2008/043791 , WO 2008/017688, WO 2007/147794, WO 2007/08814§, WO 2007/071434, WO 2007/039146, WO 2006/100106, WO 2004/058150, WO 2004/052312, WO 2004/052313, WO 03/099801 , WO 02/098424 (all by Sm ithkline Beecham ), WO 2007/027248 (Valeant). WO 2008/058393, WO 2006/119646, WO 2004/052879, WO 2004/052885, WO 00/18231, WO 00/137OS, WO 00/10573, WO 2004/041201, WO 03/090674 (all by Virapharm a), (all of which are herein incorporated by reference) and the candidates HCV 796 (ViroPharm a/Wyeth), R- 1626, R- 1656 and R-7128 (Roche), NM 2S3 (Idenlx*tavartιs) _f VCH-7S9 and VCH-916 (Virochem ), GS9190 (GifeadJ, GL60667 {Genelabs/Novartis) ₍ MKSQB (Merck) and PF868554 (Pfizer).

The term "inhibitor of another target in the HCV life cycle ^* as used herein m eans an agent (com poynd or biological) that is effective to inhibit the formation and/or replication of HCV in a m am m al other than by inhibiting the function HCV polym erase. This includes agents that interfere with either host or HCV viral targets necessary for the HCV life cycle or agents which specifically inhibit in HCV cell culture assays through an undefined or incom pletely defined m echanism , inhibitors of another target in the HCV life cycle include, for exam ple, agents that inhibit viral targets such as Core, £1, E2, p7, NS2/3 protease, NS3 heliease, internal ribosom e entry site (IRES), HCV entry and HCV assem bly or host targets such as cyciophϊlin B, phosphatidyl inositol 4-krπase lllct, CD81, SR-BI ₁ CIaudin 1, VAP-A, VAP-B. Specific exam ples of inhibitors of another target in the HCV life cycle include ISiS- 14803 (ISIS Pharm aceuticals), GS9190 {Giead), GS9132 {GileacS), A-831 (AsfraZeneca}, NM-811 (Novartis), and DEBIO-025 fDebio Pharm a),

It can occur that a patient m ay be eo-ϊnfected with hepatitis C virus and one or m ore other viruses, including but not lim ited to hum an im m unodefieiency virus (HIV) ₁ hepatitis A virus fHAV) and hepatitis B virus (HBV). Thus also contem plated is com bination therapy to treat such co-infections by co-adm inϊstering a com pound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor. HlV inhibitors include agents (com pounds or biologicals) that are effective to inhibit the form ation artd/or replication of HIV. This includes but is not lim ited to agents that interfere with either host or viral m echanism s necessary for the form ation and/or replication of HIV in a m am m al. HIV inhibitors include, but are not lim ited to;

• NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors) including but not lim ited to zidovudine (AZT), didanosiπe (ddl), zalcitabine (ddC), stavudine (d4ϊ), lam ivudπe (3TC), em tricϊtabiπe, abacavir succinate, elvuciabine, adefovir dipivoxil, lobucavir (8MS- 180194) lodenosine (FddA) and tenofovir including teπαfovir cfisopraxil and tenofaw disoproxil fum arate salt, COMBIVIR™

Iconlaϊns 3TC and AZTi TRIZiVlR™ (contains abacavir, 3TC and AZT), TRUVADA ^m {contains tenofovir and em triάtabine), EPZICOM™ {contains abaeavir and 3TC);

• NNRTIs fnon-nucieoside reverse transcriptase inhibitors) including but not lim ited to nevirapine, delauiradine, efavireπz, etravirine and rilpivirine;

• protease inhibitors including but not lim ited to ritonavir, iϊpranavir, saquinavir, nelfinavfr, indinavir, am prenavir, foeam prenawϊr, atazanavϊr, lopϊnavir, darynavir, lasiπavir, breeanavir, VX-3S5 and TMC- 114;

• entry inhibitors including but not lim ited to • CCRS antagonists finciudϊng but not lim ited Io m araviroc, vicrivϊroc,

INCB9471 and TAK-6S2),

• CXCR4 antagonists (including but not lim ited to AMD- 11070),

• fusion inhibitors (including but not lim ited to ertfyvirtide (T-2Q), TRl - 1144 and TR1-999) and • others (including but not ϊϊm rted to BMS-488043);

• integrase inhibitors (including but not lim ited to ralte-gravir (MK-051S), BMS- 707035 and elvitegravir (GS 9137));

• TAT inhibitors;

• m aturation inhibitors (including but not lim ited to berivim at (PA-457)); • im m ynom odylating agents (including but not lim ited to ievsm isole); and

• other antiviral agents including hydroxyurea, ribavirin, IL-2, IL- 12 and pensafuside,

HAV inhibitors include agents (com poynds or biologicals) that are effective to inhibit the formation and/or replication of HAV, This includes but is not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a mammal, HAV inhibitors include but are not limited to Hepatitis A vaccines.

HBV inhibitors include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of HBV in a mammal, This includes but is not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a mammal. HBV inhibitors include, but are not limited to, agents that inhibit the HBV viral DNA polymerase and HBV vaccines.

Therefore, according to one embodiment,, the pharmaceutical composition of this invention additionally comprises a therapeutically effective amount of one or more antiviral agents.

A further embodiment provides the pharmaceutical composition of this invention wherein the one or more antiviral agent comprises at least one other anti-HCV agent.

According to a more specific embodiment of the pharmaceutical composition of this invention, the at least one other antϊ-H€V agent comprises at least one immunomodulatory agent.

According to another more specific embodiment of the pharmaceutical composition of this invention, the at least one other anti-HCV agent comprises at least one other inhibitor of HCV polym erase.

According to yet another more specific embodiment of the pharmaceutical composition of this invention, the at least one other antϊ-HCV agent comprises at least one inhibitor of HCV NS3 protease.

According to still another more specific embodiment of the pharmaceutical composition of this invention, the at least one other anti-HCV agent comprises at least one inhibitor of another target in the HCV life cycle. EXA MPLES Other features of the present invention will becom e apparent from the following non- lrm iing exam ples which illustrate, bv way of exam ple, the principles of the invention. As is well known to a person skilled in the art, reactions are perform ed in an inert atm osphere {including but not lim ited to nitrogen or ArJ where necessary to protect reaction com ponents from air or m oisture. Preparation of com pounds of the invention can involve the protection and deprotectϊon of various chem ical groups. The need for protection and deproiedion, and the selection of appropriate protecting groups can be readily determ ined by one skilled in the art The chem istry of protecting groups can be found, for exam ple, in Greene, "Protective Groups in Organic Chem istry", John Wiley & Sons, New York (1981), and m ore recent editions thereof, herein incorporated by reference. Tem peratures are given in degrees Celsius ("C). Solution percentages and ratios express a volum e to volum e relationship, unless stated otherwise. Flash chrom atography is carried out on silica gel (SiO ₂ ) according to the procedure of W. C, Still et ai., J, Org, Ghent., (1978), 43, 2923 Mass spectral analyses are recorded using electrospray m ass spectrom etry, Purification on a oom biflssh is perform ed using an Isco Com biflash (colum n cartridge SiO ₃ ). Unless otherwise specified, preparative HPLC is the purification m ethod. Preparative HPLC is earned out under standard re nditions using a SunFire™ Prep C18 OBD 5μM reverse phase colum n, 19 x SO m m and a linear gradient (20 to 98%) em ploying 0.1%TFA/acetonitrile and 0.1 %TF A/water as solvents, Com pounds are isolated as TFA salts when applicable. Analytical HPLC is carried out under standard conditions using a Com biscreen ™ ODS-AQ C18 reverse phase colum n, YMC, 50 x 4.6 m m i ύ.. S μM, 120 A at 220 nM, elulion with a linear gradient as described in the following table (Solvent A is 0.06% TFA in H ₂ O; solvent B is 0.06% TFA in MeCN):

Abbreviations or sym bols used herein include; Ac: acetyl; AcOH; acetic acid; Bn: benzyl (phenyl methyl); BOC or Boc: tert-butyloxycarbonyl;

Bu: butyl;

DBU; 1 ₍ β-dia2abicydo[5.4.0Jifndec-7-eπe;

DCE; cjiehioroethane; DCM; dϊchtoromethane; DIPEA: dHsopropylethylaπύπe;

DMA: di methyl acetamide DMAP: 4-dlmethylaminopyridine;

DMF; W,W-di(nethylforfnamicJe;

DMSO: dimethylsulfoxϊd©; EC»: 50% effective concentration;

Ef: ethyl;

Et ₃ O: diethyl ether;

EtOAc; ethyl acetate;

EtOH; elhanof: Hex: ttexane; HPLC: high perform ance liquid chromatography;

ICs ₀ : 50% inhibitory concentration;

'Pr or ι-Pr: 1-methyiethyi (fso-propyl);

LC-MS: liquid chrømatography-mass spectrometry; Me; methyl; MeCN: acetonitrile; MeI: ϊQ€tometharie; MeOH: methanol; MS: mass spectrometry (ES: electrospray); NaHB(OAc) ₃ : sodium iriacetoxyborohydride;

Ph: phenyl; Pr; n- p ropy I; Psc pounds per square inch; Rpm: rotations per minute; RT: room temperature (approximately 18 "G to 25X); !-BM E; tert-butlymethylether tert-butyl or t- butyl: 1,1-dimethylethyl; tert-BuOH or f-BuOH: fe/f-butanoi TBAF. tetrabutylammonium fluoride;

TBTU: 2-(1H-bθFizotriazole-1-yl)-1.1,3,3-tetramethyl uronium tetrafluoroborate; TEA: triethyfamfrke;

TFA: trifluoroacetie acid; THF: tetrahydrofuraπ; TLC: thin layer chromatography.

Exam ple 1A: Com pound 10Θ4

Step! Add anhydrous potassium carbonate (483 g, 349 mmol) to a mixture of chloro-nitro arene (1a1, 498 g, 231 mmol) and 2-bromoptiersoi (1a2» 34 ml, 293 mmoi) in DMSO (30 ml) and heat for about 6 h at 80°C Bnng the rnmture to RT and leave at RT For about a further 16 h Dilute the mtxtore with water (150 ml) and extract with t- BME £3 x 100 mL) Combine the organic portions, and wash successively with 1 N NaOH (aqueous, 2 x 50 mL), water {50 mL), and bnne (50 mL) Subsequent drymg with anhydrous MgSO ₄ , filtering, and evaporation of the volatiles provides 1a3

Step 2

Dissolve 1a3 (700 g, 199 mmol) into a mixture consisting of EfOH (80 mL), water (11 mL) and saturated NHXI {aqueous, 11 ml) Add iron powder (333 g, 596 mmol) in one portion and heat for aboyt 7 h at 80°C Add another portion of iron powder (230 g, 412 mmol) to the mixture arid continue heating for aboyt a further 9 Ii Dilute wrth EtOAe and filter the solids Collect the filtrate and evaporate the volatiles Dissolve the resulting caide material into t-BME and wash successively wrth saturated NaHCO ₃ , water, and brine Dry the organic portion with anhydrous MgSOs filler and evaporate the volatiles Dissolve the resulting material in Ei _? 0 {55 ml_| and add 4 IM HCi in dtoxaoe (7.5 mL, 30 mmol}. Filtering the solids and drying yields 1a4.

Step 3; To a suspension of 1a4 (6.35 g, 17,7 mmo!) in DCM (SO raL), add 2- methoxypropene (7.00 mL, 73.1 mmol) and NaHBfGAc) ₃ (7.9? g _r 3? 6 mmol). Slir the mixture at RT for about 2,5 h. Dilute with EtOAc and wash the organic portion with water and brine. Dry over MgSGi ₁ , filter and evaporate the volatiles. Purification of the crude material with flash chromatography (EtOAc/Hexanes) provides 1aS.

Step 4; Reference; Keith Fagnoy et al., J, Qrg. Chβm, 2OT5, 70, 7S7S-7514, Add potassium acetate (680 mg, 5.02 mmol) and Pearlman ^' s catatyst (116 mg, 0,17 mmol) to 1a5 {503 mg, 138 mmol) in DMA (10 mL) and heat to 145 ⁰ C for about 18 h. Diiute with t-BME containing AcOH (3 mL) arid wash with water Filter the organic portion, dry over NajSOj, filter and evaporate, Dissolve the resulting material in a 0.7 M diazomethane/ethθr solution and then evaporate the volatiles. Purification of the crude material with flash chromatography (EtOAc/Hexanes) affords 1aS.

Step 5:

Dissolve irans-4-methyicyclotiexaπe carboxylic aci-d 1a? (3,00 g, 21 ,1 mmol) in OCM (20 mL) and cool to ϋ ^ύ €. Add oxalyi chloride {2,8 mL, 31,6 mmol), then DMF (10 μl_). Stir for about 1 h, warm to RT and stir for about a further 3 h. Evaporate the volatiles under reduced pressure and dilute the residue in pentane. The solids are filtered and the filtrate collected Evaporation of the filtrate to constant mass affords 1a8.

Step 6;

To a mixture of 1a6 (106 mg, 0,3? mmol) In anhydrous pyridine (3 mL) under an Ar atm osphere, add DMAP (16.8 mg, 0,14 mmol) and 1a8 (250 mg, 1,56 mmol). Heat the mixture to 60°C for about 17 h. Diiyte the mixture wrth EtOAc and wash successively with 1 N HCI (aqueous), water and brine. Dry the organic phase over MgSO ₄ , filter and evaporate the volaltles. Purification of the residue with flash chromatography (EtOAc/Hexanes) affords 1a9. Step 7: Add 1 N NaOH (aqueous, 0,4 mL) to a mixture of 1aβ (25 mg, 0.061 mmoi) in DMSO {0.4 mL) and heat to 50°C. Subsequently, add yeOH (0.4 mL). After a period of about 5.5 h _t add excess TFA until the pH is approximately <2 _* Pu rrfi cation and lyophilizallon of the volatiles affords 1004,

Exam ple 1B: Com pound 1005

Step 1; Add 1aS (30 mg, 0.11 mmol) to concentrated sulfuric acid (0.4 mL) and immerse in a soπfcatϊon bath tor about 30 min. Add water {4.6 mL} and filter the solids to afford IbI

Step 2:

To a mixture of 1b1 (21 mg, 0.058 mmol) in anhydrous pyridine (2 mL} under an Ar atmosphere, add OMAP (1 mg, 0.007 mmoi} and laθ {57 mg, 0,35 mmol). Heat to 60 ⁰ G for about 25 h. Evaporate the volatiles and dissolve the residue in DMSO (1 mL). Add S N NaOH (aqueous, 0.2 mLj and heat to S0°C for about 1.8 h, then leave at RT for about 18 h. Add excess TFA until the pH is approximately <2, Purification affords 1005,

Exam ple 1C; Com pound 1012

Step 1; Add to a mixture of 3-bromo-4-flyoronitrobeozene (1c1, 245 mg, 1.12 mmol) and 1c2 (synthesis according to the procedure in WO 2007/08771?) |264 mg, OJS mmoi) in DMSO (2 J ml_), anhydrous potassium carbonate (154 mg, 1 Λ 1 iwnoi) and stff at β5°C for about 2,5 h. Dilute the mixture with t-BME and wash successively with 1 N NaOH (aqueous), water and brine. Subsequently, dry with anhydrous MgSO ₄ , filter, and evaporate the volatrles. Purffteatϊon by flash chromatography (EtOAc/Hexanes) provides 1c3.

Step 2; Rgferenαr Keith Fagnou et aL ₍ J Am. Cfoem. Sac, 2006, 128, 581 -SSO, Stir a mixture consisting of 1c3 (750 mg, 1,41 mmol), potassium carbonate (582 mg, 4,21 mmoi), tricyclohexylphosphine tetrafluorobofate (108 mg, 0,28 mnrrøl) and DMA {? ml.) at RT while bubbling Ar gas through the mixture for about 15 mm Add palladium! Ii) acetate (68 mg ₍ 0.29 mmol) and immerse the reaction vessel into an oil bath preheated to 130°C, while maintaining a sialic Ar gas atmosphere. After about 30 m«n» oool the reaction to RT. Dilute the mixture with l-BME and wash with water. Dry with anhydrous MgSO,*, filter and evaporate the volatiles. Purification bγ flash chromatography (EtOAc/Hexaπes) provides 1c4.

Step 3; Stir a mixture of 1c4 (156 mg, 0,34 mmol) and Pearimart's catalyst (60 mg) In MeOH (10 mL) under 1 atmosphere of hydrogen gas for about 2 h Filter the solids and evaporate the vofatiles to give 1c S. Step 4

Using the protocol described in Example 1A, Step 7, 1c5 (20 mg, 0047 mmol) is converted to 1012 as the TFA salt,

Exam ple 1D; Com pound 1006

Step 1; To lai (9? mg, 0,34 mmol) in eold concentrated sulfune aεtd {2 mL) ₍ add KNO ₃ (38 mg, 0.36 mmol) and stir the mixture at 0°C for about 1 h. Dilute with EtOAc and water. To this btpiiasϊc mixture, add NaOH (solfd) and Na ₂ CO ₁ ISoHd) until the aqueous portion ts basic. Separate the organic portion, dry it over Na^SO^, filter and evaporate. Purification by flash chromatography (EtOAc/Hexanes) provides 1d1.

Step 2,

Using the protocol described tn Example 1B, Step 2), IdI {14 mg, Q.044 mmol) is converted to 1006,

Exam ple 1E: Com pound 1OT7

Step 1- Add carbonyi diimtcfazoie (3.68 g, 227 mmol) to a mixture of 3-bromo-4-fluoro benzoic acid 1e1 (2.51 g, 115 mmoi) in DMF (25 mL} and stir at RT for about 1 ft. Cool the reaction to CfC and add t-BuOH (5,7 ml, 59,4 mmol). Then add DBU (1.9 mL, 12,8 mmol) dropwise. Allow the mixture to warm to RT and stir for about 21 ft, Dilute the mixture with t-BME and wash successively with 10% titrie acid (aqueous) and saturated NaHCO^ (aqueous). Dry over MgSO ₄ , filter and evaporate the votatiies to obtain 1e2.

Step 2: Add anhydrous cesium carbonate (387 mg, 1,13 mmol) to a mixture of 1e2 (310 mg, 1.13 mmol) and 1c2 (255 mg, 0,76 mmol) tn DMSO (4 mL) and stir at S0°C for about 18 h. Dilute the mixture t-BME and wash successively with 10% cine acid (aqueous) and saturated NaHCGj (aqueous). Dry over MgSO ₄ , filter and evaporate Ihe volatiles. Purification by flash chromatography (EtOAc/Hexanes) provides 1e3,

Step 3: Reference; Kerth FagnOu et al., J.Am. CΛ#m, SOC.2006, 128, 581-590, Stir a mixture consisting of 1e3 (63 me;, 0.11 mmol), potassium carbonate (63 mg, 0,48 mmol), tricyclohexylphosphtne letrafluwebwate {6.5 mg, 0,017 mmol} and

DMA (1 mL) at RT white bubbling Ar gas through the mixture for about 15 min. Add palladιum(ll) acetate (15 mg _r 0,032 mmol) and immerse the reaction vessel into an oil bath preheated to 13CfC, while maintaining a static Ai gas atm osphere. After about 15 h, cool the reaction to RT and dilute the mixture with EtOAc, Add AcOH (500 μl_) and filter the solids, Collect the filtrate and wash with water and brine. Dry with anhydrous MgSC ₁ , filter, and evaporate the voiales. Dissolve the residue in TFA (1 ml) and then evaporate, Dissolve the residue in DMSO (1 rnL) and add 5 N NaOH (aqueous, 0.2 mL), Stir at 50 ^e C for about 2 h, Add excess TFA until the pH is approximately <2. Purification and lyophtization of the voiatϊies affords «07,

Exam ple 1F: Compound 1018

Step 1

In a fashion analogous to that for the production of 1C3 (Example 1C, Step 1) combine 3-bromo-4-fluoro benzaldebyde IfI (150 g, 739 mmol) and 1c2 (1 SO g, 45 rnmoi) in the presence of cesium carbonate (22§ g, 675 mmol) to give 1f2

Step 2 tn a fashion analogous to that for the production of 1c4 (Example 1C, Step 2), combine 1f2 (215 g, 416 mmoi) wrth polasssym carbonate (173 g, 125 mrnøl), tncyclohexytphosphine tetrafluoroborate (320 mg, 084 mmoi), DMA (100 mLj and paIladium|IIJ acetate (200 mg, 0 a? mmol; at 13Q ⁶¹ C for about 30 mm to gwe 1f3

Step3 Dissolve 1f3 (14 mg, 0033 mmoi) into a mixture of MeOH (02 mL) and THF (02 ml) at RT Add NaBH ₄ (10 mg, 026 mmol) and stir for about 1 h Evaporate the volatiies and dissolve the residue in DMSO (15 mL) Add 5 H IsIaOH (aqueous, 02 mL) and heat to 45 ⁰ C for about 45 min Add eicess AoOH Purification and lyophilizatfoπ of the volatitøs affords 1018

Exam ple 1G; Compσyndte 1054, 10S5 and 10S6

Step 1

Dissolve 1f3 (10Og 229 mmoi) in anhydrous DCM (100 mL) and add benzyl (tnphenyiphosphoranylidenejiaeelate (10? g, 2 S4 mmol) Stir this mixture for about 2 days at RT Evaporate the volatrles and puπfy wrth flash chromatography (EtQAc/Hexanes) to give 1gl

Step 2 Add 1 N NaOH {aqueous, 03 mL) to a mixture of 1g1 (30 mg _r 0088 mmol) in

DMSO (1 mL) and heal to 50°C After about 2 h at RT, add excess TFA to adjust the pH to approximately <2 Purification and lyophiltzatan of the volatiles affords 1054

Step 3 Dissolve 1f3 (100 g ₍ 023 mmol) in anhydrous THF (2 mL) and cool to -JS ⁰ C Add a solution of 14 M CHj ₁ Li in Et^O (250 μl_, 034 miTiQi) ϋropwise Then add water (100 μL) and evaporate the volatiles Dissolve the residue in DMSO (3 mL) and add 5 N NaOH (aqueous, 05 mL) Stir at RT for about 1 h Add exeess AcOH until the pH is approximately <4 Purification and lyophilizatioπ of the voiatsles affords 1Q5S

Step 4

Dissolve 10i5 {37mg _t 0085mmol) in THF {% mL) and add a 07 M diazomeihaneft- BME solution (25 mL) Evaporate the volatiles and dissolve the residue in anhydrous DMF (1 mL) Add MeI (27 μL, 042 mmoi) followed by 80% NaH/mineral oit (68 mg.017 mmoi) Stir at RT for about 2 h Add DMSO (1 mL) and 1 N NaOH {aqyeous, 05 mL) and stir at RT for aboyt 2 h Add excess AcOH until the pH is approximately <4 Purification and lyophtlization of the volatiles affords 1DSβ Exam ple 1H: Com pounds 1057, 1058 and 1140

Step 1: Add solid potassium t-butoxide {112 mg, i.00 minol) to a suspension of methyttripheπylphosphonium bromide (357 mg,, 100 mmot) in THF (10 mL) at -7i ^D C.

Warm the mixture slowly to CfG over about a 1 Ii period. To the suspension, add 113 {218 mg 0,500 mmol) dissolved in THF (5 mL), Stir for about 1 h. Add AcOH (50 μl) and evaporate the vofattles. Purification of the residue by flash chromatography (EtOAc/Hexanes) affords IhI.

Step 2: Add a boraπi-dimetfiyl sylide oomplix (46 μL, 0.46 miϊiQi) to a solution of IM (100 mg, 0 J3 mmol) in THF (S mL) at -78°C. Aftow ^! tie mixture to warm slowly to RT. Slowly add 30% H _S O _S (aqueous.0.5 mL}, followed by 1 N NaOH (aqueous, O.i mL). StIr at RT for about 24 ft Evaporate the volattfes and acidify with AeOH and DMSO. Purification and tyophilϊzalton of the røiatϊtes sffbrfs 1140.

Step 3: Add to a solution of IhI (100 mg, 0.23 mmol) in acetone (5 mL) at RT., 60% aqueous N ^L methylmofpholϊne-N-oxϊde (80 μL, 0.46 mmol), followed bf the addition of a solution of 2,5% w/w OsO* in t-BuOH (290 μU 0,023 mmol). Stir for about 2 h, then evaporate the volattles. Ada totuene (4 mL) and evaporate. Purification bγ flash chromatography (EtOAc/Hexanes) gives 1h3. Step 4.

Using the protocol described in Example IA, Step 7, 1h3 (30 mg, 0.084 mmol) is corwe rated to 1057,

Step 5,

Dissolve 1h3 (80 mg, 0.128 mmoi) in anhydrous DMF (2 mL) and add MeI (65 μL, 1.03 mmoi} _F followed hγ 60% MaH/mineral oil (28 mg, OJQ mmot). Stir at RT for about 3 h, then add DMSO {2 mL), Add 1 N NaOH (aqueous, 0.4 mL) and stir at RT for about 18 ft Add excess AeQH until the pH is approximately <4 Purification and lyαphilizattoπ of the volatile s affords 1058 ,

Exam ple 11: Compoynis 1136 and 1139

Step 1.

Following the procedure outlined in Tetmheάroπ, 2000, 56(2) _t pp 275-283, dissolve KH (40 mg, 1.00 mmoi} in anhydrous DMSO (2 mL) Add tfns solution to a mixture of gaseous Cf ₃ H (100 mg, 1,43 mmoi) in anhydrous DMF {3 mL} al -40 to -5G ^& C and stir for about 40 miπ. Add 113 (144 mg, 0.33 mmoi) in DMF (2 ml). Stir the mixture at -5O ⁰ G for about 2 h ₍ then at RT for about 3 days. Dilute with water, extract with EtOAc ₁ dry the organic portion with Na ₂ SO^, filter and evaporate. Dissolve the residue in DMSO, Purification and iyophilizatϊon of the volatrles affords 1136,

Step 2 ^* Followng the procedure outlined in JOC, 1S87, 52(12), ρp2481-2490, to B flask containing gaseous CF ₁ CF ₂ I (635 mg, 258 mmoi) and Et ₃ O (10 mL), add ira

{150 mg, 0,34 mmol) in a solution of Et ₂ O (10 mL) and cool to -78 ⁰ C, Add i 4 M CH ₃ U UBf complex in E%O (445 μi, 0,62 mirtol) portrønwise. After about 10-1 S mins, add 10% crime acid {aqueous, 4 mL) and then allow the mixture to warm to RT, Separate the layers and pass the organic portion through a small pad of Extrelut®. Collect the filtrate and evaporate. Purification of the residue by flash chromatography (EtOAc/Hexanes) affords 112 as an impure solid.

Step 3:

Using the protocol described tn Example 1A, Step 7, 112 (35 mg, 0,063 mrnol) is converted to 113§.

Exam ple U; Compounds 1141 and 1142

Step 1; Dissolve IeS (274 rng, 0.55 mmol) in MeCN {2.5 mL) and add TFA (S ml), Cool the mixture to 0°C, Add aqueoys sodrum nitrite (67 πmg/0,5 mL, 0.97 mmolj dropwise and stir for about 1 h. Add cupric bromide (434 mg, 195 mmol) tn a mixture of MeCN (2,5 mL) and water (2 mLK Add sold cuprous bromide {279 mg, 195 mmol) as a solid and stir for about 1 h. Evaporate the volatiSes, dilute with t-BME, wash with water, dry over WIgSQ ₄ , filter and evaporate. Purdtoatϊon of the residue by flash chromatography (EtOAc/Hexaπes) affords 1J1.

Step 2:

To a mixture consisting of 1J1 (35 mg, 0,072 nrimol), 3-furanboronic acid (20 mg, 0.18 mmol), toluene (1.5 mL), EtOH (1.5 mL), water (1 mL), UCI (S mg, 0.22 mmol), and Na ₅ CO ₃ (27 mg, 0.25 mmol) under an Ar gas atmosphere, add (PIiTP) ₄ Pd (8 mg, 0,00? mmol) and heat to 90 ^B C for about 20 h. Evaporate the volaliles and ihen add DMSO {2 mL) and 5 N NaOH |aqueous, 0,3 mL). SW the mixture at 5CfC for about 4 h and then acidify to approximately pH<2 with TFA. Purification and lyøphizatron of the volatile^ affords 1142,

Step 3.

U sing the protocol described in Example U ₁ Step 2, 1j1 (35 mg, 0.072 mmoS) with 2- furanboronic acid (24 mg, 022 mmol) is converted to 1141,

Exam ple 1K: Com pound 1010

Step 1: Stir a mixture of 1cS (28 mg, O.O€€ mmol), TEA (46 μL, 0.33 mmol), TBTU (27 mg, 0084 mmol), 1 _r 3'thiazole-4~carboxy1κ: acid (18 mg, 0.13 mmol} in DMSO (15 mL) for about 18 h. Add 5 N NaOH (aqueous, Q Z mL) and heat to 45°C for about 1 h. Acidify to approximately pH<=2 with TFA, purify and lyσpitize the volatiles to afford 1010.

Exam ple IL: Compounds 1631 and 10Si

Step 1:

Using tnpfieπyl(2'pyπdy1methyl)phosphonιym chloride hydrochloride as reagent and the protocol descrtbed in Example 1H, Step 1 , 113 (218 mg, 0.500 mmol) is converted to 111.

Step 2;

Expose 111 (45 mg, 0,088 mmol) in MeOH (15 mL) containing Pearimaπ's catalyst to a hydrogen gas atmosphere (1 atm ) for about 3 h. Filter the solids and evaporate the volatiles. Add DMSO (1 mL) and S N NaOH (aqueoys, 0.2 mL) and stir at RT for about 18 h. Acidify to approximately ρH<2 with TFA- Purification and lyophilization of the volatiles affords 1059 as the TFA adduct

Step 3: StIr 113 (25 mg, 0,5? mmol), morpholne {30 μL), MeOH (600 μL) and AcOH (30 μl_) at 50°C for about 1 h. Cool to RT and add sodium cysnob. ore hydride (5,0 mg, 0.079 mmol). Stir for about 18 h. Add the mixture to 10% Na _? CO ₃ (aqueous, 10 mL), whereupon a precipitate forms. The solids are collected by filtration, then are dissolved in DMSO (1 mL) and 2.5 N NaOH (aqueous, 0.1 mL). Stir the mixture at RT for about 18 ti. Acidify until tHe pH is approximately <2 with TFA. Purification and lyophilizatron of the voiatiles affords 1031 as the TFA salt.

Exam ple 1M: Compound 11 it

Step 1: Add a 1.4 M solution of CH ₃ U I Et ₂ O (300 μL, 0.42 mmol) to 113 (100 mg, 0,23 mmoi) in anhydrous THF (2 mL) at -78 ⁰ C and stir for about 30 min. Quench the reaction with AcOH (25 μL} and evaporate, Purification of tie residue with flash chromatography (EtOAc/Hexanes) gives crude 1ml which is used as such in the subsequent reaction.

Step 2; To crude 1m1 (70 mg) in THF (2 mL), add manganese dioxide (159 mg, 1 ,55 mmol) at RT and stir for about 3 h. Filter the solids and evaporate the volatiles. Dissolve the residue in DMSO (2 ml) and add 5 N NaOH {aqueous, O 3 ml_) Stir at RT for about 1 h then add excess TFA to adjust the pH to approximately <2 Purification and lyophization of the voiatiles affords 1109

Eiam pte 1N: Com pound 1050

Step 1

Expose 1g1 {235 mg, O 41 mmol) in MeOH {30 ml) containing Pearlman's catalyst {100 mg) to a hydrogen gas atmosphere (1 afm) far about 14 h Piter the solids and evaporate the volatiles to give 1Π1

Step 2 Stir a mixtyre consisting of 1n1 (60 mg, 010 mmol) ₍ DIPEEA {94 μL» 054 mmoϊ), acetamide oxinne {95 mg 013 mmot) TBTU (41 mg, Q 13 mmol) and DMF (2 mL) at RT for 18 h Dilute with t-BME, wash with water, then filter the organic portion through a pad of EXTKElϋϊ® Collect the filtrate and evaporate Dilute the residue in THF (2 mLi snd add 1 M TBAF/THF (100 μL, 010 mrnoi) Stir the mixture at RT for about 2 h Evaporate the voϊatiles and dissolve the residue in DMSO (1 mL) Add SN NaOH (aqueous, 03 mL) and stir at RT for about 2 h Add excess AcOH until the pH is approximately «4 Purification and lyophilizatioo of the votatiles affords 1050

Exam ple IG: Cornpoynds 1173, 11T4 and 1176

Step 1: Add 1.6 M vinylmagnestum brom lds/THF (400 pL, 0.63 mrnol) to 1f3 (250 mg, 0.54 rnniol} in THF (S mL) at 0°C and stir for about 1 h,. Dilute with saturated NH ₄ Cf (aqueous) and EtOAc. Separate the layers, dry the organic portion with MgSO ₄ , filter and evaporate. Purification of the residue with lash chromatography (EtOAc/Hexanes) provides 1o1.

Step 2: Add iodomethane (200 μl) and 60% w/w NaH/mineral oil (9 mg _t 0,22 mmol) to 1o1 (50 mg, 0,11 mmol) in THF (1 mL) at {PC, Warm the mixture to 40 ⁰ C for about 18 H ₁ then coot the mixture to RT, Dilute with MeOH, then add 1 N NaOH (aqueous). Stir at RT for about 24 h. Purification and Iy ophilizatlon of the volatile® affords 1173,

Step 3: Add allyt bromide (310 μL.0.38 mmol) and 95% NaH (11 mg, 0.46 mmol} to 1o1 (135 mg, 0,29 rrtmol) in THF (3 mL) at O ³ C. Waπri the mixture to RT and stir for about 14 h. Dilute with saturated NH^CI (aqueous) and EtOAc and separate the layers. Dry the organic portion with MgSOi, fitter and evaporate, Purleatioti of the residue with flash chromatography (EtOAc/Hexsnes) provides 1©3,.

Step 4:

Dϊssoiv© 1o3 {60 mg,.0.12 mmol) in degassed toluene (30 mL) and add Hoveyda- Gfu6b"s 2 ^nd generation catalyst (7 mg,, 0,008 mmol). Heat the mixture in a pre- warmed e! bath set at B0°C for about 30 rnin then coot to RT, Add silica gel and filter. Evaporate the volatites and dilute the residue with EtOAc. Filter, evaporate and take-up the residue in THF/MeOH and 1 N NaOH (aqueous), Stir this mixture at RT for about 18 h. Purification and lyophizatran of the volatiies affords 1176.

Step 5;

Using the protocol described in Example IA, Step ?, 1o1 (SO mg, 0.11 mmol) is converted to 1174,

Exam ple 1P: Com pound 1175

Step 1: Add 2 M aiyf magnesium bromWe/THF (44 μL, 0.8S mπnol) stowly to 1f3 {350 mg, 0.80 mmol) in THF (7 mL) at -78°C, and thin allow to warm to 0°C Dilute with saturated NH ₄ CI (aqueous) and EtOAc and separate the lasers Dry the organic portion wilh MgSG ₄ , filter and concentrate. Purification of the residue wrth flash chromatography (EtOAc/Hexanes) affords 1ρ1.

Step 2: Using the protocol described in Example 1O, Step 3, tpi (53 mg, 0.11 mmol) is converted to 1p2.

Step 3:

Using the protocol described in Example 1O, Step 4, 1p2 (23 mg, 0.044 mmot) is converted Io 117 S. Exam ple 1Q: Compound 2002

Step 1. Following the procedure outlined in Chemistry Letters, 1988, pp395-338« add solid methanesuifonie anhydride (426 mg, 245 mmol) and trifle aeid {200 μL, 228 mmol) to a mixture of solid 1a9 (1OO mg, O 25 mmol J and heat to approximately 8CfC for about 1 h Add this mixture to water (20 ml_), then extract with EtOAc (2 x 20 mL) Combine the organic portions and evaporate Dissolve the residue in DMSO (4 mL) and add 5 N NaOH (aqueous, 05 mL) Stir at RT for about 18 h then add excess TFA until the pB is approximately <2 Purification and iyophilization of the volatiles affords 2002

Exam ple 2At Com pound 1021

Stepi Add clilorosulfonic acid {400 μL 599 mmol) to IaS {250 mg, 061 mmol) in DCM (10 mL), and stir at RT for at»ut 18 h Dilute with t-BME, and wash with water and saturated NaHCOj (aqueous) Dry over MgSO _* ,, filter and concentrate Purification of the residue with lash chromatography (EtOAc/Hexanes) gives IaI

Step 2 Add to 3-hydroxvpheneihyJamine hydrochloride salt (21 mg _» 012 mmot) in DCM (2 mL) _t TEA (100 μL, 072 mmoϊj and ZaI {30 mg, 0 OSi rnmol) in THF (1 mL) Stir at RT for about 2 h then evaporate the volatiles Dissolve the residue in DIvISQ (1 mL) Add 1 M NaOH (aqueous, 03 mL) and stir at RT for about ISh Add excess TFA until the pH is approximately <2 Purification and lyophiizaitαn of the volatiles affords 102S Exam ple 3A: Com pound 1024

Step 1 Combine 1e3 (573 g, 007 mrnolϊ with potassium carbonate {404 g 292 mmol), tricyclohexylphosphtne tetrafluoro borate (54 mg, 015 mrnol), DMA (10 rnL) and paltactιum(ll) acetate (22 mg ₍ 0097 mrnol) at 130°C for about 90 mm Dilute wrth t- BME and add excess AcOH (04 ml) Wash with water and dry over MgSO^ ₁ filter and concentrate Dissolve the residue in t-BME (5 mL) and add a 07 M diazαmethaπe solution in t-BME {10 mL) Evaporation of the volatiϊes and purification of the residue with flash chromatography {EtOAe/Hexanes) affords 3a 1

Step 2 Dissolve 3a1 (44S mg, Q 88 mmol) in TFA (4 ml) and stir at RT for about Z h Evaporate the voiatites then co-evaporate with toluene Triturate with hexanes to give 3a2

Steps Stir a mixture of 3a2 (30 mg, 0 fJδ€ mmol) TEA (92 μl 088 mmol) TBTU (43 mg 013 mmol} and 3-hydroxyphenetfiylamιne hydrochloride salt (23 mg, 013 mmoi) in DMSO (1 ml) for about 2 h. Add 5 N NaOH (aqueous , 0,3 mL) and stir at RT for about 18 h Acidify with TFA until the pH is approximately <2 Purification and lyophilizafion of the volatiles affords 1024

Exam ple 3B: Com pound 1052 Step 1 Stir a mixture consisting of 3a2 {65 mg, 014 mmol), DIPEA (125 μL» 072 mmol), acetamide oxime (13 mg, 018 mmol), TSTU (SS mg, 01? mmol) and THF {2 mL) at RT for aboyt 3 Ii Add additional acetarrade oxtme (26 mg) and TBTLf (275 mg), then slfr for about 18 Ii Dilute with t-BME. wasli with water, then filter the organic portion through a pad of EXΪRELϋϊ® Coiled the filtrate and evaporate Dilute the residue in THF (2 mL), add 1 M TBABTHf (100 μL, 010 mmol) and stir at RT for about 2 h Evaporate the voiatsles and dissolve the residue in DMSO (1 mL) Add 5 N NaOH {aqueous,, 03 mL) and stir at RT for about 2 h Add excess AcOH until the pH is approximately <4 Purification and lyophtlizatioπ of the voϊatiles affords 1052

Exam ple 4A: Com pounds 1060, 1063 and 108S

Step 1 Stir a mixture of IU (3 OO g, 6 §9 mmol), MeOH (150 mL) and sochum borøhydnde (300 mg, 7 S3 mmoi) at RT for about 1 h Quench the reaction with excess 4 N HCI (aqueous) and stir for about 30 in in Evaporate the voiatϊies and dissolve the residue in EtOAc Wash successively with water, saturated NaHCO^ ^aqueous) and brine, dry over MgSO ₄ , filter and concentrate to provide crude 4a 1 Step 2: Add to a mixture of crude 4a1 {3,00 g, 6,66 mmol} in anhydrous DCM {150 mL) and

DMF (0.3 mL) at RT, thioπyt chloride {1.50 mL, 210 mmol} and stir for aboyt 20 min.

Evaporate the voiatiles and purify with flash chromatography (EtOAc/Hexanes) to provide partially purified material. Precipitate the product with a combination of EtOAc, Et ₃ O and hexaπes and filter the solid Io give 4a2.

Step 3: Add to a mixture of Cs ₃ CGa (13 mg, 0,058 mmol), Kl {2,5 mg, 0015 mmol), 3- aminopyridine {5,0 mg, 0.053 mmol) and MgSO ₄ (20 mg). a solution of 4a2 {20 mg. 0.042 mmol) in DMF (SOO μL). Stir at 70°C for about 4 h then at RT overnight. Filter the mixture and then wash the filter with DMSO (500 μL). Combine the filtrate and washings and add 5 N NaOH (aqueoys _t 100 μL). Stir at RT for about 3 h. Acidify with excess AcOH, Purification and lyophilϊzatioπ of the volatiles affords 1083 as the TFA salt

Step 4:

Using the protocol described in Example 4A, Step 3« 4a2 (35 mg, 0.072 mmol) with 3-mercapio-1,2,4-triazote (5.4 mg, 0.053 rnmol) is converted to 1060.

Step 5:

Using the protocol described in Example 4A _r Step 3, 4a2 (35 mg, 0.072 mmol) with 2-hydroxybenzolπfluoride (68 mg, 0.053 mmol) is converted to 10β6.

Exam ple 4B; Com pound 1038

Step 1: Add compound 4a1 {20 mg, 0.046 mmol} to a mixture of 60% w/tø NaH/mmeral oil {6.0 mg, 0.15 mmol) in DMF (0,5 mL) and stir at RT for about 15-30 minis. Add 2- iodopTOpane (118 μL, 1.18 mmol) in portions and stir for about 3 days. Dilute with DMSO (1 mL) and acidify with excess AcOH, Purification and lyophtizaten of the votatϊϊes affords 1038,

Exam ple 4C; Com pounds 1040, 10S3 and 1129

Step 1; Add to a mixture of Kl (14 mg, 0,084 mmoi) and 1-(3-h^droxypropyl)pyrrole (12.5 mg, 0.10 mmol), 60% w/w NaH/miπeral oil (5.0 mg, 0.12 mmol) in DMSO (0.5 mL) {premϊx at 8CFC for aboyt 1 h _r then coot to RT). Stir for about 10 min, then ado ^" 4a2 (20 mg, 0.044 mmoi) in DMSO (0,5 mL), Stir at RT for about 72 h. Add 5 N NaOH { aqueous, 100 μL) and stir for about 2 h. Dilute to a 1 ,5 mL volume with AcOH, Puricatioπ and lyophilization of the volatites affords 1129,

Step 2: Add to a mixture of 60% w/w NaH/mϊnerai oil (4,0 m§, 0.10 mmoi) in DMF (0,5 ml), compound 4a2 {20 mg, 0.043 mmoi) followed by benzyl alcohol (10 μL, 0.096 mmol). Stir at RT for about 1 h, them driute with DMSO (1 mL) and acidify with excess AcOH, Purification and lyophϊlizatϊon of the volatites affords 1040.

Step 3: Add potassium t-butoxide (15 mg _r 0.13 mmoi) to a mixture of KI (22 mg _r 0.13 mmoi), DMF (1 mL) and 2-phenyiethanoϊ {20 pl_ _» 0.16 mmoi) at RT. StIr far about 5-10 min. Add 4a2 (30 mg, Q.Q&6 mmol) dissolved in DMf (1 mL) and stir for aboyt 3 h. Add an additional portion of potassium t-butoxide (15 mg, 0.13 mmo!) and stir for about 18 h. Acidify with excess TFA, Purification and lyophilzation of the voSatiles affords 1053. Exam ple SA: Com pound 1166

Step 1;

Deposit 60% w/w NaH/miπeral oil (100 mg _» 2,50 rrimol) into a 100 mL round bottom flask and wash with hexaoes (20 mL), Add anhydrous DMSO (10 mL) and heat to 80°C for about 1 h, then cool. Add 4-jodo benzyl alcohol (246 mg _> 105 mrnoi) and Kl |280 mg» 1.69 mmot) and stir tor about 10 rnin. Add 4a21400 mg, OJS mmolj and stir far about 18 h at RT Add the mixture to 1 N HCI (aqueous, 200 mL), whereupon a precipitate forms. Filter tte solids. Dissolvt the solids in EtOAc and wash with brine, dry over MgSO ₄ , filter and concentrate. Dissolve the residue in MeCN (8 mL) and add DBU (116 μL.0.77 mmol) and iodomethane (200 μL, 3,22 mmol) portonwise over about 8 h. Stir for about 18 h at RT Evaporate the voiatiles and dissolve the residue in EtOAc. Wash successively with brine, saturated NaHGGj (aqueous) and 1 N HCI (aqueous) and brine Dry over MgSO ₄ , filter and concentrate. Purification of the residue by flash chromatography fEtOAciHexanes) affords Sal

Step 2 ¹ Reference; lmmaculada Dinares etaf,« Eur, J, Org, CMm, 2005, 1637-1643,

Add a solution of Sal (19 mg, 0.029 mmoi) in DMF (500 μL) to a mixture of Cs?CO ₃ (24 mg, 0074 mmol), cuprous iodide (1 ,8 mg, 0.009 mmol) and 2-methy imidazole (3,0 mg, 0.036 mmol). Piace under an atmosphere of Ar gas and add trans-1,2- bis|methylamϊno)cvdohexane (3,0 mg ₍ 0.021 mmol). Stir at 100°C for about 36 h, coot to RT ₁ then add i N NaOH (aqueous, 72 μL) Stir at 55 ⁰ C for about 2 h Dilute to a 1.5 mL volume with AcOH. Purification and l^ophilization of the volatiles affords 1166 as the TFA salt Exam ple SB: Com pounds 11 Zl and 1138

Step 1:

To 4a2 {?S mg, 016 rnmol) fn THF (2 mL) at RT, add sod rum mefrsylthiolate {14 mg, 020 mfflol) and sUr for about 3 h Add DMF (2 mL) and heat to 7CfC for about 18 h Add a further portion of sodtom methylthiolate {10 mg, 0.14 mmoi) and sir for about 3 h Evaporate the volatiles and dflute with t-BME. Wash with water, dry over MgSO ₄ , filter and concentrate. PuricatJoπ of the residue by flash ehromatograpHy {EtOAdHexariis) affords 5b1

Step 2:

Using the protocol described in Example 1A, Step 7, 5b1 (15 mg, 0032 mmol) is converted to 1137.

Step 3; Add Oxone® (150 mg, 0.24 mmol) to a mixture of 5b1 (28 mg, 0.080 mmol}. acetone (8 mL) and water (2 mL) at RT Sir for about 4 h Evaporate the acetone, co-evaporate with EtOH {3 mL). Add DMSO {3 mL) and 5 N NaOH (aqueous, 1 mL) to the residues and stir at RT for about 30 min, Acidify with excess AcOH, Purification and lyophilizatton of the volatiles affords 1138

Exam ple 6 A: Com pounds 11B0 and 1190

Step 1 Add 1 MfTHF 2-m#thoxy phenyl magnesium bromide (6iO μL, O 87 mmol) to 1f3 (100 mg, 023 mmol) in THF (5 mL) at0°C, and stir for about 1 h Add 1 N HC!

{aqueous, 100 μL} and rttute with t-BME Wash with 1 N HCI (aqueous), dry over Na ₂ SCX, filter and concentrate Dissolve the residue in anhydrous DMF (2 mL) and add methyt iodide {73 μL, 115 mmol) foilowe-d by 60% NaH/mnerai oif {46 mg, 115 mmol) Stir at RT for about 1 h, then add water (100 μLj. DMSO (2 mL), and 5 N NaOH (aqueous 1 mL) stir at 50°C for about 30 mfn Cooϊ to RT and add excess AeOH (500 μL) Stir for about 45 mm Add this mixture to water {15 mL), whereupon a grey precipitate forms Collect the solids by filtration and dissolve the solids in DMSO (45 mL) Purification and lyophilizatioπ of the votatiles affords 1190.

Step 2 Add 05 MfFHF cydopropyl magnesium bromide |300 μL, 015 mmol) to a solution of 1f3 (50 mg, 012 mmol) in THF (2 mL) at 0°C, and stir for about 1 h Add water (100 μL) and evaporate the volatiles Add DMSO (15 mL) and 5 N NaOH {aqueous, 03 ml) and stir at RT for about 1-2 h Acidify with excess AcOH Purification and lyophilizatton of the voiatiles affords 1180

Exam ple 7A: Com pound 1189

Step 1: Suspend 7a1 {193 g, 303 mmol) in concentrated sulfuric acid (150 mL) at RT and add KNO ₃ {& 6Sg 954 mmol) portonwise Stir the mixture for about 18 h, then pour slowly over 18 kg of tee Stor unttl the ice melts and then filter the solids Wash with water and dry at RT and ambient humidity Dissolve the resulting solid in t-BME and add freshly prepared diazomethane/t-BME solution until the intermediate aαd is no longer detectable by RP-HPLC Add AeOH to quench excess diazom ethane, then- wash with water and saturated NaHCOj (aqueous) Dry the organic portion over Na ₂ SO^ _I1 filter and concentrate Io give 7a2

Step 2

Using the protocol descnbed tn Example 1C Step 1, stir 7a2 (1 OO g, 360 mmol) and hydroqyinoπe monobeiizyl ether (758 mg 378 mmol) in the presence of cesium carbonate (146 g, 450 mmol) to give 7a3

Step 3

Using the protocol described in 1C Step 2, combine 7a3 (141 g 307 nπmol) with potassium carbonate (127 g, S 21 mmol) tπcyclohexylphosphme tetrafluoroborate (238 mg, 082 mmol), DMA (10 mL) and palladιum(il) acetate (147 mg, 022 nmmoi) at 130 ^e C for about 30 min to give 7a4

Step 4 Stir a mixture consisting of 7M ₁ (874 mg» 2.32 mmol), stannous chloride (2,19 g, 11.6 mrnol) and IVieQH (50 mL) at 70°C for about 6 h. Dilute the reaction with EtQAε {400 ml) and then add saturated NaHCOa (aqueous, 400 mL). Stir the biphasic mixture for about 2 days. F titer the solids and then collect the filtrate. Separate the layers and dry the organic portron over NSsSO ₄ , filter and concentrate. The solid is trituated with a 25% t-BME/hexanes mixture, filtered and washed with hexanes to gi¥# 7a5.

Step 5: Add 4 IVI H€ϋdϊoxaπe (363 μL, 1,45 irimol), 2-methoxy propene (1.11 ml, 11.6 mmol) and NaHB(OAc) ₃ (770 g, 3.64 mmof) to a mixture of 7a5 (505 mg, 1.45 mmoi) in DCM (30 mL), Stir at RT for about 2 h. AtJd saturated NaHCO ₃ (aqueous) and stir for about 30 min Dilute with t-BME and separate the layers. Wash the organic portion with brtne, dry over MgSO^, filter and concentrate to give TaS.

Step 6; Heat a mixture consisting of 7a§ (104 mg, 0.27 mmol), lai (51 mg, 0,30 mmol), pyridine (108 μL, 1.34 mmol) and DCE (2 mL) at 150°C for 20 min In a microwave, Dilute with EtOAc. Wash with 1 M HCI (aqueous) and brine, then dry over HgSO^, filter and concentrate. Purification of the residue bγ flash chromatography (EtOAc/Hexanes) affords 7a7,

Step 7-

Using the protocol described m Example 1N, Step 1, 7a7 (80 mg, 0,16 mmol) is converted to 7a8,

Step 8:

Using the protocol described in Example 1A ₁ Step 7, 7a8 (20 mg, 0,047 mmoi) is converted to 1189.

Exam ple 7B: Com pound 2025

Step 1-

Using the protocol described in Example 7A, Step 6, ?a6002 mg, 0,26 mmol) is converted to 7b1

Step 2-

Expose a mixture of 7b1 (60 mg, 0.12 mmol), MeOH (30 mL), TFA and Pearlman's catalyst with stirring to a hydrogen atmosphere (1 atm ) for about 2 b Frier the catalyst and evaporate the voiatiles Add DMSO (15 mL) and 5 N NaOH {aqueous, 03 mL) and stir at RT for about 30 mϊn Acidify with excess AcOH Purification and lyopiiiizatøn of the volatiles affords 2025,

Exam ple BA: Com pounds 2003, 2001, 200S and 2022

Step 1" Add thϊonyl chloride (40 m L, 0.55 rπol) dropwtse to 5-hydroxy"2"n ^' rtrobenzoic acid 8a1 (50.0 g, 0.270 m ol) in MeOH (500 m L). Heat to 76°C for about 2 h. Add a further portion of thionyl chloride {20 m L, 0,27 m ol) dropwϊse and continue healing for about 13 h. Add a flnal portion of thionyl chloride (20 m L, 0.2? m olj and continue heating for about 1 h. Allow the m ixture to cool to RT and concentrate under reduced pressure. Dilute wrth EtOAc. Wash with saturated NaHCOj (aqueous) and bnne, dry over MgSO ₄ , filter and concentrate to dryness. Crystallize the residue with DCM and hexaπes to provide 8a2.

Step 2. Stir a m ixture consisting of Sa2 (51.2 g, 0,26 m ot), potassium carbonate (150 g, 1.09 m ol), benzyf brom ide (39 m L, 0,33 m ol} and acetone at RT for about 18 h. Filter the solids and collect and concentrate the filtrate. Dilute the filtrate with EtOAc. Wash with water, then brine, dry over MgSO ₄ , filter and evaporate to dryness Crystallize the residue with EtOAc and hexanes to provide 8a3,

Step 3:

Using the protocol descnbed in Exam ple 1A _r Step 2, treat BaS (61 4 g, 0.24 m ol) with elemental iron {225 g, 4,0 mol), acetic acid {95 mL) and EtOH (1 ,2 L) Heat to reflux to give a solid following workup and crystallization from DCM and teaπes. Dissolve this solid in Et ₂ O |400 mL) and then add 2 M HCIZEt ₂ O (180 mL) and stir for about 2 h. Filter the solids and dry to provide Sa4,

Step 4:

Using the protocol described in Example 1A, Step 3, convert 8a4 (105.2 g, 0.38 mol) to give 8a5 following crystallization from EtOAc and iiexaoes,

Step 5:

Hydrogenate a mixture consisting of SaS (9.3 g, 31.1 mmol), EtOAc (20-0 mL), MeOH (200 mL), and 10% Pd/C (0,9 g) at 30 psi H ₂ (g) for about 6-8 h at RT. filter the solids and concentrate to provide an oil Trituate with hexanes to give 8a8,

Step 6;

Using the protocol described tn Example 1C, Step 1» Saβ (4 flO g, 229 mrnol) is converted to 8a7.

Step ?: Using the protocol described in Example 1C, Step 2, Sa? (1.50 g, 3.82 mmoi) is converted to Saβ,

Step 8; Heat a mixtyre of βaβ (60 mg, 0.19 rnmol), p-toluoyl chloride (51 μl, 0,38 mmoi) and pyridine (1 mL) to 70°C for about 5 h. Add a further portion of p-toluoyl chloride (51 μL, 0,3 Smmol) and continue heating for about a further 3 h Evaporate the volatiies and dilute with EtOAc. Wash with 10% citric acid (aqueous) and saturated NaHCO ₃ (aqueous). Pass the organic portion through a pad of EXTRELUT®, concentrate, then purity by flash chromatography (EtOAc/Hexanes) to provide ftai.

Step 9:

Using the protocol described in Example 1F, Step 3, 8a9 (40 mg, 0.0S3 mmoi) is converted to 20-05. Step 10,

Using the protocol described in Example 4A, Step 1 , 8a8 (1.79 g, 5,75 mmol) is converted to βa 11.

Step 11, Add a solution of 8a11 {800 mg _> 1 ,92 mmoi) in OMF {9 ml) dropwise to a mixture of 60% w/to NaH/mtneral oil (92 mg, 2.30 mmot), DMF (3 mi_) and iodomethane (1B0 jjL» 2,88 mmol) at -10°C. Stir for about 2 h, then quench wilh saturated NH ₄ C! (aqueous), DHuIe with EtOAc anύ water. Separate and wash the organic portion with bone, dry over MgSO ₄ , filter and concentrate Purification of the residue by flash chromatography (EtOAc/Hexanes) affords crude 8a12,

Step 12; Heat a mixture of crude 6a12 (45 mg, 014 mmol), p-teiuoy! chloride (36 μt, 027 rrirrtol) and pyridine (1 ,5 rήL) to 70°C for about 5 h. Evaporate the voϊatiles and add DMSO (1 mL) and 5 N NaOH (aqueous, 0,3 ml), Stir at RT for about 3 h. Acidify with excess AcOH, Purification and lyophilization of the volatiles affords 20Oi.

Step 13' Suspend 4-bromo-2-fluorobeozojc acid (55 mg, 0,25 mmol) m thionyl chloride (500 μl_) and add DMF (10 μL), Stir for about 18 h at RT. Evaporate the volatiles, then co- evaporate with toluene. Dissolve the residue tn pyridine (1 mL) and add solid SaS (60 mg _f 0.19 mmol). Sltr at RT for aboyt 3 h. Evaporate the volatntes and dilute with EϊOAc, Wash with 10% citric acid |aqueoys) and saturated NaHCOj (aqueous). Pass the organic portion through a pad of EXTRELUT®, concentrate, and punty the residue wilt flash chromatography (EtGAc/Hexanes) to provide Sa 14

Step 14:

Using the protocol described In Example IF ₁ Step 3, 8a14 (45 mg, 0,088 mmol) is ϋøπverte-d to 2003,

Step 15; Suspend 4-bromo-3-mettiylbenzotε acid (39 mg, 0,18 mmol) in thionyf chloride (600 μL) and add DMF (10 μL) Stir for about 1 h at TQ ⁰ C, Evaporate the votatiles, then co-evaporate with DCE, To the rematrting residue,, add Sa12 (20 mg, 0,0€ mmol) fn DCE and add pyridine (25 μL, 0.31 mmol). Heat to 1S0°C for 15 min in a microwave. Diiyte with THF and treat with polystyrene-trisamine for about 2 h at RT. Filter the solids, collect the filtrate and concentrate. Add DMSO (1 mL) and S N NaOH (aqueous, 0.15 mL) and stir at RT for about 3 h. Acidify with excess AcOH. Purification and fyophilizattoπ of the voiatifes affords 2022.

Exam ple SA; Com pound 2018

Step 1:

Using the protocoi described sn Example SA, Step 15, 1a6 (20 mg, 0,071 mmol) is converted to 201 β.

Exam ple 1OA: Com pounds 2<Mt§, 2011 and 2012

Step 1

Using the procedure outlined in Tetrabe-dron Letters, 2002.43, pp 3585-35€7» add 60% wΛv NaH/mrnerat otl (18Og, 45 mmol) to 7a2 (S 00 g, 180 mmol), 2- {methyisulfonyl|ethanoi (335 g, 27 mmoi) and DMF (35 mL) in four equal portions over a period of about 20 mm After slirnng at RT for about 1 h, add a further portion of 80% w/w fslaH/miπeraf oil (300 mg) and stir far about 30 mm Qyench with AcOH, dilute with water and extract with t-BME Dry the organic portion over Na _^ SO^ filter and concentrate Purification of the residue by flash chromatography (EtOAc/Hexanes) afforcfs 1Oa1

Step 2

Combine 10ai (427 g, 15 S mmol} with MeOH (100 rnL) and stannoys chioπde {117 g, 61 i mmol) to give a solid following workup Dissolve this solid in t-BME (100 mL), add 2 M HCt/Et/3 (20 mL) and stir for about 1 h Evaporate the volatiles and tπtuate the residue with t-BME and hexanes to give 1<5a2 Step 3:

Using the protocol described in Example 1A, Step 3, 10a2 |3.96 g, 014 mmol) is converted to 1Qa3 following purification y flash chromatography (EtOAdHexanes)

Step 4:

Using the protocol described in Example 1C, Step 1, combine 2-methyl-4-fluoro benzalctehyde 10a4 (366 mg, 2,84 mmol) and 10a3 {610 mg, 2.12 mmol} in the presence of cesium carbonate (1.2Og.7.70 mmol) at B0°C to give 1OaS.

Step 5:

Using the protocol described m Example 1C, Step 2, 10a 5 (470 mg _f 1.16 mmol) is converted to 1Oaβ

Step 6;

Using the protocol described In Example 7A, Step 6, 1ia6 (200 mg, 0,62 mmol) is converted to Iθa7.

Step 7: Using the protocol described tn Example 4A, Step 1, 1Qa7 {173 mg, 0.38 mmol) is converted to 1OaB.

Step 8;

Using the protocol described tn Example 1A _r Step 7, 10a8 (20 mg» 0.044 mmol) is converted to 20βS.

Step 3:

Using the protocol described In Example W ₁ Step 5 _» 10aβ (30 mg, 0,068 mmoi) is converted to 2011.

Step 10:

Using the protocol described m Example 1H, Step S, convert 1OaB (50 rng, 011 mmol) in the presence of 5-(chloromethyl)-1 ,3-dimethyMH-pyrazσle (24 mg» 0,17 mmol) to give 2012. Exam ple 11 A: Com pounds 2014, 2015, 2020 and 2021

Step 1

Using the protocol described \n Example 1C, Step 1, stir 7a2 (200 g, 721 πnmol) arid 3-hydroxybenzaldehyde 11a1 (972 mg, 760 mmol) in the presence of cesium carbonate (Z 84 g, 863 mmol) to give i 1a2

Step 2

Using the protocol described m Example 1C ₁ Step 2, combine Ha2 (233 g, 610 mmol) with potassium carbonate (252 g 183 mmol), ϊπeycloriexylpliQseinne tetrafluoroborate |4€8 mg» 123 mmol) DMA (35 ml) and palϊadιum(Ii) aeetete (292 mg, 127 mmol) at 130°C for about 30 mm to give 11a3

Step 3

Using the protocol described m Example 1N, Step 1, 11a3 (840 mg, 281 mmol) is converted to 11a4 following purification by flash chromatography (EtOAc/Hexanes)

Step 4 Using the protocol described fn Example 7A, Step 5, 11a4 (340 mg« 1,23 mmol) is converted to 11 a5.

Step 5; Heat a mixture consisting of 11aS (25 mg, 0.080 mmol), 1a! {32 mg, 0.20 mrnolj, pyπdme (65 μL, 0.80 mmol) and DCE (03 mL) and teat at 150 ⁰¹ C for 20 mm in a microwavt. Evaporate the volatites, add DMSO (1.5 mL) and 5 N NaOH (aqueous, 0.3 mL) and stir at RT for about 2 h. Acidify with excess AcOH, Puπfrcation and lyophilization of the voiatiles affords 2014.

Step 6: Suspend 4-bromo-2-fluorobeιizoic acid (44 mg, 0,20 mm ol) In thionyl chloride (300 μL) and add DMF (10 μL), then stir for about 2 h at RT. Evaporate the voiatiles, then co-evaporate with toluene. Dissolve the residue in DCE {0,5 mL), add pyridine (65 μL, OJO mmol), then lias (25 mg, G.QΘG mmoϊ) and heat at I5θ ^β c tor 20 miπ in a microwave, Evaporate the voiatiles, add DMSO (1 ,5 ml) and 6 N NaOH (aqueous, 0,30 mL) and stir at RT for about 2 h. Acidify with excess AcOH, Purification and lyophϊiization of the voiatiles affords 2015.

Step 7; Heat a mixture consisting of 11a5 (126 mg, 0,40 mmol), 1aS (161 mg, 1,01 mmol), pyridine (325 μL, 4,21 mmof) and DCE (6 mL) and heat at 150 ^ft C for 20 min in a microwave, Evaporate the volatϊies, add OMSO {3 mL) and 5 IM NaOH {aqueous, 0,5 mL) and stir at RT for about 1 h. Pour trie mixture into 0,5 M KHSO ₄ {aqueous, 25 mL) and extract with EtOAc. Wash the organic portion with water and brtne, dry over Na ₇ SO ₄ . filter and evaporate. Dissolve the residue in t-BME, then add freshly prepared diazomethane/ether solution Titrate until characteristic yellow persists.

Evaporate and purify the residue with flash chromatography (EtOAc/Hexaπes) to give 1IaS-

Step 8;

Using the protocol described in Example 1OA, Step 10, 11a8 (40 mg, 0,091 mmoi) is converted to 2021, Steps

Using the protocol described in Example 1H ₁ Step 5» 11aβ {30 mg, 0089 mmol) is converted to 2020

Exam ple 12ft; Com pounds 2027 and 2029

Step i Add Uiionyl chlortde (19 mL, 261 mmof) to a solution of 2-amtno-5-hydroxybenzoιc acid, 12a1 (200 g, 131 mmol) in MeOH |50 mL) Stir at 70 ^Q C for about 48 h AM a fyrther porltoπ of thionyl chfoπde (1 δ mL, 261 mmol) and continue heating for about 72 h Concentrate to dryness, then suspend solids in t-BME Stir for about 24 h, then filter and air dry to provide 12a2

Step 2

Using the protocol described in Example 1C, Step 1. combine 3-bromo-4-fluoro beozaWehyete 1f1 (253 g, 125 mm©!) and 12a2 (231 g, 113 mmol) in the presence of cesium carbonate (737 g, 227 mmol) to give I2a3

Step 3

Using the protocol described in Example 11A _r Step Z, I2a3 (177 g, S 06 mmol) is converted to 12a4

Step 4 Stir a mixture consisting of 12a4 (2QQ mg» 0.74 mmol), 2-bremøethyi methyl ether {?Q0 μL, 7.43 mmol), Kl (616 mg.3.71 mraolj, DIPEA (1300 μL _r 7.43 mmol) and DMF (5 mL) at 120°C for about 18 h. Dilute with EtOAc, wash with 1 M NaOH (aqueous), water and brine, dry over Na ₂ SO., filter and evaporate. Purification of the residue by flash chromatography (EiGAc/Hexaπes) affords 12aS,

Step 5:

Using the protocol described in Example 7 A, Step 6, 12a5 {75 mg, 0.23 mmol) is converted to 12a§ .

Step 6:

Using the protocol described m Example 4A, Step 1, 12aS (76 mg, 0.17 mmol) is converted to 12a7.

Step?;

Using the protocol described In Example 1H ₁ Step 5, 12a7 (25 mg, 0.055 mmol) is converted to 2027,

Step 8; Using the protocol described in Example 1OA, Step 10, 12a7 (47 mg, OJO mrnol) to give 202S.

Exam ple 13 A: Com pounds 2028 and 2630

Stepi;

In a fashion artalogoys to that for the production of 4a1 |Example 4A ₁ Step 1), convert 12a4 (580 mg, 2.15 rnmol) to pϊve 13a1.

Step 2; Stir a morture of 13a1 (570 mg, 2.10 rπmol), DMF (5 ml), imidazole (429 mg, 6 JO mmol) and t-butyldi methyl silyl chloride {633 mg, 4,20 mmol) at RT for about 1 h. Dilute with t-BME, wash successively with pcrtions of 10% crtrtc acid (aqueous), saturated NaHCOj (aqueous), water at\ά brine. Dry ewer Na ₂ SO ₄ , filter and evaporate. Puπficaϊon of the residue by flash chromatography fEtQAe/Hexanes) affords 13a2.

Step 3: Fgllowiπga protocol similar to that descrrbed at pages 60 ■§ 1 of WO 06/119848. Stir a mixture consisting of 13a2 (200 mg, 0.52 mmol), cyclobutaπone (7? μL, 1 ,04 mmol}, dibutyltin chloride {B mg, 0,026 mmol), phertylsilane (70 μL, 0,57 mmol) and THF (5 ml ) for about 24 h at 70 ^β C, Add further portions of cyclobutanone (77 μL, 1 ,04 mmol J, dibutyltin chloride {8 mg, 0,026 mmol) and phertylsifane (70 μL, 0,57 mmol), and centrnue heating for about 24 h. Dilute with t-BME, and wash wth saturated NaKCO ₃ (aqueous). Dry over IMa _? SO _< , filter and concentrate. Purification of the residue by flash chromatography | EtG Ac/He xanes) affords 13a3,

Step 4: Heat a mixture consisting of 13a3 (165 mg, 0,37 mmol), 1a8 {120 mg, 0.75 mmol), pyridine (152 μL.1.88 mmot) and DCE (2.5 mL) at 150°C for 20 min in a microwave. Diute with t'BME and 1 M HCI (aqueous) and separate the layers Wash the organic portion with brine, dry over MgSO^, filter and concentrate. Dissolve the residue in THF {5 mL) and add 1 M TBAF/THF sofuiton (1 mL). Stir for about 1 h. Evaporate the vo tattles and add MeOH (5 mL), DMSO {2 mL) and 5 N NaOH {aqueous, 1 mL). Stir at 50 ^u C for about 3 h and then at RT for about 18 h. Dilute with i-BME and 1 M HCI (aqueous) and separate the layers. Wash the organic portion with brine, dry over MgS O4, filter aocJ concentrate. Dissolve the residue in t-BME and add excess freshly prepared diazometriane/etfier solution, concentrate and purify tie residue with flash chromatography (ElOAc/hexaπes) to give 13a4.

Step 5:

Using the protocol described tn Example IH ₁ Step 5, 13a4 (25 mg, 0.056 mmol) is converted to 202ft,

Step 6:

Using the protocol described in Example 1QA _r Step 10, 13a4 (SO mg, 0,11 mmol) is converted to 2030.

Exam ple 14A: Com pound 101?

Using the protocol described in Example IA, Steps 1-7, synthesize 1017 beginning wilh 4-methyl-2-bromophenol.

Exam ple 15A: Com pound 3002

Step 1

Usiog the protocol described tπ Example 12A ₁ Step 1, 1Sa1 |25g _« 135 mmol) is converted to 1§a2

Step 2

Using the protocol described tn Example 1A ₁ Steps 1-7, synthesize 3002 beginning with 2~bra mo phenol and 15a2

Exam ple 16A: Com pound 3001

Step 1 Rifliin∞. L W Lawrence Woo et al , J M&d Chem 2007, SO, 3540-3560

Disscte 3 _' hydroxy benzoic acri 1$a1 (18.20 g _r 130,4 mmol) in acettc acid (180 ml) and cool to O ¹⁰ C Add bromtπe (2134g, 1332 mmol) as a solution in acetic acid dropwise over about 30 mm Evaporate the solvent under reduced pressure to give a we! sold mass Add water {200 mL) and stir initially at RT ₍ then warm slowiy to SCfC, stirring constantly Coo! stowΛy the now homogeneous mature to CfC, whereupon a solid forms Add a further portion of water (200 mL) and stir the suspension at RT overnight. Filter and dry the solids to provide 16a2,

Step 2; Reference: ϋlrich Widmer, Synthesis, 1983, 135-136, Dissolve 1βa2 (4,55 g, 20.97 mmol} in anhydrous toluene (20 mL) and heat to 80°C, Add dimethylfomnamide di-t-butylacetat (10 mL, 427 rnniol) portionwise over about a 2 h period. Cool the mixture to RT, Evaporate the volatiles and purify the residue with flash chromatography (EtGAcΛeκanes) to give 16a3.

Step 3:

In a fashion analogous to that for the production of 1c3 {Example 1C, Step 1), combine 1§a2 (585 rng, 2,95 mmol} and 18a3 (729 mg, 2.67 mmol) in the presence of cesium carbonate (996 mg» 3.03 mmol J to give 1βa4.

Step 4.

In a fashion analogous to that for the production of 1c4 (Example 1C, Step 2), combine I6a4 (779 mg, 172 mmol) with potassium carbonate {724 mg, 5.24 mmof}, tricyclohexylptøspbine tetrafluoroberate (128 mg, 0.35 mmol), DMA (5 mL) and palladiump) acetate (80 mg, 0.35 mrno!) at 130 ^e C for about 24 h. Dilute the reaction wih EtOAc ₁ wash with 0.5 IVI KHSO ₄ (aqueous) and brine, dry over MgSO ₄ , filter and evaporate, Purify the residue with flash chromatography (EtOAc/hexaoes) to give 16a5.

Step 5: In a fashion analogous to that for the production of 1n1 f Example 1 W, Step 1 ) _r convert 16a5 (250 mg, 0,87 mmol) to give 16a6.

Step §;

Using the protocol described in Example 7A, Step 5, 16a$ (240 mg, 0,70 mmol} is converted to 16a7.

Step 7- Heat a mixture consisting of 18a7 (2S mg, 0.065 mmol}, 1aS {21 mg, 0,13 mmol), pyridine (42 μL, 0,52 mmoi) and DCE |700 mL) at 150°C for 20 min in a microwave. Evaporate the volatites. Add TFA {1 mL) and sir for about 1 h at RT, then evaporate, AM DMSO (1.5 m L) and 5 N NaOH {aqueous, 0.30 mL) and stir at RT fee about 2 h. Acidify with excess AcOH. Purification and lyophifizatjoπ of the votatiles affords 3001.

Exam ple ITA: Compounds 3003 and SOM

Step 1: Using the protocol described for the production of 1c2, 17a1 is converted to 17a2.

Step 2:

Using the protocol described in Exampfe 1C, Step 1, stir 17a2 (270 g, 0 ^{^} .78^ mmol) and 2-πuoro-3-bromobenzatdehyde I7a3 (.245 mg, 1.21 mmol) in the presence' of cesium carbonate (360 mg, 1,17 mmol} to give I7a4.

Step 3:

Using the protocol described in Example 11 A, Step 2, 17a4 (100 g _s 0.1§ mmot) is converted to 17a5.

Using the protocol described in Example 1F _» Step 3, 17a5 (65 mg.0.14 mmot) is converted to 3003.

Step 5: Add to a mixture of 3003 (25 mg, 0.059 mmot) in THF (1 mL), a freshly prepared solution of ctiazomethaneft-BME solution. Evaporate the THF and add DMF (2 mL), 80% w/w NaH/mlneral oil (10 mg) and iodo methane (20 μL), Stir for about 1 h at RT, Add DMSO (1 mL} and 5 N NaOH (aqueous, 0,5 mL) and stir at RT for about 1 h. Acidify with excess TFA. Purification and lyophizatioπ of the volatiles affords 30U4,

Exam ple 18 A: Com pound 2033

Step 1- Potassium carbonate {400 mg, 283 mmoi) is added to a DMSO (40 mL} solution of aryl fluon-de 1AaI (438 mg, 2.4 mmol) and {S)-(+)-i-methoxy-2-propyIamine (858 mg, 9.63 mmol) The mixture is heated at ?0 ^# C for about 20 h, cooled to RT and diluted with water Concentrated HCf ts then added to make the mixture acidic The solution is stirred at RT for about 1 h, basified with aqueous 25 N NaOH and extracted with EtOAc. The organic phase is washed with brine, dried over Na^SO^, filtered and concentrated under reduced pressure, The crude product 18a2 is used directly in the next step,

Step 2: Hydrogen peroxide (374 μL, 3.3 mmol} is added to a O ⁴ C MeOH (3,0 mL) solution of the aldehyde 18a2 and sulfuric aαd (180 μL, 2.9 mmol). The solution is stirred at

O ³ C for about 2 h, basified with aqueous 2 S H NaOH and extracted with EtOAc The organic phase is washed with brine, dried over Nas-Sd, filtered and concentrated under reduced pressure, The crude residue is purified by flash chromatography to afford phenol 1Sa3

step 3-

Using the protocol desert bed in Example 1C, Step 1, combine I8a3 (150 mg, 0.63 mmolj and 1f1 (140 mg _« 0,69 mmol) in the presence of cesium carbonate {407 mg, 1.25 mmo!) to give 18a4.

Step 4:

Using the protocol described in Example 11A ₁ Step 2, 18a4 (225 rng, 0.53 mmol) is converted to 1βa5.

Step S: Using the protocol described in Example 7A ₁ Step 6, 1iaS (135 mg, 0.39 mmol} is converted to Ifiafi.

Step 6'

Using the protocol described m Example 6A, Step 2, convert 1Sa8 (55 mg, 0,12 mmol) with 1 M 2-mettioxyphenyi magnesium bromide/THF (150 μl, 0,15 mmoi) to 2033.

Exam ple 1fA: Com pound 2032

Stepl Add to a mixture of 8a4 (60 g, 0204 mot) in MeOH (2 L), 1, 3-d (hydroxy acetone (113 g _r 125 mol) and stir at RT for about 15 mm Add NaHB(OAe) ₃ {641 g.102 mol) as a solution in MeOH (200 rnL) and stir at RT for atout 2-3 ft Add saturated NaHCOj (aqueous, 500 mL) and evaporate the MeOH Extract with EtOAc, wash the organic portion wrth water and bnπe, dry over Na _? SO+, liter aod evaporate Puπfy the residue with flash chromatography (EtOAc/hexanes) to give 19a1

Step 2 Add to a mixture of I9a1 (SO g, 181 mrnol), DMF (200 mL) and methyl iodtde (77 g, 542 mmoi) a suspension of NaH (7 g 239 mmol) in DMF (200 rnL) at RT Stir overnight, then quench with saturated NH ₄ CI (aqueous, 200 mL) and extraet with

EtOAc Wash the organic portron with water aod brine Dry over Na ₂ SO ₄ , filter and concentrate Purify the residue wrth flash chromatography fEtOAcΛexanes) to give

19a2

Steps Reflux a mixture of 19a2 (100 g, 278 rnmof), toluene (2QfJ mL) pvπdiπe (11 Og ₁ 139 mmoij and 1a8 {67 g, 417 mmol) for about 2 days Cool to RT, filter the solids and discard Collect the filtrate, concentrate and purify the residue with flash chromatography {EtQAe/fiexanes) to give 19a3.

Step 4: Shake a mixture of 19a3 (12.63 g, 26,1 mmol), 10% PdfGHfe/C, EtOAc {75 iπLj and MeOH (75 mLj under a 10 psi H ₂ (g) atmosphere for about 18 h. Filter the mixture through Celtte®, collect the filtrate and concentrate. Trstyate the crude mateπai with hexanes, filter and dry the solids. Dissolve the material in a 50% mixture of MeOK/EtOAc (200 mLj, add activated charcoal (10 g) and reflux for about 1 Ii Filter and evaporate to give 1Sa4,

Step 5- in a fashion analogous to that for the prodyction of 1c3 ^Example 1C, Step 1), oombtne 19a4 (150 mg, 038 mmoi) and 1f1 (85 mg, 0.42 mmol) in the presence of cesium carbonate |24@ mg, 0.76 mmol) to give 19a 5.

Step S,

Using the protocol described in Example 11A ₁ Step 2, 1SaS (180 mg, 0,31 mmol) is con verted to 19a6.

Step 7:

Using the protocol described in Example 6A, Step 2, convert 19aS (58 mg» 0,12 mmol) with 1 M 2-methoxyphenyI magnesium bromide/THF {150 μL, 0.15 mmol} to 2032,

Exam p Ie 20 A: C om pound 2031

Step l Reference WO 06/119646 pp 60-61

Dissolve ia4 (12 g, 32 m m o!) in water (100 m LJ and add 1 M NaOH {aqueous) until the m ixture is slightly basic Extract with EtOAc Wash the organic portion with water and brine, dry over Na ₂ SO^ filter and evaporate Dissolve the soiids in anhydrous THF (20 m l} and add 1 ,4-cyclohexadιoπe m oπwrthylene ketal {5 g 32 m m ol) and dibutyttin rtchloπde (O 48 g 1 58 m m ol) Stir at RT for about 10 m m Add phenyl silane (4 30 m L, 34 7 m m olj and stir for about 3 days Evaporate the volatiles and dissolve the ressdue in EtOAe Wash with saturated NaHCO, (aqueous), and tonne dry over Na^SO^ filter and concentrate to give crude 20a1

Step 2

Using the protocol described fπ Exam ple 19A Step 3 20a1 is coπyerted to 20a2

Step 3 Stir a m ixture of 2§a2 toluene (40 m L), TFA (40 m L) and water (1 1 m L) far about 2 h Evaporate the volatiles snd dilute with EtOAc Wash with saturated NaHCO^ (aqueous) and brine, dry over Na ₂ SO ₄ filter and concentrate to give crude 20a3 Step 4.

Using the protocol described in Example 4A, Step 1 , 2§a3 is converted to 20a4.

Step 5: Using the protocol described in Example 1SA ₁ Step 2, 20*4 is converted to 2OaS.

Step 6:

Using the protocol described in Example 19A, Step 4, 2OaS is converted to 2§a6

Step ? ^•

Using the protocol descnbe-d tn Example 1C, Step 1. combine 2§aβ (153 mg, 0.38 raraoi) and 1fl (85 mg, 042 mmol) m the presence of cesium carbonate {248 mg, 0,76 mrnol) to give 20a7.

Step 8;

Using the protocol described in Ex-ample 11A, Step 2, 2§a7 (185 mg, 0.31 mmol) is converted to 20ai.

Step 9 Using the protocol described for the production of 1180, convert 20aβ (56 mg, 0,12 mmo!) witn 1 M 2-metr»xypheπyl magnesium brorπide/THF (150 μt, 0,15 mmol) to 2031

Exam ple 21 A €ell-basei iyeiferas© reporter HCV RNA Replication Assay Repress nteiive compounds of the invention are tested for activity as inhibitors of hepatitis C virus RNA replication in cells expressing a stable subgenomϊe HCV repiicon, using the assay described in WO 2005/02β501« herein incorporated by reference

Tables ef eompeunis

The following tables fist compounds representative of the invention. Representative compounds listed in Tables 1 to 3 below are tested in the assay of Example 21 A and are found to have EC ₅₀ values below 40 μM. Retention times (t _R ) for each compound are measured using the standard analytical HPLC conditions described in the Examples. As is well known to one skilled in the art, retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different HPLG Instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions. The synthetic method used to generate each compound in Tables 1 to 3 is identified in the table, A person skilled in the art will recognize that obvious modifications to the synthetic methods may be re-quired to generate each of the specific compounds listed in Tables 1 to 3.

Each of the references, including all patents, patent applications and publications, listed in the present application is incorporated herein bv reference in its entirety, as if each of them is individually incorporated. Further, it would be appreciated thai, in the above teaching of invention, the skilled in the art could m ake certain changes or m odifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended daim s of the application.