WO2005019191A2 - Agents anti-infectieux - Google Patents

Agents anti-infectieux Download PDF

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Publication number
WO2005019191A2
WO2005019191A2 PCT/US2004/027000 US2004027000W WO2005019191A2 WO 2005019191 A2 WO2005019191 A2 WO 2005019191A2 US 2004027000 W US2004027000 W US 2004027000W WO 2005019191 A2 WO2005019191 A2 WO 2005019191A2
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WIPO (PCT)
Prior art keywords
alkyl
oxo
group
methyl
hydrogen
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PCT/US2004/027000
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English (en)
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WO2005019191A3 (fr
Inventor
Douglas K. Hutchinson
John R. Bellettini
David A. Betebenner
Richard D. Bishop
Thomas B. Borchardt
Todd D. Bosse
Russell D. Cink
Charles A. Flentge
Bradley D. Gates
Brian E. Green
Mira M. Hinman
Peggy P. Huang
Larry L. Klein
Allan C. Krueger
Daniel P. Larson
M. Robert Leanna
Dachun Liu
Darold L. Madigan
Keith F. Mcdaniel
John T. Randolph
Todd W. Rockway
Teresa A. ROSENBERG
Kent D. Stewart
Vincent S. Stoll
Rolf Wagner
Ming C. Yeung
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Abbott Laboratories
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Publication of WO2005019191A2 publication Critical patent/WO2005019191A2/fr
Publication of WO2005019191A3 publication Critical patent/WO2005019191A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/30—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with hydrocarbon radicals, substituted by hetero atoms, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel anti-infective agents. Specifically, the present invention relates to compounds, a composition, a method for inhibiting hepatitis C virus (HCV) polymerase, a method for inhibiting HCV viral replication, and a method for treating or pre enting HCV infection, and processes for making the compounds, and synthetic intermediates employed in the processes.
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • HCV will increase to 38,000/year by the year 2010.
  • the present invention provides a compound of formula (I)
  • A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle; 1 is hydrogen, alkyl, alkenyl, alkynyl, -C(0)OR a , -C(0)NR a R b or R lp ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R a , -OC(0)OR a , -OC(0)NR a R b , -OS0 2 R a , -OS0 2 NR a R b , -SR,, -S(0)R a , -S0 2 R a , -SO.OR,, -S0 2 NR a R b ,
  • R 2 is hydrogen, alkyl, alkenyl or alkynyl; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC ⁇ R,, -OC(0)OR a , -OC(0)NR a R b , -OS0 2 R a , -OSO ⁇ R,,, -SR,, -S(0)R a , -S0 2 R a , -SO.OR,, -S0 2 NR a R b , -NRA, -N(R s )C(0)R a , -N(R e )C(0)OR a , ⁇
  • R 1 and R 2 together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl; wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halo, -OH, -O(alkyl), -NH 2 , -N(H)(alkyl), -N(al
  • R 3 is hydrogen, cyano, formyl, halo, oxo, nitro, -OR,, -OC(0)R a , -OC(0)OR a , -OC(0)NR a R b , -OS0 2 R,, -OS0 2 NR a R b , -SR a , -S(0)R a , -S0 2 R,, -S0 2 OR a , -S0 2 NR a R b , -NR a R b , -N(R e )C(0)R a , -N(R e )C(0)NR a R b , -N(R e )C(0)OR a , -N(R e )S0 2 R a , -N(R e )S0 2 NR a R b , -N(R e )S0 2 N(R e )C(0)OR a
  • R 4 is hydrogen, cyano, formyl, halo, oxo, nitro, -OR j ,, -OC(0)R a , -OC(0)OR a , -OC(0)NR a R b , -OSO , -OS0 2 NR a R b , -SR,, -S(0)R a , -S0 2 R a , -S0 2 0R meaning -S0 2 NR a R b , -NR,R b , -N(R e )C(0)R a , -N(R e )C(0)NR a R b , -N(R e )C(0)OR a , -N(R e )S0 2 R,, -N(R e )S0 2 NR a R b , -N(R e )S0 2 N(R e )C(0)OR a , -
  • R 5 is -OR d , -SR d , -NR d R e , -N(H)C(0)R d , -N(H)C(0)OR d , -N(H)S0 2 R d , or -N(H)S0 2 NR d R e ;
  • R 6 is hydrogen, alkyl, alkenyl, alkynyl or -alkylR 106 ;
  • R 8 at each occurrence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, -OR a , -OC(0)R meaning -OC(0)OR,, -OC(0) R a R b , -OS0 2 R a , -OS0 2 NR,R b , -SR meaning -S(0)R,, -S0 2 R,, -S0 2 OR,, -S0 2 NR,R b , -NR,R b , -N(R e )C(0)R,, -N(R e )C(0)NR,R b , -N(R e )C(0)OR,, -N(R e )S0 2 R,, -N(R e )S0 2 NR,R b , -N(R e )S0 2 N(R e )
  • R 10 is hydrogen or alkyl
  • R 11 is hydrogen or alkyl
  • R at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R j ,; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1,
  • R d at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR 106 ; alternatively, R c and R d , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heteroaryl and heterocycle is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR ft -OC(0)R f , -OC(0)ORp -OC(0)NR,R g , -OS0 2 R f , -OS0 2 R f R g , -SR ft -S(0)R f , -S0 2
  • Re at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R 103 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -O(R 106 ), -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl)(R 106 ), -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(O)N(alkyl) 2 , and R 103 ;
  • R g at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl and -alkylR 106 ; alternatively, R f and R g , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heterocycle and heteroaryl is independently substituted with 0, 1,
  • R j at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , haloalkyl and -alkylR 103 ;
  • R k at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; alternatively, R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, formyl, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -OR 106 , -NH2 2 J -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl)(R 106 ), -C
  • Rp 5 Rq> Rlp 5 R-lq> ⁇ 2 ⁇ R-3p> R-3q, R p> R-4q> R-7p> ⁇ -7q, ⁇ J R* ⁇ Rgp' 3Xi ⁇ ⁇ qJ ai eaCn occurrence, are independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; wherein each of the R p , R q , R lp , R lq , R 2q , R 3p , R 3q R 4p , R 4q , R 7p , R 7q _ R Sp , R 8q , Rg p , and R, q , at each occurrence, is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,
  • R 101 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , -alkylR 103 , -alkenylR ⁇ 03 , -alkynylR 103 , haloalkyl, cyanoalkyl, -alkylC(O)R 104 , -alkylC(O)OR 104 , -alkylC(O)NR 104 R 105 , -alkyl-OR 104 , -alkyl-OC(O)R 104 , -alkyl-OC(O)OR 104 , -alkylSR 104 , -alkylS(O)R 104 , -alkylSO 2 R 104 , -alkylSO 2 OR 104 , -alkylSO 2 NR 104 R 105 , -alkylNR 104 R 105 , -alkylNR
  • R 106 at each occurrence is independently selected from the group consisting of aryl and heteroaryl, wherein each R 106 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -JNH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 ,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or combination of compounds of formula (I) or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier.
  • the invention is also directed to a prodrug of a compound of the present invention, or pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention provides a method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt thereof.
  • this invention is directed to methods of inhibiting the replication of hepatitis C virus.
  • the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof.
  • this invention is directed to methods of treating or preventing infection caused by hepatitis C virus.
  • Yet another embodiment of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt form, stereoisomer or tautomer, or combination thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically hepatitis C virus (HCV).
  • RNA-containing virus specifically hepatitis C virus (HCV).
  • alkenyl refers to a straight or branched chain group of 2, 3, 4, 5, 6, 7, or 8 carbon atoms containing at least one carbon-carbon double bond.
  • alkenyl groups include allyl, propenyl, 3-methylbut-2-enyl, 4-ethylpenta-2,4-dienyl, and the like.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appendened to the parent molecular moiety through an alkyl group, as defined herein.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • alkyl groups include propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3- dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon of 2, 3, 4, 5, or 6 carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl groups include ethynyl, 2-methyl-3-butynyl, 3-pentynyl, and the like.
  • aryl refers to a phenyl group, or a bicyclic hydrocarbon fused ring systems wherein one or more of the rings is a phenyl group.
  • Bicyclic fused ring systems have a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • aryl groups include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl (naphthalenyl), phenyl, tetrahydronaphthyl, and the like.
  • the aryl groups of the present invention can be substituted or unsubstituted, and can be connected to the parent molecular moiety through any substitutable carbon atom of the group.
  • cyano refers to -CN.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
  • cycloalkenyl refers to a non-aromatic, partially unsaturated, monocyclic or bicyclic ring system, having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and zero heteroatom.
  • the three-, four- or five- membered ring have one double bond.
  • the six-membered ring has one or two double bonds.
  • the seven and eight- membered rings have one, two, or three double bonds.
  • the bicyclic fused ring systems have a monocyclic cycloalkenyl group fused to a monocyclic cycloalkyl group, as defined herein, or a second monocyclic cycloalkenyl group, as defined herein.
  • cycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, and the like.
  • the cycloalkenyl groups of the present invention can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable carbon atom of the group.
  • cycloalkyl refers to a saturated monocyclic, or bicyclic fused ring system having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and zero heteroatom.
  • the bicyclic fused ring systems have a monocyclic cycloalkyl group fused to a second mocyclic cycloalkyl group, as defined herein.
  • the cycloalkyl groups of the present invention can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable carbon atom of the group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.1]heptyl, 6,6- dimethylbcyclo[3.1.1]heptyl, adamantyl, and the like
  • formyl refers to -CHO.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
  • heteroaryl also includes bicyclic fused ring systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • heteroaryl groups include benzimidazolyl, benzothienyl, benzoxadiazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoqumolinyl, isothiazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiaz ⁇ lyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, triazinyl, and the like.
  • heteroaryl groups of the present invention can be unsubstituted or substituted and are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom of the groups.
  • the nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide.
  • the nitrogen containing rings can be optionally N-protected.
  • heterocycle refers to cyclic, non-aromatic, saturated or partially unsaturated, three, four, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heterocycle also includes bicyclic fused ring systems where a heterocycle ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group.
  • heterocycle groups of the invention can be unsubstituted or substituted and are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group.
  • heterocycle groups include azetidinyl, 4,5-dihydro-l,3-oxazol-2-yl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, l,l-dioxidoisothiazolidin-2-yl, isoi ⁇ dolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl, and the like.
  • the nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide.
  • the nitrogen containing heterocyclic rings can be optionally N-protected.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxy ethyl, 3-hydroxy ⁇ ropyl, and 2-ethyl-4-hydroxyheptyl. It is understood that each of the following terms as defined hereinabove: alkenyl, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, may be unsubstituted or substituted.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfanyl, triphenylmethylsulfanyl, and the like; sulfinyl groups such as p- methylphenylsulfinyl, t-butylsulfinyl, and the
  • N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • nitro refers to -N0 2 .
  • the present invention provides a compound of formula (I)
  • A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
  • R 2 is hydrogen, alkyl, alkenyl or alkynyl; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R a , -OC(0)OR a , -OC(0)NR,R b , -OS0 2 R,, -OS0 2 NR a R b , -SR,, -S(0)R meaning -S0 2 R crab -S0 2 OR
  • R 4 is hydrogen, cyano, formyl, halo, oxo, nitro, -OR,,, -OC(0)R philosophical -OC(0)OR a , -OC(0)NR,R b , -OS0 2 R truth -OS0 2 NR,R b , -SR,, -S(0)RNase -S0 2 R,, -S0 2 OR,, -S0 2 NR a R b , -NR a R b , -N(R e )C(0)R,, -N(R e )C(0)NR,R b , -N(R e )C(0)OR a , -N(R e )S0 2 R,, -N(R e )S0 2 NR,R b , -N(R e )S0 2 N(R e )C(0)OR a , -C(0)R,, -C(0)OR nothing -C(0)
  • R 5 is -OR d3 -SR d , -NR.R,, -N(H)C(0)R d , -N(H)C(0)OR d , -N(H)S0 2 R d , or -N(H)S0 2 NR d R e ;
  • R 6 is hydrogen, alkyl, alkenyl, alkynyl or -alkylR 106 ;
  • R 10 is hydrogen or alkyl
  • R ⁇ is hydrogen or alkyl
  • R a at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R,,; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, -OR c , -OC(O)R 0 , -OC(0)OR c , -OC(0)NR c R d , -OSO 2 R 0 , -OS0 2 NR c R d , -SR C , -S(O)R 0 , -S0 2 R c , -S0 2 OR c , -S0 2 NR c R d , -NR c R d , -N(R e )C(0)R c , -N(R e )C(0)NR c R
  • R d at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR 106 ; alternatively, R c and R d , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heteroaryl and heterocycle is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f
  • each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 susbstituents independently selected from the group consisting of cyano, halo, nitro, oxo, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f , -S0 2 R f , -S0 2 OR f , -S0 2 NR f R g , -NR f R g , -N(R e )C(0)R f ,
  • R e at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, and -alkylR 106 ;
  • R f at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R, 03 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -O(haloalkyl), -O(R 106 ), -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl)(R 106 ), -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(0)N(H)(alkyl), -C(0)N(alkyl) 2 , and R
  • R g at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl and -alkylR 106 ; alternatively, R f and R g , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heterocycle and heteroaryl is independently substituted with 0, 1,
  • R j at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , haloalkyl and-alkylR 103 ;
  • R k at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; alternatively, R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, formyl, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -OR 106 ,
  • Rp, Rq, Rip, Rlq, R2q? R ⁇ p' ⁇ q, R 4 pJ R 4 q' ⁇ 7p> R-7q, ⁇ "SpJ ⁇ 8qJ ⁇ 9p> Sn ⁇ ⁇ 9q> ai eaCn occurrence, are independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; wherein each of the R p , R q , R lp , R lq , R 2q , R 3p , R 3q R 4p , R 4q , R 7p , R 7Qi R 8p , R 8q , Rp p , and Rg q , at each occurrence, is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro
  • R 101 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , -alkylR 103 , -alkenylR 103 , -alkynylR 103 , haloalkyl, cyanoalkyl, -alkylC(O)R 104 , -alkylC(O)OR 104 , -alkylC(O)NR 104 R 105 , -alkyl-OR 104 , -alkyl-OC(O)R 104 , -alkyl-OC(O)OR 104 , -alkylSR 104 , -alkylS(O)R 104 , -alkylSO 2 R 104 , -alkylSO 2 OR 104 , -alkylSO 2 NR 104 R 105 , -alkylNR 104 R 105 , -alkylNR
  • R 103 at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle; wherein each R 103 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, nitro, cyano, oxo, formyl, haloalkyl, -OR 104 , -OC(O)R 104 , -OC(O)OR 104 , -OC(O)NR 104 R 105 , -OSO 2 NR 104 R 105 , -SO 2 R 105 , -S(O)R 104 , -NR 104 R 105 , -N(R 105 )C(O)NR 104 R 105 , -N(R 105 )COR 104 , -N(R 105 )SO 2 R 104 , -
  • R, 06 at each occurrence is independently selected from the group consisting of aryl and heteroaryl, wherein each R 106 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(0)N(alkyl) 2 , -SH, -Salkyl, -S(0)alkyl, -S0 2 alkyl, -C(0)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alky
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 6 is hydrogen or alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 1 is -C(0)OR,, -C(0)NR,R b , R lp , alkyl or alkenyl; and R 2 is alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 1 is -C(0)OR encounter -C(0)NR,R b , R jp , alkyl or alkenyl, wherein the alkyl and alkenyl are independently substituted with 0, 1 or 2 substituents selected from the group consisting of halo, -OR,, -0C(0)R fate -OC(0)NR,R b , -C(0)ORhorizon -C ⁇ R j R,,, and -R ⁇ q ; and R 2 is alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is alkyl, or alkyl substituted with one R lq , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 101 and wherein R 10] is alkyl,
  • R is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or R lp ; wherein R lp is heterocycle; and R 2 is alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -00(0) ⁇ , wherein R a is methyl, ethyl, or isopropyl, -OC(0)NR a R b , wherein R ⁇ is methyl, ethyl or isopropyl and R b is hydrogen,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl substitutent wherein the methyl is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or
  • R lp wherein R lp is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heterocycle or heteroaryl, wherein each of the ring is substituted with (R 8 ) m .
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 3 and R 4 are indepentdently selected from the group consisting of hydrogen and alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein A is a monocyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein A is phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein A is a bicyclic ring selected from the group consisting of aryl and heteroaryl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein A is benzimidazolyl, benzthiazolyl or benzoxazolyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 5 is -OR d wherein R d is hydrogen, and R 6 is hydrogen or alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 5 is -OR d wherein R d is hydrogen, and R 6 is hydrogen or alkyl.
  • the first embodiment of the present invention provides a compound of
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen
  • R 6 is hydrogen or alkyl.
  • the first embodiment of the present invention provides a compound of formula (I) R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl and R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl and R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl.
  • the first embodiment of the present invention provides a compound of formula (I)
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, and R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein B is
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, and R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl and A is a bicyclic heteroaryl ring.
  • the first embodiment of the present invention provides a compound of formula (I) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.
  • the first embodiment of the present invention provides a compound of formula (I) wherein B is R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl and A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycle or heteroaryl.
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl and A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidin
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl;
  • A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyr
  • R 5 is -OR d wherein Rj is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl;
  • A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl;
  • A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyr
  • -C CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a cycloalkyl ring; and -R lq ; wherein R ⁇ q is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, or alkyl substituted with one R lq , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 10 ⁇ and wherein R 101 is alkyl,
  • the first embodiment of the present invention provides a compound of
  • R 5 is -OR d wherein R ⁇ is hydrogen, R 6 is hydrogen or alkyl, R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl;
  • A is a monocyclic ring selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • -C(0)NR a R b wherein , is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl substitutent wherein the methyl is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c ishydrogen or methyl, or
  • R lp wherein R ⁇ p is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, or 3-methylpentyl.
  • a second embodiment fo this invention is directed to a compound of formula (II)
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, -C(0)OR a , -C(0)NR,R b or R lp ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R,, -OC(0)OR literally -OC(0)NR,R b , -OS0 2 R,, -OS0 2 NR,R b , -SR,, -S(0)RNase -S0 2 R a , -S0 2 OR a , -S0 2 NR,R b , -NR,R b , -N(R e )C(0)R,, -N(R e e )
  • R 2 is hydrogen, alkyl, alkenyl or alkynyl; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R a , -OC(0)OR a , -OC(0)NR a R b , -OS0 2 R,, -OS0 2 NR,R b , -SR a , -S(0)R a , -S0 2 R,, -S0 2 OR,, -S0 2 NR,R b , -NR,R b , -N(R e )C(0)R,, -N(R e )C(0)0RNase -N(R e )C(0)NR,R b , -N(R e )S0 2 Rstrich -N(R
  • R 6 is hydrogen, alkyl, alkenyl, alkynyl or -alkylR 106 ;
  • R 8 at each occurrence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, -OR,, -OC(0)R meaning -OC(0)OR formula -OC(0)NR,R b , -OS0 2 R truth -OS0 2 NR,R b , -SR,, -S(0)R,, -S0 2 R,, -S0 2 OR,, -S0 2 NR,R b3 -NR,R b , -N(R e )C(0)RNase -N(R e )C(0)NR,R b , -N(R e )C(0)OR a , -N(R e )S0 2 R a , -N(R e )S0 2 NR,R b , -N(R e )S0 2 N(R e )C(0)OR
  • R at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R,,; ⁇ wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1,, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, -OR c , -OC(0)R c , -00(0)0 ⁇ , -OC(0)NR c R d , -OS0 2 R c , -OS0 2 NR c R d , -SR C , -S(0)R c , -S0 2 R c , -SO.OR,, -S0 2 NR c R d , -NR c R d , -N(R e )C(0)R c , -N(R e )C(0)NR c R d , -N(R
  • R b at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR ⁇ 06 ; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the hetrocycle and heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR c , -OC(0)R c , -OC(0)OR c , -OC(0)NR c R d , -OS0 2 R c , -OS0 2 NR c R d , -SR C , -S(0)R c
  • R c at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R 103 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f , -S0 2 R f , -S0 2 OR f , -S0 2 NR f R g , -NR f R g , -N(R e )C(0)R f , -N(R e )C(0)NR f R g
  • R d at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR 106 ; alternatively, R c and R d , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heteroaryl and heterocycle is independently substituted with 0, 1,
  • R f at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R 103 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1,
  • R g at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl and -alkylR 106 ; alternatively, R f and R g , together with the nitrogen atom to which
  • R j at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 03 , haloalkyl and -alkylR 103 ;
  • R k at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; alternatively, R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, formyl, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -OR 106 , -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl)(R 106 ), -C
  • each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR 101 , -OC(O)R 101 , -OC(O)OR 101 , -OC(O)NR 101 R 102 , -OSO 2 R 101 , -OSO 2 NR 101 R 102 , -SR 101 , -S(O)R I01 , -SO 2 R 101 , -SO 2 OR 101 , -SO 2 NR 101 R 102 , -NR 101 R 102 , -N(R 102 )C(O)R 101 ,
  • R 101 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , -alkylR 103 , -alkenylR ⁇ 03 , -alkynylR 103 , haloalkyl, cyanoalkyl, -alkylC(O)R 104 , -alkylC(O)OR I04 , -alkylC(O)NR 104 R 105 , -alkyl-OR 104 , -alkyl-OC(O)R 104 , -alkyl-OC(O)OR 104 , -alkylSR 104 , -alkylS(O)R 104 , -alkylSO 2 R 104 , -alkylSO 2 OR 104 , -alkylSO 2 NR 104 R 105 , -alkylNR 104 R 105 , -alkylN(
  • R 106 at each occurrence is independently selected from the group consisting of aryl and heteroaryl, wherein each R 106 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 ,
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 6 is hydrogen or alkyl.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 1 is -C(0)OR nest -C(0)NR,R b , R lp , alkyl or alkenyl; and R 2 is alkyl.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R, wherein R, is alkyl, -OC(0)NR a R b , wherein R ⁇ is alkyl, R b is hydrogen, -C(0)OR, wherein R, is alkyl,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of -C(0)OR nest wherein R a is alkyl, and
  • R lq is aryl, -C(0)OR,, wherein R a is alkyl, or alkyl substituted with one R lq , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 01 and wherein R m is alkyl, -C(0)NR a R b , wherein R, is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein
  • R 2 is alkyl
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -OC(0)R a , wherein R a is methyl, ethyl, or isopropyl,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of -C(0)OR a , wherein R a is methyl, , ethyl or isopropyl, and -R ⁇ q , wherein R lq is aryl, -C(0)OR classroom wherein R, is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R Iq , wherein R !q
  • R is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substituent selected from the group consisting of -OR c , and -00(0 ⁇ , and wherein R c is hydrogen or methyl, or R lp ; wherein R, p is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbuty
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen, and R 6 is hydrogen or alkyl.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 1 is -C(0)ORcliff -C(0)NR,R b , R lp , alkyl or alkenyl; and R 2 is alkyl.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is alkyl, or alkyl substituted with one R ⁇ q , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 0j and wherein R 101 is alkyl,
  • R a is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(0)R c , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or
  • Ri p wherein R lp is heterocycle; and / R 2 is alkyl.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or methyl, R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R a , wherein R, is methyl, ethyl, or isopropyl, -OC(0)NR a R b , wherein R, is methyl, ethyl or isopropyl and R b is hydrogen,
  • R Jq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R ⁇ , and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or R ip ; wherein R Jp is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-di
  • the second embodiment of the present invention provides a compound of formula (TI) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R' is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo, -OR,, wherein R j , is hydrogen,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(0)R c , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or
  • R lp wherein R Jp is heterocycle; R 2 is alkyl; R 7 is formyl,
  • R is hydrogen or alkyl substituted with one cyano, and R b is hydrogen
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R a is alkyl, or alkyl substituted with 1, 2 or 3 halo, and R e is hydrogen or alkyl,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R, is R p wherein R p is aryl, -N(R e )C(0)OR a , wherein R, is alkyl and R e is hydrogen or alkyl, -N(R e )SOR a , wherein R, is alkyl, and R e is hydrogen or alkyl,
  • R e is hydrogen or alkyl
  • R a is alkyl, alkenyl
  • R p is selected from the group consisting of heteroaryl and aryl, or alkyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo
  • R c is hydrogen
  • R d is hydrogen
  • -N(R e )S0 2 NR,R b wherein R e is hydrogen or alkyl
  • R b is hydrogen
  • R is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of: -OR c , wherein R c is hydrogen,
  • R ⁇ and R d are hydrogen, and -OC(O)NR 0 R d , wherein R c and R ⁇ together with the nitrogen atom to which they are attached, form a heterocycle ring; alternatively, R ⁇ and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring; -N(R e )S0 2 N(R e )C(0)R a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl substituted with one R q wherein R q is aryl, or alkyl substituted with one substituent selected from the group consisting of
  • R a is hydrogen or alkyl substituted with one -OR c wherein R c is alkyl, -NR a R b , wherein R a is hydrogen and R b is hydrogen,
  • Rg is hydrogen or alkyl
  • R ⁇ is alkyl, or alkyl substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is heterocycle; -N(R e )S0 2 NR a R b , wherein R ⁇ R b are hydrogen, and R e is hydrogen or alkyl,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, R, is alkyl substituted with R q , wherein R q is aryl, -C(0)NR,R b wherein R, is hydrogen and R b is hydrogen, and
  • R 7q wherein R 7q is heterocycle; and n is 0 or 1.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R' is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl,
  • R a is methyl, ethyl, or isopropyl, -C-CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
  • R !q is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl,
  • 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is methyl, ethyl or isopropyl, and -R !q , wherein R lq is aryl, -C(0)OR thoughts wherein R, is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R lq , wherein R lq is a pyrrolidine ring, unsubstituted or substituted with one -C(O)OR ]0 classroom wherein R 101 is methyl, ethyl or isopropyl,
  • R ⁇ is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR 0 , and -OC(0)R c , and wherein R c is hydrogen or methyl, or R lp ; wherein R lp is 4,5-dihydro-l ,3-oxazol-2-yl;
  • R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5- dimethylhexyl, or 3-methylpentyl;
  • R 7 is fo ⁇ nyl,
  • R is hydrogen, or methyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R c is hydrogen, and R d is hydrogen,
  • R e at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl.
  • R is hydrogen, or methyl substituted with one cyano, and R b is hydrogen
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl
  • R is methyl or ethyl wherein each of the methyl or ethyl is unsubstituted or substituted with 1, 2 or 3 halo, and R e is hydrogen or methyl, -N(R e )C(0)NR,R b , wherein R, is hydrogen, R b is hydrogen, and R e is hydrogen or methyl,
  • R a is hydrogen
  • R b is hydrogen
  • R e is hydrogen or methyl
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R ⁇ is R p , wherein R p is phenyl,
  • R a is tert-butyl and R s is hydrogen or methyl, -N ⁇ JSOR a , wherein R ⁇ is methyl, and R e is hydrogen or methyl, -NCRJSOzR.
  • R e is hydrogen or methyl
  • R a is methyl, ethyl, propyl, isopropyl, butyl, ethylenyl or R p
  • R p is selected from the group consisting of imidazolyl, thienyl, benzimidazolyl, phenyl, and naphthyl, wherein each of the methyl, ethyl, propyl, isopropyl and butyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo,
  • R c is hydrogen
  • R d is hydrogen
  • R d is hydrogen
  • -N(R e )S0 2 NR a R b wherein R e is hydrogen or methyl
  • R b is hydrogen
  • R ⁇ is hydrogen, methyl, or ethyl, wherein each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of: -OR c , wherein R c is hydrogen,
  • R c and R d are hydrogen, and -OC(0)NR c R d , wherein R c and R ⁇ together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is azetidine; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is pyrrolidine or azetidine; -N(R e )S0 2 N(R e )C(0)R a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R a is methyl, ethyl, propyl or butyl;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R, is methy substituted with one R q wherein R q is phenyl; methyl substituted with one substituent selected from the group consisting of
  • R is hydrogen and R b is hydrogen;
  • -N(R e )SOR is hydrogen, wherein R, is methyl, and R e is hydrogen or methyl;
  • R e is hydrogen or methyl
  • R is methyl or ethyl
  • each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is morpholinyl; -N(R e )S0 2 NR,R b , wherein R, and R b are hydrogen, and R e is hydrogen or methyl;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, R, is methyl substituted with R q , wherein R q is phenyl;
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R' is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R,, wherein R, is alkyl, -OC(0)NR,R b , wherein R ⁇ is alkyl, R b is hydrogen,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R ⁇ is alkyl, and -Ri q , wherein R lq is aryl, -C(0)OR a , wherein R j , is alkyl, or alkyl substituted with one R ⁇ q , wherein R Jq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ and wherein R ⁇ 01 is alkyl, -C(0)NR a R b , wherein R, is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(0)R c , and -OR c wherein R 0 is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from
  • R lp wherein R ⁇ p is heterocycle; R 2 is alkyl; R 7 is formyl,
  • R is hydrogen, or alkyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R c is hydrogen, and R d is hydrogen,
  • R ⁇ at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R ⁇ is hydrogen or alkyl substituted with one cyano
  • R b is hydrogen
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R a is alkyl, or alkyl substituted with 1, 2 or 3 halo, and R e is hydrogen or alkyl,
  • R is hydrogen, R is hydrogen, and R e is hydrogen or alkyl
  • R ⁇ is hydrogen
  • R b is hydrogen
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R, is R p wherein R reputation is aryl, -N(R e )C(0)OR territory wherein R, is alkyl and R e is hydrogen or alkyl, -N(R e )SOR, wherein R a is alkyl, and R e is hydrogen or alkyl, -N(R e )S0 2 R, wherein R e is hydrogen or alkyl, R a is alkyl, alkenyl, R p , wherein R p is selected from the group consisting of heteroaryl and aryl, or alkyl substituted with 1, 2 or 3
  • R e is hydrogen or alkyl
  • R b is hydrogen
  • R is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of:
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R, is alkyl substituted with one R q wherein R q is aryl, or alkyl substituted with one substituent selected from the group consisting of
  • R j is hydrogen and R b is hydrogen, -N R SORj, wherein R, is alkyl and R e is hydrogen or alkyl, -N(R e )S0 2 R a , wherein R e is hydrogen or alkyl, and R a is alkyl, or alkyl substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is heterocycle;
  • R a , R b are hydrogen, and R e is hydrogen or alkyl, -N(R e )S0 2 N(R e )C(0)ORlaud wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, R a is alkyl substituted with R q , wherein R q is aryl,
  • R is hydrogen and R b is hydrogen, and R 7q , wherein R 7q is heterocycle;
  • R 8 is halo or -OR a , wherein R ⁇ is hydrogen or alkyl; m is 0 or 1 ; and n is O or 1.
  • the second embodiment of the present invention provides a compound of formula (II) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -OC(0)R a , wherein R a is methyl, ethyl, or isopropyl, -OC(0)NR a R b , wherein R a is methyl, ethyl or isopropyl and R b is hydrogen, -C(0)OR a , wherein R, is methyl, ethyl, or isopropyl,
  • -G CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogent or methyl, and R b is methyl, alternatively, R ⁇ and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or R Xp ; wherein R lv is 4,5-dihydro- 1 ,3-oxazol-2-yl;
  • R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5- dimethylhexyl, or 3-methylpentyl;
  • R 7 is formyl, -OR a , wherein R a is hydrogen, or methyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R c is hydrogen, and R d is hydrogen,
  • R e at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl.
  • R a is hydrogen, or methyl substituted with one cyano, and R b is hydrogen,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl
  • R is methyl or ethyl wherein each of the methyl or ethyl is unsubstituted or substituted with 1, 2 or 3 halo, and R e is hydrogen or methyl,
  • R a is hydrogen
  • R b is hydrogen
  • R ⁇ is hydrogen or methyl
  • R,. is hydrogen
  • R ⁇ is hydrogen
  • -N(R e )S0 2 NR a R b wherein R e is hydrogen or methyl
  • R b is hydrogen
  • R a is hydrogen, methyl, or ethyl, wherein each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of: -OR c , wherein R c is hydrogen,
  • R c and R d are hydrogen, and -OC(0)NR c R d , wherein R c and R d together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is azetidine; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is pyrrolidine or azetidine;
  • R c at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R ⁇ is methyl, ethyl, propyl or butyl;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R a is methy substituted with one R q wherein R q is phenyl; methyl substituted with one substituent selected from the group consisting of N 3 ,
  • R ⁇ is methyl, and R e is hydrogen or methyl; -N(R e )S0 2 R a , wherein R c is hydrogen or methyl, and R, is methyl or ethyl; wherein each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is morpholinyl; -N(R e )S0 2 NR a R b , wherein R, and R b are hydrogen, and R c is hydrogen or methyl; -N(R e )S0 2 N(R e )C(0)OR, wherein R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, R, is methyl substituted with R q , wherein R q is phenyl;
  • R 8 is halo or OR, wherein R, is hydrogen or methyl; m is 0 or 1 ; and n is O or l.
  • Exemplary compounds of the second embodiment include, but not limited to, the following:
  • the present invention is directed to a compound of formula (III)
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, -C(0)ORcliff -C(0)NR,R b or R lp ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)RNase -OC(0)OR,, -OC(0)NR,R b , -OS0 2 R a , -OS0 2 NR a R b , -SR a , -S(0)R a , -SOA, -S0 2 OR,, -S0 2 NR,R b , -NR,R b , -N(R e )C(0)RNase -N(R e )C(0)OR a , -N(R e )C(0)NR a R b ,
  • R 2 is hydrogen, alkyl, alkenyl or alkynyl; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R,, -OC(0)OR literally -OC(0)NR,R b , -OSO.R,, -OS0 2 NR a R b , -SR,, -S(0)R,, -S0 2 RNase -S0 2 OR,, -S0 2 NR a R b , -NR,R b , -N(R e )C(0)R a , -N(R e )C(0)OR,, -N(R e )C(0)NR,R b , -N(R e )S0 2 Ra, -N(R e )S0 2
  • R 5 is -OR d , -SR d , -NR d R e , -N(H)C(0)R d , -N(H)C(0)OR d , -N(H)S0 2 R d , or -N(H)S0 2 NR d R e ;
  • R 6 is hydrogen, alkyl, alkenyl, alkynyl or -alkylR ⁇ 06 ;
  • R s at each occurrence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, -OR,, -OC(0)R a , -0C(0)0R réelle -OC(0)NR,R b , -OS0 2 R,, -OS0 2 NR,R b , -SR,, -S(0)R, 5 -S0 2 R,, -S0 2 OR a , -S0 2 NR,R b , -NR,R b?
  • R b at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylRi 06 ; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the hetrocycle and heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR c -OC(0)R c , -OC(0)OR c , -OC(O)NR 0 R d , -OS0 2 R c -OS0 2 NR c R d , -SR C , -S(0)R c ,
  • each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 susbstituents selected from the group consisting of cyano, halo, nitro, oxo, -OR c -OC(O)R 0 , -OC(0)OR c -OC(0)NR c R d , -OS0 2 R c , -OS0 2 NR c R d , -SR C , -S(0)R c -S0 2 R c , -S0 2 OR c , -S0 2 NR c R d , -NR c R d , -N(R e )C(0)R c -N(R e )
  • R c at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R ⁇ 03 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f , -S0 2 R f , -S0 2 OR f , -S0 2 NR f R g , -NR f R g , -N(R e )C(0)R f , -N(R e )C(0)NR f R g
  • R f at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R ⁇ 03 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -O(R 106 ), -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl)(R ⁇ 06 ), -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(O)N(alkyl) 2 , and R 103 ;
  • R g at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl and -alkylR ⁇ 06 ; alternatively, R f and R g , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heterocycle and heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -O(haloalkyl), -OR 106 , -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R W6 ), -N(al l)(R
  • R j at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R i03 , haloalkyl and -alkylR, 03 ;
  • R k at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; alternatively, R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, t[ cyano, formyl, halo, oxo, -OH, -O(alkyl), -0(cyanoalkyl), -0(haloalkyl), -OR ⁇ 06 , -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R, 06 ), -N(alkyl)(R 106 ),
  • R p , R q , Ri p , R ⁇ q , R 2q , R 7p , R 7q> R 8p , and R 8q , at each occurrence, are independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; wherein each of the R p , R q , R ⁇ p , R lq , R 2q , R 7p , R 7q R 8p , and R 8q , at each occurrence, is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR 101 , -OC(O)R, 0 ⁇ , -OC(O)ORi 0 i, -OC(O) Ri 0 iRi 02 , -OSO 2 R
  • Rioi at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , -alkylR ⁇ 03 , -alkenylR 103 , -alkynylR 103 , haloalkyl, cyanoalkyl, -alkylC(O)R 104 , -alkylC(O)OR ⁇ 04 , -alkylC(O)NR 104 R 105 , -alkyl-OR 104 , -alkyl-OC(O)R ⁇ 04 , -alkyl-OC(O)OR ⁇ 04 , -alkylSR, 04 , -alkylS(O)R 104 , -alkylSO 2 R 104 , -alkylSO 2 OR ⁇ 04 , -alkylSO 2 NR ⁇ 04 R, 05 , -alkylNR ⁇ 04 R, 05 , -alkyl
  • R ⁇ 03 at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle; wherein each R ⁇ 03 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, nitro, cyano, oxo, formyl, haloalkyl, -OR ⁇ 04 , -OC(O)R 104 , -OC(O)OR ⁇ 04 , -OC(O)NR, 04 R, 05 , -OSO 2 NR ⁇ 04 R, 0S , -SO 2 R, 05 , -S(O)R, 04 , -NR 104 R 105 , -N(R, 05 )C(O)NR 104 R ⁇ 05 , -N(R ⁇ 05 )COR, 04 , -N(R, 05 )SO
  • R ⁇ 02 , R 104 , and R 105 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl and benzyl; alternatively, R, 0 ⁇ and R ⁇ 02 together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein the heterocycle or heteroaryl ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 ,
  • R ⁇ 06 at each occurrence is independently selected from the group consisting of aryl and heteroaryl, wherein each R 106 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(0)N(alkyl) 2 , -SH, -Salkyl, -S(0)alkyl, -S0 2 alkyl, -C(0)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alky
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R j is hydrogen.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 6 is hydrogen or alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 1 is -C(0)OR,, -C(0)NR,R b , R lp , alkyl or alkenyl; and R 2 is alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo, -OR,, wherein R, is hydrogen,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, or alkyl substituted with one R lq , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ and wherein R 101 is alkyl,
  • R is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(O)R 0 , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or R Jp ; wherein R jp is heterocycle; and R 2 is alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R, wherein R, is methyl, ethyl, or isopropyl, -OC(0)NR,R b , wherein R a is methyl, ethyl or isopropyl and R b is hydrogen,
  • R ⁇ is methyl, ethyl, or isopropyl
  • R ⁇ q is aryl, -C(0)OR a , wherein R a is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R ⁇ q , wherein R ⁇ q is a pyrrolidine ring, unsubstituted or substituted with one -C(0)OR ⁇ , wherein R 101 is methyl, ethyl or isopropyl,
  • R ⁇ is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R ⁇ and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or R ⁇ p ; wherein R ⁇ p is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-d
  • the third embodiment of the present invention provides a compound of formula (III) wherein R s is -OR d wherein R d is hydrogen, and R 6 is hydrogen or alkyl.
  • R s is -OR d wherein R d is hydrogen
  • R 6 is hydrogen or alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR j wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 1 is -C(0)OR a , -C(0)NR,R b , R ⁇ p , alkyl or alkenyl; and R 2 is alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl, R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -OC(0)R a , wherein R, is alkyl
  • -C CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a cycloalkyl ring; and -R lq ; wherein R ⁇ q is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R ⁇ q is aryl, -C(0)OR a , wherein R ⁇ is alkyl, or alkyl substituted with one R ⁇ q , wherein R ⁇ q is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 10 ⁇ and wherein R 10 ⁇ is alkyl,
  • R ⁇ is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(O)R 0 , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl substituent is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or R lp ; wherein Rj p is heterocycle; and R 2 is alkyl.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or methyl, R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R, wherein R a is methyl, ethyl, or isopropyl
  • -OC(0)NR,R b wherein R, is methyl, ethyl or isopropyl and R b is hydrogen, -C(0)OR, wherein R, is methyl, ethyl, or isopropyl
  • -C CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R ⁇ q , wherein R ⁇ q is a pyrrolidine ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ , wherein R i0 ⁇ is methyl, ethyl or isopropyl, -C(0)NR,R b , wherein R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c , wherein ⁇ .
  • R b is methyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR trench and -OC(O)R 0 , and wherein R c is hydrogen or methyl, or R lp ; wherein R lp is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5- dimethylhexyl, or 3-methylpentyl.
  • R 5 is -OR d wherein R d is hydrogen, R 6 is hydrogen or alkyl
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R ! is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -OC(0)Rchemistry wherein R a is alkyl, -OC(0)NR a R b , wherein R a is alkyl, R b is hydrogen,
  • R ⁇ q is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, and -Ri q , wherein R Jq is aryl, -C(0)OR,, wherein R, is alkyl, or alkyl substituted with one R lq , wherein R jq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 10 ⁇ , wherein R ⁇ 01 is alkyl, -C(0)NR,R b , wherein R, is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of -OR c and
  • R lp wherein R lp is heterocycle; R 2 is alkyl; R 7 is formyl,
  • R is hydrogen, or alkyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R 0 is hydrogen, and R d is hydrogen,
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and alkyl, -NR,R b , wherein R, is hydrogen or alkyl substituted with one cyano, and R b is hydrogen,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R a is alkyl, or alkyl substituted with 1, 2 or 3 halo, and R e is hydrogen or alkyl,
  • R is hydrogen
  • R b is hydrogen
  • R e is hydrogen or alkyl
  • R e is hydrogen or alkyl
  • R b is hydrogen
  • R is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of:
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycle ring; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R, is alkyl,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R, is alkyl substituted with one R q wherein R q is aryl, or alkyl substituted with one substituent selected from the group consisting of N 3 ,
  • R, is hydrogen and R b is hydrogen, -N(R e )SOR a , wherein R, is alkyl and R g is hydrogen or alkyl, -N(R e )S0 2 R a , wherein R e is hydrogen or alkyl, and R a is alkyl, or alkyl substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is heterocycle;
  • R,, R b are hydrogen
  • R e is hydrogen or alkyl, -N(R e )S0 2 N(R e )C(0)OR, wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, R, is alkyl substituted with R q , wherein R q is aryl,
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; R' is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is methyl, ethyl, or isopropyl
  • R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c wherein Rc is hydrogen or methyl, and R b is methyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a pyrrolidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or
  • R lp wherein R ⁇ p is 4,5-dihydro-l,3-oxazol-2-yl; R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5- dimethylhexyl, or 3-methylpentyl; R 7 is formyl,
  • R is hydrogen, or methyl substituted with one substituent selected from the group consisting of cyano and -C(O)NR 0 R d , wherein R c is hydrogen, and R j is hydrogen,
  • R c at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl.
  • R is hydrogen, or methyl substituted with one cyano
  • R is methyl or ethyl wherein each of the methyl or ethyl is unsubstituted or substituted with 1, 2 or 3 halo, and R e is hydrogen or methyl,
  • R ⁇ is hydrogen
  • R b is hydrogen
  • R e is hydrogen or methyl
  • R is hydrogen
  • R b is hydrogen
  • R e is hydrogen or methyl
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and methyl, and R a is R p , wherein R p is phenyl,
  • R e is hydrogen or methyl
  • R is methyl, ethyl, propyl, isopropyl, butyl, ethylenyl or R p
  • R p is selected from the group consisting of imidazolyl, thienyl, benzimidazolyl, phenyl, and naphthyl, wherein each of the methyl, ethyl, propyl, isopropyl and butyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo,
  • R 0 is hydrogen, -NR c R d , wherein R c and R d are hydrogen, and -OC(0)NR c R d , wherein R c and R d together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is azetidine; alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring wherein the heterocycle is pyrrolidine or azetidine;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R ⁇ is methyl, ethyl, propyl or butyl; -N(R e )S0 2 N(R e )C(0)OR, wherein R, at each occurrence is independently selected from the group consisting of hydrogen and methyl, and R, is methy substituted with one R q wherein R q is phenyl; methyl substituted with one substituent selected from the group consisting of N 3 ,
  • R e at each occurrence is independently selected from the group consisting of hydrogen and methyl, R, is methyl substituted with R q , wherein R q is phenyl;
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; RMs alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R, wherein R, is alkyl, -OC(0)NR,R b , wherein R a is alkyl, R b is hydrogen, -C(0)ORspend wherein R a is alkyl,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is alkyl, and -Ri q , wherein R lq is aryl, -C(0)OR a , wherein R a is alkyl, or alkyl substituted with one R ⁇ q , wherein R ⁇ q is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 10 ⁇ , wherein R ⁇ 0 ⁇ is alkyl, -C(0)NR a R b , wherein P ⁇ is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R 3 and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected
  • R 2 is alkyl; R 7 is formyl,
  • R is hydrogen or alkyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R 0 is hydrogen, and R d is hydrogen,
  • R at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R a is hydrogen or alkyl substituted with one cyano, and R b is hydrogen
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl
  • R a is alkyl, or alkyl substituted with 1, 2 or 3 halo
  • R c is hydrogen or alkyl
  • R b is hydrogen
  • R e is hydrogen or alkyl
  • R a is hydrogen
  • R b is hydrogen
  • R e is hydrogen or alkyl
  • R is R p wherein R p is aryl, -N(R e )C(0)OR a , wherein R a is alkyl and R e is hydrogen or alkyl, -N(R e )SOR a , wherein ⁇ is alkyl, and R,, is hydrogen or alkyl, -N(R e )S0 2 R a , wherein R e is hydrogen or alkyl, R a is alkyl, alkenyl, R p , wherein R p is selected from the group consisting of heteroaryl and aryl, or alkyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, -C(0)OR c wherein R c is hydrogen or alkyl,
  • R,. is hydrogen, -NR c R d , wherein R c and R d are hydrogen, and -OC(0)NR c R d , wherein R c and R d together with the nitrogen atom to which they are attached, form a heterocycle ring; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring;
  • R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl,
  • R is alkyl substituted with one R q wherein R q is aryl, or alkyl substituted with one substituent selected from the group consisting of N 3 , -OR,, wherein R, is hydrogen or alkyl substituted with one -OR c wherein R c is alkyl,
  • R is hydrogen and R b is hydrogen, -N(R e )SORpole wherein R, is alkyl and R e is hydrogen or alkyl, -N(R e )S0 2 R a , wherein R c is hydrogen or alkyl, and R a is alkyl, or alkyl substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is heterocycle;
  • R, R b are hydrogen, and R e is hydrogen or alkyl
  • R c at each occurrence is independently selected from the group consisting of hydrogen and alkyl, R ⁇ is alkyl substituted with R q , wherein R q is aryl,
  • R is hydrogen and R b is hydrogen, and R 7q , wherein R 7q is heterocycle;
  • R 8 is halo or -OR,, wherein R, is hydrogen or alkyl; m is 0 or l; and n is O or 1.
  • the third embodiment of the present invention provides a compound of formula (III) wherein R 5 is -OR d wherein R d is hydrogen; R 6 is hydrogen or alkyl; RMs propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a py ⁇ olidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or methyl, or R ip ; wherein R lp is 4,5-dihydro-l,3-oxazol-2-yl; R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl,
  • R is hydrogen, or methyl substituted with one substituent selected from the group consisting of cyano and -C(0)NR c R d , wherein R c is hydrogen, and R d is hydrogen,
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen, methyl and ethyl.
  • R is hydrogen, or methyl substituted with one cyano
  • R is methyl or ethyl wherein each of the methyl or ethyl is unsubstituted or substituted with 1, 2 or 3 halo, and R,, is hydrogen or methyl,
  • R is hydrogen
  • R b is hydrogen
  • R e is hydrogen or methyl
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and methyl, and R, is R p , wherein R p is phenyl, -N(R e )C(0)OR a , wherein R, is tert-butyl and R e is hydrogen or methyl,
  • R is methyl
  • R e is hydrogen or methyl
  • -N(R e )S0 2 R a wherein R ⁇ is hydrogen or methyl
  • R, is methyl, ethyl, propyl, isopropyl, butyl, ethylenyl or R p
  • R p is selected from the group consisting of imidazolyl, thienyl, benzimidazolyl, phenyl, and naphthyl, wherein each of the methyl, ethyl, propyl, isopropyl and butyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo,
  • R e is hydrogen or methyl
  • R b is hydrogen
  • R a is hydrogen, methyl, or ethyl, wherein each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of:
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and methyl, and R a is methyl, ethyl, propyl or butyl; -N(R e )S0 2 N(R e )C(0)ORlaud wherein R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and methyl, and R, is methy substituted with one R q wherein R q is phenyl; methyl substituted with one substituent selected from the group consisting of N 3 ,
  • R a is hydrogen and R b is hydrogen; -N(R e )SORcoming wherein R, is methyl, and R e is hydrogen or methyl; -N(R e )S0 2 R a , wherein R e is hydrogen or methyl, and R, is methyl or ethyl; wherein each of the methyl or ethyl is independently unsubstituted or substituted with one substituent selected from the group consisting of halo and R q ; wherein R q is morpholinyl;
  • R a and R b are hydrogen, and R e is hydrogen or methyl;
  • -N(R c )S0 2 N(R e )C(0)OR wherein R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen and methyl, R a is methyl substituted with R q , wherein R q is phenyl;
  • Exemplary compounds of the third embodiment include, but are not limited to, the following: l,l-dibutyl-4-hydroxy-3- ⁇ 7-[(methoxymethoxy)methyl]-l,l-dioxido-4H-thieno[2,3- e][l,2,4]thiadiazin-3-yl ⁇ -2(lH)-naphthalenone;
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, in combination with a pharmaceutically acceptable carrier.
  • the fourth embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or combination of compounds selected from the group consisting of
  • the fourth embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or combination of compounds selected from the group consisting of
  • any one of the aforementioned pharmaceutical compositions can be used for the treatment or prevention of an infection caused by an RNA-containing virus, specifically when the RNA-containing virus is hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • the present invention is directed to a method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer or combination thereof.
  • the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or combination thereof.
  • the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein the RNA-containing virus is hepatitis C virus.
  • the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof.
  • the sixth embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant.
  • the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a
  • the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein said second antiviral agent inhibits replication of HCV by inhibiting host cellular functions associated with viral replication.
  • the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof, wherein said second antiviral agent inhibits replication of HCV by targeting proteins of the viral genome.
  • the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including ci ⁇ hosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof.
  • the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or combination thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • the sixth embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer or combination thereof.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.
  • HIV human immunodeficiency virus
  • the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, to prepare a medicament for the treatment of infection caused by RNA-containing virus in a patient.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, to prepare a medicament for the treatment of infection caused by hepetitus C virus in a patient.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or a combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon- alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant.
  • the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon- alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein said second antiviral agent inhibits replication of HCV by inhibiting host cellular functions associated with viral replication.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, wherein said second antiviral agent inhibits replication of HCV by targeting proteins of the viral genome.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compouns having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and an agent or combination of agents that treat or alleviate symptoms of HCV infection including ci ⁇ hosis and inflammation of the liver, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but is not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • the seventh embodiment of the present invention provides the use of a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof, and one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, to prepare a medicament for the treatment of an infection caused by an RNA- containing virus in a patient.
  • a compound or a combination of compounds having formula (I), (II) or (III), or a therapeutically acceptable salt form, stereoisomer, or tautomer, or combination thereof and one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, to prepare a medicament for the treatment of an infection caused by an RNA- containing virus in a patient.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.
  • HIV human immunodeficiency virus
  • a “patient” is any individual treated with a compound of the present invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, as defined herein.
  • Patients include humans, as well as other animals such as companion animals (e.g. dogs and cats) and livestock.
  • Patients may be experiencing one or more symptoms of a condition responsive to inhibition of HCV, or may be free of such symptom(s) (i.e. treatment may be prophylactic).
  • the present invention provides an intermediate of formula
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, -C(0)OR,, -C(0)NR a R b or R, p ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R a , -OC(0)OR a , -OC(0)NR,R b , -OS0 2 R,, -OS0 2 NR a R b , -SR,, -S(0)RNase -S0 2 R,, -S0 2 OR,, -S0 2 NR,R b , -NR,R b , -N(R e )C(0)R,, -N(R e )C(0)OR,
  • R 2 is hydrogen, alkyl, alkenyl or alkynyl; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, -OR,, -OC(0)R,, -OC(0)ORhorizon -OC(0)NR,R b , -OS0 2 R a ,
  • R 1 and R 2 together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl; wherein each of the cycloalkyl and cycloalkenyl is unsubstituted or substituted with 1,
  • R 4 is hydrogen, cyano, formyl, halo, oxo, mtro, -OR a , -OC(0)R fate -OC(0)OR a , -OC(0)NR a R b , -OS0 2 R a , -OS0 2 NR a R b , -SR a , -S(0)R a , -S0 2 R,, -S0 2 OR meaning -S0 2 NR a R b5 -NR a R b , -N(R e )C(0)R,, -N(R e )C(0)NR,R b , -N(R e )C(0)OR,, -N(R e )S0 2 Roul -N(R e )S0 2 Roul -N(R e )S0 2 Roul -N(R e )S0 2 Roul -N(R e )S0 2
  • R 8 at each occu ⁇ ence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, -OR,, -OC(0)R,, -OC(0)OR,, -OC(0)NR,R b , -OS0 2 R a , -OS0 2 NR a R b , -SR,, -S(0)R meaning -S0 2 R truth -S0 2 OR
  • R at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R p ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1,
  • R b at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR ⁇ 06 ; alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the hetrocycle and heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR c , -OC(O)R 0 , -OC(0)OR c , -OC(0)NR c R d , -OS0 2 R c , -OS0 2 NR c R d , -SR c -S
  • R c at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R ⁇ 03 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f , -S0 2 R f , -S0 2 OR f , -S0 2 NR f R g , -NR f R g , -N(R e )C(0)R f , -N(R e )C(0)NR f R
  • R d at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR ⁇ 06 ; alternatively, R c and R d , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heteroaryl and heterocycle is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OR f , -OC(0)R f , -OC(0)OR f , -OC(0)NR f R g , -OS0 2 R f , -OS0 2 NR f R g , -SR f , -S(0)R f
  • R e at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl, and -alkylR ⁇ 06 ;
  • R f at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R ⁇ 03 ; wherein each of the alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -O(R 106 ), -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R ⁇ 06 ), -N(alkyl)(R ⁇ 06 ),
  • R g at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R ⁇ 06 , haloalkyl and -alkylR, 06 ; alternatively, R f and R g , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl; wherein each of the heterocycle and heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -OR 106 , -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R 106 ), -N(alkyl
  • R j at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, Rj 03 , haloalkyl and -alkylR ⁇ 03 ;
  • R k at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; alternatively, R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, formyl, halo, oxo, -OH, -O(alkyl), -O(cyanoalkyl), -0(haloalkyl), -OR ⁇ 06 , -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -N(H)(R ⁇ 06 ), -N(alkyl)(R 106 ),
  • Rioi at each occu ⁇ ence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, Rj 03 , -alkylR ⁇ 03 , -alkenylR ⁇ 03 , -alkynylR ⁇ 03 , haloalkyl, cyanoalkyl, -alkylC(O)R, 04 , -alkylC(O)OR, 04 , -alkylC(O)NR ⁇ 04 R, 05 , -alkyl-OR ⁇ 04 , -alkyl-OC(O)R ⁇ 04 , -alkyl-OC(O)OR ⁇ 04 , -alkylSR ⁇ 04 , -alkylS(O)R ⁇ 04 , -alkylSO 2 R 104 , -alkylSO 2 OR ⁇ 04 , -alkylSO 2 NR 104 R ⁇ 05 , -alkylNR ⁇ 04 R, 05 ,
  • R ]03 at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle; wherein each R ⁇ 03 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, nitro, cyano, oxo, formyl, haloalkyl, -OR ⁇ 04 , -OC(O)R 104 , -OC(O)OR ⁇ 04 , -OC(O)NR 104 R 105 , -OSO 2 NR ⁇ 04 R ⁇ 05 , -SO 2 R 105 , -S(O)R 104 ,
  • R I04 and R ]05 together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein the heterocycle or heteroaryl ring is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(
  • R, 06 at each occu ⁇ ence is independently selected from the group consisting of aryl and heteroaryl, wherein each R ⁇ 06 is independently substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, -OH, -Oalkyl, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -C(0)OH, -C(0)Oalkyl, -C(0)NH 2 , -C(0)N(H)(alkyl), -C(0)N(alkyl) 2 , -SH, -Salkyl, -S(0)alkyl, -S0 2 alkyl, -C(0)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH,, -alkylN(H)(
  • R 12 and R 13 are independently selected from the group consisting of alkyl, alkenyl and alkynyl.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) wherein R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring, R 1 is -C(0)OR,, -C(0)NR,R b , R lp> alkyl or alkenyl; and R 2 is alkyl.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring,
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R is hydrogen, -OC(0)R fate wherein R, is alkyl, -OC(0)NR a R b , wherein R a is alkyl, R b is hydrogen, -C(0)ORpiping wherein R a is alkyl,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, or alkyl substituted with one Rj q , wherein R !q is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ , wherein R ⁇ 0 ⁇ is alkyl,
  • R a is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c , wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c , and wherein R c is hydrogen or alkyl, or
  • R tp wherein R lp is heterocycle; and R 2 is alkyl.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo, -OR a , wherein R a is hydrogen,
  • R lq is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is methyl, ethyl or isopropyl
  • -R Iq wherein R ⁇ q is aryl, -C(0)0R a , wherein ⁇ is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R lq , wherein R ⁇ q is a py ⁇ olidine ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ , wherein R m is methyl, ethyl or isopropyl,
  • R ⁇ is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR 0 , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a py ⁇ olidine ring substituted with one methyl wherein the methyl is substituted with one substitutent selected from the group consisting of -OR c and -0C(0)R c , and wherein R c is hydrogen or methyl, or R Jp ; wherein R ip is 4,5-dihydro-l,3-oxazol-2-yl; and R 2 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring, R 1 is -C(0)OR rule -C(0)NR,R b , R lp , alkyl or alkenyl; R 2 is alkyl; R 12 is alkyl and R 13 is alkyl.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring,
  • R 2 is alkyl;
  • R 12 is alkyl; and
  • R 13 is alkyl.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R a is hydrogen, -OC(0)R a , wherein R a is alkyl, -OC(0)NR a R b , wherein R, is alkyl, R b is hydrogen, -C(0)ORspend wherein R, is alkyl,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R is alkyl, and -R iq , wherein R ⁇ q is aryl, -C(0)OR classroom wherein R, is alkyl, or alkyl substituted with one R lq , wherein R ⁇ q is a heterocychc ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 classroom wherein R ⁇ 01 is alkyl, -C(0)NR,R b , wherein R, is alkyl, or alkyl substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c , wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R perpetrat and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of -OR
  • R !p wherein R ip is heterocycle; R 2 is alkyl; R 12 is alkyl; and R 13 is alkyl.
  • the eighth embodiment of the present invention provides an intermediate of fo ⁇ nula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R ⁇ is hydrogen, -OC(0)R a , wherein R, is methyl, ethyl, or isopropyl, -OC(0)NR a R b , wherein R réelle is methyl, ethyl or isopropyl and R b is hydrogen,
  • R a is methyl, ethyl, or isopropyl, -C ⁇ CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
  • R !q is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • ⁇ is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R ⁇ q , wherein R !q is a py ⁇ olidine ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ , wherein R 101 is methyl, ethyl or isopropyl, -C(0)NR a R b , wherein R, is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(0)R c , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form a py
  • the eighth embodiment of the present invention provides an intermediate of fo ⁇ nula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring,
  • R 1 is -C(0)OR a , -C(0)NR a R b , R lp , alkyl or alkenyl;
  • R 2 is alkyl;
  • R 12 is alkyl,
  • R 13 is alkyl,
  • R 8 is halo or -OR, wherein R a is hydrogen or alkyl, and m is 0 or 1.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring,
  • R 2 is alkyl;
  • R 12 is alkyl;
  • R 13 is alkyl,
  • R 8 is halo or -OR, wherein R, is hydrogen or alkyl; and m is 0 or 1.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo,
  • R lq is aryl or cycloalkyl; alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of -C(0)OR,, wherein R, is alkyl, and
  • R ⁇ q is aryl, -C(0)OR a , wherein R a is alkyl, or alkyl substituted with one R ⁇ q , wherein R lq is a heterocychc ring, unsubstituted or substituted with one -C(O)OR 10 ⁇ , wherein R 101 is alkyl, -C(0)NR a R b , wherein Rg is alkyl, or alkyl substituted with one substituent selected from the group consisting of-OC(0)R c , and -OR c , wherein R c is hydrogen or alkyl, and R b is alkyl, alternatively, R, and R b , together with the nitrogen atom to which they are attached, form a heterocychc ring substituted with one alkyl substitutent wherein the alkyl is substituted with one substituent selected from the group consisting of -OR c , and -OC(0)R c and wherein R
  • R 2 is alkyl; R 12 is alkyl; R 13 is alkyl, R 8 is halo or -OR, wherein R a is hydrogen or alkyl; and m is O or 1.
  • the eighth embodiment of the present invention provides an intermediate of formula (IV) R 3 and R 4 together with the carbon atoms to which they are attached form an aryl ring;
  • R 1 is propyl, butyl, methyl, ethyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl, wherein each of the propyl, butyl, methyl, ethyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 5,5-dimethylhexyl, 3-methylpentyl is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo, -OR a , wherein R a is hydrogen, -OC(0)R a , wherein R, is methyl, ethyl, or isopropyl, -OC(0)NR a R b , wherein R
  • -C CR j R k , wherein R j and R k together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
  • R ]q is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; allyl, 3-methylbut-2-enyl, or 4-ethylpenta-2,4-dienyl, wherein each of the allyl, 3-methylbut-2-enyl or 4-ethylpenta-2,4-dienyl is unsubstituted or substituted with one substituent selected from the group consisting of
  • R a is methyl, ethyl or isopropyl, wherein each of the methyl, ethyl or isopropyl is unsubstituted or substituted with one R lq , wherein R lq is a py ⁇ olidine ring, unsubstituted or substituted with one -C(O)OR ⁇ 0 ⁇ , wherein R 1M is methyl, ethyl or isopropyl, -C(0)NR a R b , wherein R a is methyl or ethyl, wherein each of the methyl or ethyl is unsubstituted or substituted with one substituent selected from the group consisting of -OC(O)R 0 , and -OR c , wherein R c is hydrogen or methyl, and R b is methyl, alternatively, R a and R b , together with the nitrogen atom to which they are attached, form
  • R 8 is halo or -OR, wherein R a is hydrogen or methyl; and m is 0 or 1.
  • Exemplary compounds of the seventh embodiment having formula (IV), of the present invention include but not limited to the following: 2-[bis(methylthio)methylene]-4,4-bis(3-methylbutyl)naphthalene-l,3(2H,4H)-dione; 2-[bis(methylthio)methylene]-7-fiuoro-4,4-dipropylnaphthalene-l,3(2H,4H)-dione; 2-[bis(methylthio)methylene]-4,4-dibutyl-7-fluoronaphthalene-l,3(2H,4H)-dione;
  • the present invention provides a process for the preparation of a compound of formula (V)
  • M is Na + , K + , Ca 2+ and Mg 2+ ; a is 1 when M is Na + or K + ; a is 2 when M is Ca 2+ or Mg 2+ ;
  • A is a monocyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
  • R 1 is alkyl, alkenyl, or alkynyl
  • R 2 is alkyl, alkenyl or alkynyl
  • R 8 at each occu ⁇ ence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, cyanoalkyl, hydroxyalkyl or alkoxyalkyl; and
  • R a is alkyl, alkenyl or alkynyl; m is O or 1; wherein said process comprises the step of:
  • the present invention provides a process for the preparation of a compound of formula (V) wherein R 1 is alkyl or alkenyl, R 2 is alkyl or alkenyl, m is 0, and R_, is alkyl.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein R 1 is methyl or allyl, R 2 is 3-methyl butyl, 3,3-dimethyl butyl, allyl or 3-methylbut-2-enyl, m is 0, and R, is methyl.
  • the eight embodiment of the present invention provides a process for the preparation of sodium (4R)-4-(3,3-dimethylbutyl)-4-methyl-2- ⁇ 7-[(methylsulfonyl)amino ]- 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3 -yl ⁇ -3 -oxo-3 ,4-dihydronaphthalen- 1 -olate.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (a) R 1 is alkyl or alkenyl,
  • R 2 X include, but are not limited to, l-bromo-3 -methyl but-2-ene (prenyl bromide), 3-methylbutyl bromide, and 3,3-dimethyl-l-iodobutane
  • examples of the bases in step (a) include, but are not limited to, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydroxide, and potassium hydroxide, preferably lithium diisopropylamide and lithium bis(trimethylsilyl)amide, and more preferably lithium bis(trimethylsilyl)amide.
  • step (a) examples include, but are not limited to, tetrahydrofuran, N,N-dimethylformamide, dioxane, and dimethoxyethane; preferably tetrahydrofuran and dioxane; and more preferably tetrahydrofuran.
  • the reaction in step (a) is generally performed at a temperature from about 25°C to about 70°C; preferably at a temperature from about 40°C to about 65°C, and most preferable at a temperature from about 50°C to about 60°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (b) the chlorinating agent include, but are not limited to, oxalyl chloride with a catalytic amount of N,N-dimethylformamide, thionyl chloride and phosphorus oxychloride; prefe ⁇ ed chlorinating agent is thionyl chloride and oxalyl chloride with a catalytic amount of N,N-dimethylformamide; most prefe ⁇ ed chlorinating agent is oxalyl chloride with about 1% in total volume of N,N-dimethyl formamide.
  • the chlorinating agent include, but are not limited to, oxalyl chloride with a catalytic amount of N,N-dimethylformamide, thionyl chloride and phosphorus oxychloride; prefe ⁇ ed chlorinating agent is thionyl chloride and oxalyl chloride
  • solvent examples include, but are not limited to, dichloromethane, hexanes, heptanes, and tetrahydrofuran; prefe ⁇ ed solvent is hexanes or heptanes; more prefe ⁇ ed solvent is heptanes.
  • the reaction can be performed at a temperature from about 0°C to about 30°C; preferably at a temperature from about 10°C to about 25°C, and most preferable at a temperature from about 20°C to about 25°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (c) the examples of the reagent having formula CH 2 (C(0)OR t ) 2 include, but are not limited to, CH 2 (C(0)OC 2 H 5 ) 2 , CH 2 (C(0)0(t-butyl)) 2 ; preferably CH 2 (C(0)OC 2 H 5 ) 2 .
  • the base include, but are not limited to, triethylamine and dusopropyethyl amine, preferably triethylamine.
  • step (c) can be performed at a temperature from about 20°C to about 60°C; preferably at a temperature from about 40°C to about 60°C, and more preferable at a temperature from about 50°C to about 55°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (d) the acid is sulfuric acid or methanesulfonic acid, and preferably methanesulfonic acid.
  • the reaction of step (d) can be performed at a temperature from about 0°C to about 50°C; preferably at a temperature from about 10°C to about 40°C, and most preferable at a temperature from about 20°C to about 25°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (e) R A is tert-butyloxycarbonyl or benzyloxycarbonyl, preferably tert-butyloxycarbonyl.
  • R A is tert-butyloxycarbonyl or benzyloxycarbonyl, preferably tert-butyloxycarbonyl.
  • the base include, but are not limited to, triethylamine, N,N-diisopropylethylamine, sodium hydroxide, cesium carbonate and DABCOTM (l,4-diazabicyclo[2.2.2]octane, Aldrich, catalog number 29,073-4), preferably DABCOTM or triethylamine, and more preferably triethylamine.
  • solvent examples include, but are not limited to toluene, water, xylene, acetonitrile, and s-butanol, preferably acetonitrile or toluene, and more preferably, toluene.
  • the reaction can be performed at a temperature from about 60°C to about 140°C; preferably at a temperature from about 80°C to about 105°C, and more preferably at a temperature from about 90°C to about 100°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (f) the deprotecting agent include, but are not limited to, anhydrous hydrogen chloride in dioxane or trifluoroacetic acid; and more preferably anhydrous hydrogen chloride in dioxane.
  • the solvent include, but are not limited to, ethyl acetate, toluene, dichloromethane and dioxane; preferably dichloromethane or dioxane; more preferably dichloromethane.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (g) examples of the neutralizing agent include, but are not limited to, NajCO-,, NaHC0 3 , and pH 7 phosphate buffer; preferably NaHC0 3 or a pH 7 phosphate buffer; and more preferably a pH 7 phosphate buffer.
  • the solvent examples include, but are not limited to, dichloromethane, toluene, ethyl acetate, and isopropyl acetate, preferably toluene or ethyl acetate; and more preferably ethyl acetate.
  • the reaction can be performed at a temperature from about 0°C to about 40°C; preferably at a temperature from about 10°C to about 30°C, and more preferably at a temperature from about 20°C to about 25°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein examples of the solvent that can be employed in step (h) include, but are not limited to, isopropyl acetate, dichloromethane, tetrahydrofuran, ethyl acetate and acetone, preferably acetone or dichloromethane, and more preferably dichloromethane.
  • the reaction can be performed at a temperature from about 0°C to about 40°C; preferably at a temperature from about 10°C to about 30°C, and more preferably at a temperature from about 20°C to about 25°C.
  • the ninth embodiment of the present invention provides a process for the preparation of a compound of formula (V) wherein in step (i) examples of the base include, but are not limited to, alkali metal ethoxide, alkali metal hydroxide, and alkali metal carbonate, preferably alkali metal hydroxide or alkali metal ethoxide; more preferably alkali metal ethoxide and most preferably sodium ethoxide.
  • the solvent include, but are not limited to, water, acetone, ethanol, acetonitrile, and mixture of water and ethanol; preferably acetone or ethanol; more preferably ethanol.
  • the reaction can be performed at a temperature from about 10°C to about 80°C; preferably at a temperature from about 30°C to about 75°C, and most preferable at a temperature from about 50°C to about 75°C.
  • the process of the ninth embodiment of the present invention further comprises the process of resolving the chiral amine salt by contacting the compound of formula (34) with a chiral amine, isolating the chiral acid-amine salt and contacting the chiral acid-amine salt with an acid in a solvent.
  • the chiral amine include, but are not limited to, (R) 2- amino- 1-butanol, (S) phenethylamine, (+) pseudoephedrine, (-) and cinchonidine; prefe ⁇ ed chiral amine is (+) pseudoephedrine or (S) phenethylamine; more prefe ⁇ ed chiral amine is (S) phenethylamine.
  • the solvent examples include, but are not limited to, acetone, methyl tert- butyl ether, ethanol and ethyl acetate, preferably methyl tert-butyl ether or ethyl acetate; and more preferably ethyl acetate.
  • the reaction can be performed at a temperature from about 0°C to about 60°C, preferably at a temperature from about 10°C to about 40°C, and more preferably at a temperature from about 20°C to about 30°C.
  • the steps of isolating the chiral acid-amine salt comprises of filtering precipitate, dissolving the precipitate in a solvent to a solution, cooling the solution to room temperature and filtering the precipitate, wherein the solvent is ethyl acetate.
  • the acid used to contact the chiral acid-amine salt include aqueous hydrochloric acid, sulfuric acid, and phosphoric acid; preferably sulfuric acid or aqueous hydrochloric acid; more preferably aqueous hydrochloric acid.
  • Examples of the solvent employed include, but are not limited to, ethyl acetate, heptanes or isopropyl acetate; preferably heptanes or ethyl acetate; and more preferably ethyl acetate.
  • the reaction can be performed at a temperature from about 0°C to about 40°C; preferably at a temperature from about 10°C to about 30°C, and more preferably at a temperature from about 20°C to about 25°C.
  • the ninth embodiment of the present invention provides a process for the preparation of sodium (4R)-4-(3,3-dimethylbutyl)-4-methyl-2- ⁇ 7-[(methylsulfonyl)amino]- 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3 -yl ⁇ -3 -oxo-3 ,4-dihydronaphthalen- 1 -olate or sodium (4R)-4-methyl-4-(3-methylbutyl)-2- ⁇ 7-[(methylsulfonyl)amino]- 1 , 1 -dioxido-4H- 1 ,2,4- benzothiadiazin-3-yl ⁇ -3-oxo-3,4-dihydronaphthalen-l-olate, wherein in step (a) R 1 is methyl, R 2 is 3,3-dimethylbutyl, X is iodo, the base is lithium bis(trimethylsilyl)amide, and the
  • step (f) the deprotecting agent is anhydrous hydrogen chloride in dioxane, and the solvent is dichloromethane; in step (g) the neutralizing agent is pH 7 phosphate buffer and the solvent is ethyl acetate; in step (h) the sulfonating reagent is R a S0 2 Cl wherein R a is methyl, and the solvent is dichloromethane; and in step (i) the base is sodium ethoxide and the solvent is ethanol.
  • the process further comprises contacting the compound of formula (34) from step (a) with (S)- ⁇ -methyl benzylamine in ethyl acetate, isolating the chiral-amine salt by filtration of the precipitate, dissolution of the precipitate in ethyl acetate to a solution, cooling the solution to room temperature and filtering the precipitate, and contacting the chiral acid-amine salt with hydrochloric acid in ethyl acetate.
  • formula (I) wherein B is a six membered ring
  • All tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the present invention. Examples of some of the possible tautomer forms of the compounds of this invention include, but are not limited to:
  • Compounds of this invention may contain at least one chiral center and may exist as single stereoisomers (e.g. single enantiomer), mixtures of stereoisomers (e.g. any mixture of enantiomers or diastereomers) or racemic mixtures thereof.
  • all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, mixtures of enantiomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers.
  • substantially free is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
  • the stereochemistry of the chiral centers present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral center present in the compound.
  • stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecif ⁇ c synthesis from commercially available optically pure (enantiomerically pure) or substantially optically pure starting materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures.
  • Exemplary procedures that may be useful for the resolution/separation of mixtures of stereoisomers include enzymatic resolution, chromatographic separation, crystallization/re-crystallization , and conversion of enantiomers in an enantiomeric mixture to diastereomers followed by separation/resolution of the diastereomers using techniques known in the art, such as recrystallization and or chromatographic resolution, and regeneration of the individual enantiomers.
  • Other useful methods may be found in "Enantiomers, Racemates, and Resolutions, " J. Jacques et al.,
  • Stereospecif ⁇ c synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
  • Starting materials of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.
  • the resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries.
  • Enzymes such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
  • the present compounds may exhibit the phenomena of tautomerism or structural isomerism.
  • drawings within this specification can only represent one possible tautomeric or structural isomeric form, it should be understood that the invention encompasses any tautomeric or structural isomeric form, or mixtures thereof, which possess the ability to inhibit hepatitis C, and is not limited to any one tautomeric or structural isomeric form utilized within the drawings.
  • any variable for example R 7 , R 8 , R a , R b , R c , R d , R e , R f , R g , R j , R k , R p , R q , R lp , lq? etc.
  • its definition on each occu ⁇ ence is independent of its definition at every other occu ⁇ ence.
  • combinations of substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
  • the compounds of the present invention can exist as pharmaceutically acceptable salts.
  • the term "pha ⁇ naceutically acceptable salt,” as used herein, represents acid or base salts or zwitterionic forms of the compounds of the present invention which are water or oil- soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a basic group (for example, a nitrogen containing group) with a suitable acid.
  • Representative acid addition salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, butyrates, camphorates, camphorsulfonates, caproates, caprylates, citrates, chlorobenzoates, digluconates, dinitrobenzoates, formates, fumarates, glutamates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochloride, hydrobromide, hydroiodides, 2-hydroxyethansulfonates, lactates, maleates, mandelates, methoxybenzoates, methylbenzoates, malonates, mesitylenesulfonate, methanesulfonates, naphthylenesulfonates, nicotinates, nitrates, nitrites, 2-naphthalenesulfon
  • amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, nitric acid, sulfuric, and phosphoric, and the like, and organic acids such as acetic, fumaric, trifluoroacetic, mandelic, methanesulfonic, pyruvic, oxalic, glycolic, salicylic, oxalic, maleic, succinic, tartaric, aspartic, glutamic, cinnamic and citric.
  • inorganic acids such as hydrochloric, hydrobromic, nitric acid, sulfuric, and phosphoric, and the like
  • organic acids such as acetic, fumaric, trifluoroacetic, mandelic, methanesulfonic, pyruvic, oxalic, glycolic, salicylic, oxalic, maleic, succinic, tartaric, aspartic, glutamic, cinnamic and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting an acidic group (for example, a carboxy group or an enol) with a suitable base such as the alkoxide, (for example, ethoxide or methoxide-and the like) hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the alkoxide, (for example, ethoxide or methoxide-and the like) hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, copper, manganese, iron, zinc, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, teframethylammonium, tefraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.
  • nontoxic quaternary amine cations such as ammonium, teframethylammonium, tefraethylammonium, methylamine, dimethylamine,
  • organic amines useful for the formation of basic addition salts include amino acids such as glycine and arginine, primary, secondary and tertiary amines such as ethylenediamine, ethanolamine, and diethanolamine, and cyclic amines such as dicyclohexylamine, morpholine, piperidine, and piperazine.
  • amino acids such as glycine and arginine
  • primary, secondary and tertiary amines such as ethylenediamine, ethanolamine, and diethanolamine
  • cyclic amines such as dicyclohexylamine, morpholine, piperidine, and piperazine.
  • Representative pharmaceutically acceptable salts of the compounds of the present invention include sodium, potassium, calcium, magnesium, triethylamine, trifluoroacetate, methanesulfonate, hydrobromide and hydrochloride.
  • the present compounds can also exist as pharmaceutically acceptable prodrugs.
  • pharmaceutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug of formula (I), (II) or (III) in vivo metabolically or by solvolysis when such prodrugs is administered to a mammalian subject.
  • Prodrugs of the compounds of formula (I), (II) or (III) can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds respectively.
  • modifications include, but not limited to, treatment of a compound of formula (I), (II) or (III), containing an amino, amido or hydroxyl moiety with a suitable derivatising agent, for example, a carboxylic acid halide or acid anhydride, treatment of a compound of formula (I), (II) or (III), containing a carboxyl moiety, to an ester or amide and treatment of a compound of formula (I), (II) or (III), containing a carboxylic acid ester moiety to an enol-ester.
  • a suitable derivatising agent for example, a carboxylic acid halide or acid anhydride
  • Prodrugs include compounds wherein hydroxy, amine, carboxy, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves under physiological conditions to form a free hydroxyl, amino,carboxy, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxy, carboxy and amine functional groups in the compounds of formula (I), (II) or (III).
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl sulf
  • the compounds of formula (I), (II) or (III), or a tautomer, stereoismer, or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other antiviral agents.
  • the specific pharmaceutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds of fo ⁇ nula (I), (II) or (III), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the antiviral effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches can also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes thereof
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
  • the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, sihcones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • agents such as host immune modulators, for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like, or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase, for example, ribavirin and the like.
  • agents such as host immune modulators, for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like, or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase, for example, ribavirin and the like.
  • cytokines that modulate immune function.
  • vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV.
  • IRS internal ribosome entry site
  • Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication.
  • These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or US6348587B1 or WO0160315 or WO0132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP1162196A1 or WO0204425 or inhibitors of HCV protease such as, for example, peptidomimetic type inhibitors such as BILN2061 and the like or inhibitors of HCV helicase.
  • inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or US6348587B1 or WO0160315 or WO0132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP1162196A
  • agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of other viruses for co-infected individuals.
  • agents include but are not limited to therapies for disease caused by hepatitis B (HBV) infection such as, for example, adefovir, lamivudine, and tenofovir or therapies for disease caused by human immunodeficiency virus (HLV) infection such as, for example, protease inhibitors: ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir; reverse transcriptase inhibitors: zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125;
  • agents to be administered in combination with a compound of the present invention include any agent or combination of agents that treat or alleviate symptoms of HCV infection including ci ⁇ hosis and inflammation of the liver.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • terapéuticaally effective amount of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated; the treatment desired; the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts, stereoisomers of tautomers thereof, administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • HCV polymerase inhibition assay biochemical IC sn : Either two-fold serial dilutions (fractional inhibition assay) or a na ⁇ ower range of dilutions spanning the IC50 of the inhibitor (tight binding assay) of the inhibitors were incubated with 20 mM Tris-Cl pH 7.5, 5 mM MgCl 2 , 50 mM NaCl, 1 mM dithiothreitol, 1 mM ethylene diamine tetraacetic acid (EDTA), 300 ⁇ M GTP and 150 to 300 nM NS5B (HCV Strain IB (J4, Genbank accession number AF054247, or H77, Genbank accession number AF011751)) for 15 minutes at room temperature.
  • HCV Strain IB J4, Genbank accession number AF054247, or H77, Genbank accession number AF011751
  • the reaction was initiated by the addition of 20 ⁇ M CTP, 20 ⁇ M ATP, 1 ⁇ M 3H-UTP (10 mCi/umol), 150 nM template RNA and 0.4 U/ ⁇ l RNase inhibitor (RNasin, Promega), and allowed to proceed for 2 to 4 hours at room temperature. Reaction volume was 50 ⁇ l. The reaction was terminated by the addition of 1 volume of 4 mM spermine in 10 mM Tris-Cl pH 8.0, 1 mM EDTA. After incubation for at least 15 minutes at room temperature, the precipitated RNA was captured by filtering through a GF/B filter (Millipore) in a 96 well format.
  • a GF/B filter Millipore
  • the filter plate was washed three times with 200 ⁇ l each of 2 mM spermine, 10 mM Tris-Cl pH 8.0, 1 mM EDTA, and 2 times with ethanol. After air drying, 30 ⁇ l of Microscint 20 scintillation cocktail (Packard) was added to each well, and the retained cpm were determined by scintillation counting.
  • IC50 values were calculated by a two-variable nonlinear regression equation using an uninhibited control and a fully inhibited control sample to determine the minimum and maximum for the curve. Tight- binding assays were performed on those compounds exhibiting IC50 values less than 0.15 ⁇ M in the fractional inhibition assay in order to more precisely measure the IC50 values. Retained cpm were plotted vs. inhibitor concentration and fit to equation 1 using non-linear regression (ref. 1) to obtain the IC50 values.
  • HCV polymerase IB with IC50's in the range of 0.002 ⁇ M to 500 ⁇ M.
  • Replicon cells were plated at 3xl0 3 cells per well in 96- well plate in DMEM medium containing 5% fetal calf serum. At day 1, culture medium was removed and replaced with fresh medium containing eight serial 2-fold dilutions of compound. The final concentration of DMSO in medium was 0.5%. The untreated control culture was treated in an identical manner except no inhibitor was added to the medium. Plates were incubated in a CO2 incubator at 37°C. On Day 4, 100 ⁇ L lysis buffer (RTL) (Qiagen) was added to each well after removal of culture medium. RNA was purified according to manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 ⁇ l of water.
  • RTL lysis buffer
  • the HCV RNA level was quantified from a portion (5 ⁇ L out of 200 ⁇ L) of the purified RNA by real-time RT- PCR method.
  • the primers and probe are derived from specific sequence in the 5'UTR region.
  • RT-PCR reaction was performed at 48 °C for 30 min, followed by 40 cycles set to 95°C, 15 s; 54°C, 30 s; and 72°C, 40 s.
  • the percentage reduction of HCV RNA in the presence of compound was calculated and the 50% inhibitory concentration (IC 50 ) was calculated by non-linear regression analysis using the Prism program.
  • the compounds of the present invention inhibit replicon production with EC50's in the range of 0.005 ⁇ M to >100 ⁇ M.
  • Cytotoxity assays were performed in replicon cells. Briefly, HCV replicon cells were plated at 3x10 3 cells per well in 96-well plate in DMEM medium containing 5% FCS. At day 1, culture medium was removed and replaced with fresh medium containing eight serial 2-fold dilutions of compound. The final concentration of DMSO in medium was 0.5%. All experiments were performed in duplicate. The untreated control culture was treated in an identical manner except no inhibitor was added to the medium. Plates were incubated in a C ⁇ 2 incubator at 37°C.
  • the compounds of the present invention When tested by the above method, the compounds of the present invention exhibited CPE reduction with TC50's in the range of 6.6 ⁇ M to >100 ⁇ M.
  • hepatitis C Cell culture assays for agents targeted toward hepatitis C are not yet available because of the inability to produce infectious virus in a sustained cell line.
  • the hepatitis C virus genome encodes a large polyprotein, which after processing produces the necessary functional components to synthesize progeny RNA.
  • Selectable cell lines that produce high and sustained levels of subgenomic HCV RNA have been derived from human hepatoma cells (Huh7) as described in the references above.
  • the mechanism of RNA replication in these cell lines is considered to be identical to the replication of full length HCV RNA in infected hepatocytes.
  • the compounds and methods of this invention are inhibitors of HCV RNA replication in the replicon assay systems described above. This forms the basis of the claim for their potential as therapies in treating disease resulting from hepatitis C viral infection.
  • THF is tetrahydrofuran
  • DBU is l,8-diazabicyclo[5.4.0]undec- 7-ene.
  • This invention is intended to encompass compounds having formula (I), (II) or (III) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • ring D represents the ring formed by R 3 , R 4 (as defined in formula (I)), and the carbon atoms to which they are attached, and is selected from the group consisting of aryl, heteroaryl, cycloalkenyl, cycloalkyl and heterocycle, can be prepared as shown in Scheme 1.
  • D include, but are not limited to, phenyl, furanyl and thienyl.
  • R p is hydrogen, alkyl, alkenyl, alkynyl or benzyl, wherein the alkyl, alkenyl and benzyl are unsubstituted or substituted, can be monoalkylated with one equivalent of an alkylating agent having formula R !
  • X wherein X is Cl, Br or I, in the presence of appropriate amount of a base (for example, if R p is hydrogen, about two equivalents of the base can be used, if R p is other than hydrogen, than about one equivalent of the base can be used) in a solvent such as, but not limited to, tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or mixtures thereof, at a temperatures from about -78°C to about 70°C to afford compounds of formula (2).
  • a base for example, if R p is hydrogen, about two equivalents of the base can be used, if R p is other than hydrogen, than about one equivalent of the base can be used
  • a solvent such as, but not limited to, tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or mixtures thereof, at a temperatures from about -78°C to about 70°C to afford compounds of formula (2).
  • Compounds of fo ⁇ nula (2) can be alkylated again by treatment with the same or a second alkylating agent by reaction with a base and an alkylating agent having formula R 2 X, wherein X is Cl, Br or I.
  • the reaction can be carried out in a solvent such as, but not limted to, tetrahydrofuran, diethyl ether, N, N- dimethylfo ⁇ namide, or mixtures thereof, at a temperatures from about -78°C to about 70°C.
  • the reaction can be performed with or without an additive such as lithium or sodium iodide or hexamethylphosphoric triamide (HMPA) and the like.
  • HMPA hexamethylphosphoric triamide
  • compounds of formula (1) can be transformed in a one step operation to compounds of formula (3) by using an excess of an alkylating agent, in the presence of about two equivalents of the base (if R p is not hydrogen) or about three equivalents of the base (if R p is hydrogen), in a solvent such as tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or mixtures thereof, at a temperature from about 0°C to about 100°C, with or without the presence of an additive such as lithium, sodium or potassium iodide, tetrabutylammonium iodide, 18-crown-6, or hexamethylphosphoric triamide (HMPA), and the like.
  • an alkylating agent in the presence of about two equivalents of the base (if R p is not hydrogen) or about three equivalents of the base (if R p is hydrogen), in a solvent such as tetrahydrofuran, diethyl ether, N, N-dimethyl
  • R p examples include, but not limited to hydrogen, methyl, ethyl, tert-butyl and benzyl.
  • alkylating agents include, but not limited, to methyl iodide, ethyl iodide, 3,3-dimethyl-l-iodobutane, 3,3-dimethyl-l-bromobutane, l-chloro-3-methyl-2- butene, allyl bromide, l-bromo-3 -methy lbut-2-ene, crotyl bromide and crotyl iodide.
  • bases include, but not limited to, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, lithium diisopropyl amide, lithium tetramethyl piperidide, and potassium tert-butoxide,
  • Compounds of fo ⁇ nula (3) wherein R p is methyl can be converted into carboxylic acid of fo ⁇ nula (4) by treatment with potassium trimethylsilanoate in a solvent such as tetrahydrofuran, dioxane, dichloromethane, acetonitrile, toluene, and the like, or mixtures thereof, at a temperature from about 60°C to about 100°C.
  • a solvent such as tetrahydrofuran, dioxane, dichloromethane, acetonitrile, toluene, and the like, or mixtures thereof
  • Compounds of formula (3) wherein R p is benzyl can be converted to compounds of formula (4) by hydrogenation with hydrogen over a metal catalyst such as 5-10% palladium on carbon or platinum oxide (Adam's catalyst) and the like, in a solvent such as ethyl acetate, ethanol, methanol, or mixtures thereof, at a pressure of about 1-20 atmospheres and at a temperature from about 25°C to about 80°C.
  • a metal catalyst such as 5-10% palladium on carbon or platinum oxide (Adam's catalyst) and the like
  • a solvent such as ethyl acetate, ethanol, methanol, or mixtures thereof
  • Compounds of formula (5) can be prepared from compounds of formula (4) by refluxing for several days with excess thionyl chloride.
  • a prefe ⁇ ed method of transformation can be accomplished by treatment of a hexane or heptane solution of acid (4) and one equivalent of N, N-dimethylformamide with an excess of oxalyl chloride.
  • the acid chloride (5) is reacted with the magnesium salt of either diethyl or dimethyl malonate (generated in acetonitrile according as described by Rathke (Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50, 2622) at a temperatures of about 40°C to about 60°C.
  • ketodiester (6) wherein R is methyl or ethyl
  • R is methyl or ethyl
  • the ketodiester (6) is then subjected to Friedel-Crafts-type cyclization by treatment with an acid such as, but not limited to, concentrated sulfuric acid, methanesulfonic acid, or polyphosphoric acid, and the like, at a temperature from about 25°C to about 100°C, to afford the diketo ester (7).
  • an acid such as, but not limited to, concentrated sulfuric acid, methanesulfonic acid, or polyphosphoric acid, and the like
  • Transformation of the diketo ester (7) to the compounds of formula (8) can be achieved by treatment with a dilute aqueous acid such as, but not limited to, hydrochloric acid or sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, admixed with a solvent such as tetrahydrofuran, dioxane, and the like, at preferably reflux temperature.
  • a dilute aqueous acid such as, but not limited to, hydrochloric acid or sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, admixed with a solvent such as tetrahydrofuran, dioxane, and the like, at preferably reflux temperature.
  • a prefe ⁇ ed method of step (b) is to treat compounds of formula (10) with one equivalent of anhydrous potassium or cesium carbonate in a solvent such as pyridine, picoline or collidine at a temperature from about 80°C to about 150°C.
  • a more prefe ⁇ ed method for the transformation is to treat compounds of formula (10) with 1,8 diazabicyclo[5.4.0]undec-7-ene in a solvent such as pyridine, picoline or collidine, and the like, at a temperature from about 80°C to about 150°C.
  • Examples of the base are, but not limited to, pyridine, picoline and collidine.
  • alkoxydihydroresorcinol derivative (14) wherein R is methyl, ethyl, n- propyl, or isobutyl can be converted to compounds of formula (15) by (a) reacting with a base in a solvent such as, but not limited to, tetrahydrofuran or 2-methyltet ⁇ ahydrofuran, or mixtures thereof, at a temperature from about -78°C to about 0°C, and with or without the presence of an additive, and (b) treating the product from step (a) with an alkylating agent of fo ⁇ nula R ⁇ X, wherein X is Cl, Br, or I, at a temperature from about -78°C to about 25°C.
  • a solvent such as, but not limited to, tetrahydrofuran or 2-methyltet ⁇ ahydrofuran, or mixtures thereof
  • Compounds of formula (15) can be further alkylated with the same or a second alkylating agent of fo ⁇ nula R 4 X, wherein X is Cl, Br, or I, by the conditions as described in steps (a) and (b) to afford compounds of formula (16).
  • alkylating agents include, but not limited to, allyl bromide, methyl iodide, l-chloro-3-methyl-2-butene, ethyl iodide, crotyl bromide and crotyl iodide.
  • base include, but are not limited to, lithium bis(trimethylsilyl)amide
  • LiHMDS Lithium tetramethyl piperidide
  • LDA lithium diisopropyl amide
  • HMPA hexamethylphosphoric triamide
  • DMPU N, N'-dimethylpropylene urea
  • DI 1, 3-dimethyl-2-imidazolidinone
  • Compounds of formula (16) can be directly hydrolyzed to the diketone derivatives of formula (17) by treatment with an acid such as dilute aqueous hydrochloric acid, dilute aqueous sulfuric acid, aqueous sodium bisulfate or aqueous trifluoroacetic acid in a solvent, such as tetrahydrofuran, acetone, dioxane, and the like, or mixtures thereof, at a temperatures from about 0°C to about 25°C.
  • Compounds of formula (18) can be prepared from diketones of formula (17), using the conditions for the transformation of compounds of formula (8) to compounds of formula (13).
  • compounds of fo ⁇ nula (16) wherein R 10 and R 11 are hydrogen can be treated with a base such as, but not limited to, lithium diisopropyl amide (LDA) in a solvent such as tefrahydrofuran, 2- methyltetrahydrofuran or diethyl ether, and the like, or mixtures thereof, in the presence of an additive such as hexamethylphosphoric triamide (HMPA) or 1, 3-dimethyl-2-imidazolidinone (DMI) at a temperature from about -78°C to about 0°C, followed by the addition of phenyl selenyl chloride and warming the reaction to ambient temperature.
  • HMPA hexamethylphosphoric triamide
  • DI 1, 3-dimethyl-2-imidazolidinone
  • the resulting selenium derivative (19) can be treated with an oxidizing agent such as, but not limited to, aqueous hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, peracetic acid or monoperphthalic acid, at a temperatures from about 30°C to about 50°C.
  • the resulting dienone (20) can be hydrolyzed using a base such as, but not limited to, lithium hyroxide hydrate in a solvent mixture such as methanol or ethanol in water, at a temperatures of about 50°C to about 100°C to afford the diketone (21).
  • the diketone (21) can be transformed to compounds of formula (22) using the conditions for the transformation of compounds of formula (8) to compounds of fo ⁇ nula (13).
  • Compounds of formulae (18) and (22) can be converted to compounds of formulae (23) and (24), respectively, using the conditions for the transformation of compounds of formula (13) to compounds of formula (11).
  • the reaction is typically performed in a solvent such as, but not limited to, tetrahydrofuran, dichloromethane, diethyl ether, N,N-dimethylformamide, dimethoxyethane or tert-butyl methyl ether, at a temperature from about room temperature to about 100°C.
  • a solvent such as, but not limited to, tetrahydrofuran, dichloromethane, diethyl ether, N,N-dimethylformamide, dimethoxyethane or tert-butyl methyl ether
  • the base include, but are not limited to cesium carbonate.
  • the palladium reagent include, but are not limited to, tris(dibenzylideneacetone)dipalladium(0) and allylpalladium chloride dimmer.
  • ligand examples include, but are not limited to, l,2-diaminocyclohexane-N,N'-bis(2'- diphenylphosphinobenzoyl) and (+)-l l(S), 12(S)-Bis[2'-(diphenylphosphino)benzamido]- 9,10-dihydro-9,10ethanoanthracene.
  • Compounds of formula (29) wherein R 2 is an alkyl or substituted alkyl, as defined in formula (I), can be converted to compounds of formula (30) by reaction with a base and an alkylating agent having formula R 2 X, wherein X is Cl, Br or I, optionally in the presence of hexamethylphosphoric triamide (HMPA) or l,3-Dimethyl-2- imidazolidinone (DMI).
  • HMPA hexamethylphosphoric triamide
  • DI l,3-Dimethyl-2- imidazolidinone
  • the reaction can be performed at a temperature from about -78°C to about room temperature for about 1 to 48 hours.
  • the reaction is generally carried out in an aprotic solvent such as, but are not limited to, tetrahydrofuran, dimethoxyethane or tert-butyl methyl ether.
  • the base include, but are not limited to, lithium diisopropylamide, and lithium hexamethyl
  • Compounds of formula (30) can be converted to compounds of formula (32) by reaction with a trialkylorthoformated of formula CH(OR 3 ) 3 , and p-toluenesulfonic acid in an alcoholic solvent such as, but not limited to, methanol.
  • the reaction is generally carried out at a temperature from about room temperature to about 70°C.
  • compounds of formula (32) can be obtained from compounds of fo ⁇ nula (31) wherein R 1 is an electron withdrawing group such as -0(0)1 ⁇ or -C(0)OR a , by reaction with an alkylating agent having formula R 2 X, wherein X is Cl, Br, or I, with a metal, ammonia and a proton source.
  • the reaction can be carried out at about -78°C and optionally in the presence of a co-solvent such as, but are not limited to, tetrahydrofuran and diethyl ether.
  • a co-solvent such as, but are not limited to, tetrahydrofuran and diethyl ether.
  • the metal include potassium or sodium.
  • the proton sounce include, but are not limited to, tert-butanol and a weak acid such as, but not limited to, water.
  • Conversion of compounds of formula (32) to compounds of fo ⁇ nula (20) can be achieved by reaction with pyridinium dichromate and tert-butyl hydroperoxide.
  • the reaction can be performed in a solvent such as, but not limited to, benzene, chloroform or dichloromethane, at a temperature from about room temperature to about 60°C, for about 1 hour to about 24 hours.
  • Example 1A methyl 2-allyl-2-phenyl-4-pentenoate
  • a solution of methyl 2-phenylacetate (12.0g, 80 mmol), allyl bromide (17.3 mL, 200 mmol) and sodium iodide (1 g) in tetrahydrofuran (160 mL) at 0°C was treated portionwise with sodium hydride (7.36 g, 60 % in oil, 184 mmol) over 10 minutes.
  • the solution was allowed to warm to 25°C and heated at reflux for 18 hours.
  • the mixture was cooled to 0°C, treated with glacial acetic acid (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water.
  • Example IB methyl 2-phenyl-2-propylpentanoate
  • ethyl acetate 125 mL
  • 10% palladium on carbon 600 mg
  • sti ⁇ ed at 25°C under hydrogen gas 6 hours
  • the solution was filtered through celite® and the filtrate was concentrated in vacuo to give the title compound (7.63 g, 100%).
  • Example IE diethyl 2-(2-phenyl-2-propylpentanoyl)malonate A solution of diethyl malonate (3.03 g, 18.77 mmol) and anhydrous magnesium chloride in acetonitrile (36 mL) at 0°C was treated with triethylamine (5.2 mL, 37.55 mmol) , sti ⁇ ed at 0°C for 30 min, sti ⁇ ed at 25°C for 3 hours, cooled to 0°C and treated dropwise with a solution of the product of Example ID (18.77 mmol) in acetonitrile (15 mL) over 10 min and sti ⁇ ed at 50°C for 18 hours.
  • Example IE The product of Example IE (4.51 g, 12.4 mmol) was treated with concentrated sulfuric acid (25 mL) and sti ⁇ ed at 25°C for 3 hours. The mixture was then poured into a mixture of ice and water (500 mL) and sti ⁇ ed until all the ice melted. The mixture was extracted with ethyl acetate (2 x). The combined organic layers were washed with water and saturated sodium chloride solution, dried (Na;,S0 4 ), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methyl t-butyl ether in hexane to afford the title compound (1.73 g, 44%).
  • Example 1G N- [2-(aminosulfonyl)phenyl] - 1 -hydroxy-3 -oxo-4,4-dipropyl-3 ,4-dihydro-2- naphthalenecarboxamide
  • a suspension of the product of Example IF (490 mg, 1.55 mmol) and 2- aminobenzenesulfonamide (Aldrich) (267 mg, 1.55 mmol) in toluene (25 mL) was sti ⁇ ed at reflux for 18 hours, cooled to 25°C and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (410 mg, 60 %). !
  • Example 1H 3 ( 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3 -yl)-4-hydroxy- 1 , 1 -dipropyl-2( lH)-naphthalenone
  • 10 % potassium hydroxide solution 9 mL
  • Example II sodium 2-(l , 1 -dioxido-4H-l ,2,4-benzothiadiazin-3-yl)-3-oxo-4,4-dipropyl-3,4-dihydro- 1 - naphthalenolate
  • a suspension of the product of Example 1H (55 mg, 0.13 mmol) in 1 :1 acetonitrile- water was treated with IN NaOH solution (130 ⁇ L 0.13 mmol) and sti ⁇ ed at 25°C for 2 hours. The solution was then lyophilized to afford the title compound (59 mg, 100%) a fluffy white solid.
  • Example 2A 4-(benzyloxy)-2-fluoro- 1 -nitrobenzene
  • 2-fluoro-4-hydroxynitrobenzene 5.08 g, 32.36 mmol
  • cesium carbonate 11.71 g, 36.24 mmol
  • benzyl bromide 4.31 mL, 36.24 mmol
  • tefrabutylammonium iodide 50 mg
  • N, N-dimethylformamide 50 mL
  • Example 2B 4-(benzyloxy)-2-(benzylsulfanyl)- 1 -nitrobenzene
  • a solution of the product of Example 2A (7.72 g, 31.26 mmol), sodium carbonate (3.31 g, 31.26 mmol) and benzyl mercaptan (3.90 mL, 30.21 mmol) in absolute ethanol (50 mL) was sti ⁇ ed at reflux for 6 hours, cooled to 25°C and added to water (200 mL). The precipitate was collected by filtration, washed with water and dried to give the title compound (10.71g, 98%).
  • Example 2E 7Y-[2-(aminosulfonyl)-4-(benzyloxy)phenyl]-l-hydroxy-3-oxo-4,4-dipropyl-3,4-dihydro-2- naphthalenecarboxamide
  • a suspension of the product of Example IF (617 mg, 1.95 mmol) and the product of Example 2D (542 mg, 1.95 mmol) in toluene (20 mL) was sti ⁇ ed at reflux for 18 hours and concentrated in vacuo to afford the title compound (1.1 g, 100%). !
  • Example 2F 3-[7-(benzyloxy)-l ,1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3-yl]-4-hydroxy-l , 1 -dipropyl-2(lH)- naphthalenone
  • a solution of the compound of Example 2E (300 mg, 0.547 mmol) in anhydrous pyridine (5.2 mL) was treated with 1,8 diazabicyclo[5.4.0]undec-7-ene (82 ⁇ L, 0.55 mmol) and sti ⁇ ed at 140°C for 18 hours, cooled to 25°C and the pyridine removed by short path distillation under high vacuum (50 °C/0.3 mm ⁇ g).
  • Example 3 2- ⁇ [3-( 1 -hydroxy-3-oxo-4,4-di ⁇ ro ⁇ yl-3 ,4-dihydro-2-naphthalenyl)- 1 , 1 -dioxido-4H- 1 ,2,4- benzothiadiazin-7-yl]oxy ⁇ acetamide
  • 2-bromoacetamide 9 mg, 0.064 mmol
  • cesium carbonate 22 mg, 0.067 mmol
  • tefrabutylammonium iodide 3 mg
  • the solution was acidified with 1M citric acid solution (1 mL) and extracted with ethyl acetate. The organic layer was washed with water (3 x) and saturated sodium chloride solution, dried (Na ⁇ O ⁇ , filtered and concentrated in vacuo. A suspension of the residue in acetonitrile (2 mL) was treated with IN sodium hydroxide solution (26 ⁇ L) and sti ⁇ ed at 25°C for 2 hours. The solution was lyophilized to afford the title compound (12 mg, 52%).
  • Example 4 1 , 1 -dibutyl-3-( 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3 -yl)-4-hydroxy-2( lH)-naphthalenone
  • Example 4B methyl 2-butyl-2-phenylhexanoate
  • a solution of the product of Example 4A (7.78g, 30.16 mmol) in methanol (70 mL) was treated with Adams' catalyst (Pt0 2 , 790 mg) and hydrogenated under 60 psi hydrogen pressure for 16 hours at 25°C.
  • the catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (7.59 g, 96%).
  • H NMR 300 MHz,
  • Example 4F ethyl 4,4-dibutyl-l-hydroxy-3-oxo-3,4-dihydro-2-naphthalenecarboxylate
  • the title compound (1.2g, 21%) was prepared following the procedure of Example IF, substituting the product of Example 4E for the product of Example IE.
  • a solution of the product of Example 4G (298 mg, 0.63 mmol) and cesium carbonate (123mg, 0.38 mmol) in pyridine (6 mL) was sti ⁇ ed at 140°C for 18 hours, cooled to 25°C and the pyridine removed by short path distillation under high vacuum (50 °C/0.3 mm Hg). A suspension of the residue in ethyl acetate was treated with saturated ammonium chloride solution.
  • Example 41 sodium 4,4-dibutyl-2-( 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3-yl)-3 -oxo-3 ,4-dihydro- 1 - naphthalenolate
  • the title compound (142 mg, 88%) was prepared following the procedure of Example
  • Example 5B 1 1 -dibutyl-4-hydroxy-2( lH)-naphthalenone
  • a solution of the product of Example 4F (200 mg, 0.58 mmol) in dioxane (3 mL) and 10 % HCl solution (10 mL) was sti ⁇ ed at 100°C for 5 hours, cooled to 25°C and extracted with dichloromethane (3 x). The combined organic layers were dried (Na ⁇ O ⁇ , filtered and concentrated in vacuo. The residue was recrystallized from hexanes to give the title compound (140 mg, 88%).
  • Example 5E l,l-dibutyl-4-hydroxy-3-(7-hydroxy-l,l-dioxido-4H-l,2,4-benzothiadiazin-3-yl)-2(lH)- naphthalenone
  • the title compound was prepared following the procedure of Example 2G, substituting the product of Example 5D for the product of Example 2F to afforded the title compound (70 mg, 100%).
  • Example 6 3 -( 1 , 1 -dioxido-4H- 1 ,2,4-benzothiadiazin-3-yl)-4-hydroxy- 1 , 1 -diisopentyl-2( 1H)- naphthalenone
  • Example 6A methyl 5-methyl-2-(3-methyl-2-butenyl)-2-phenyl-4-hexenoate
  • the title compound (11.4 g, 100%) was prepared following the procedure of Example 1A, substituting l-chloro-3-methyl-2-butene for allyl bromide.
  • ⁇ NMR (300 MHz, CDC1 3 ): ⁇ 7.28 (m, 5 H), 4.88 (m, 2 H), 3.64 (s, 3 H), 2.75 (m, 2 H), 2.63 (dd, J 14.34, 6.62 Hz, 2 H), 1.66 (s, 6 H), 1.49 (s, 6 H).
  • Example 6B methyl 2-isopentyl-5-methyl-2-phenylhexanoate The title compound was prepared following the procedure of Example 4B, substituting the product of Example 6A for the product of Example 1 A.
  • Example 6C 2-isopentyl-5-methyl-2-phenylhexanoic acid The title compound was prepared following the procedure of Example 1C, substituting the product of Example 6B for the product of Example IB.
  • Example ID The title compound was prepared according to the procedure of Example ID, substituting the product of Example 6C for the product of Example lC.
  • Example IE The title compound was prepared following the procedure of Example IE, substituting dimethyl malonate for diethyl malonate, and substituting the product of Example 6D for the product of Example ID.
  • ⁇ NMR 300 MHz, CDC1 3 ): ⁇ 7.32 (m, 5 H), 4.54 (s, 1 H), 3.56 (s, 6 H), 2.00 (m, 4 H), 1.49 (m, 2 H), 0.87 (m, 16 H).
  • Example 6F methyl l-hydroxy-4,4-diisopentyl-3-oxo-3,4-dihydro-2-naphthalenecarboxylate
  • the title compound was prepared according to the procedure of Example IF, substituting the product of Example 6E for the product of Example IE.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne des composés de formule générale (I), qui sont des inhibiteurs de la polymérase du virus de l'hépatite C (HCV). L'invention concerne également une composition et un procédé permettant d'inhiber la polymérase du virus de l'hépatite C (HCV), des procédés de production desdits composés, ainsi que des intermédiaires synthétiques utilisés dans ces procédés.
PCT/US2004/027000 2003-08-25 2004-08-19 Agents anti-infectieux WO2005019191A2 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
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WO2006093801A1 (fr) * 2005-02-25 2006-09-08 Abbott Laboratories Derives de thiadiazine utiles en tant qu’agents anti-infectieux
US7479489B2 (en) 2004-08-23 2009-01-20 Roche Palo Alto Llc Heterocyclic antiviral compounds
US7538105B2 (en) 2003-08-25 2009-05-26 Abbott Laboratories Anti-infective agents
WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
US7576103B2 (en) 2004-12-21 2009-08-18 Roche Palo Alto Llc Tetralin and indane derivatives and uses thereof
US7662958B2 (en) 2006-07-19 2010-02-16 Rolf Wagner Anti-infective agents
US7674810B2 (en) 2005-05-04 2010-03-09 Roche Palo Alto Llc 1,1-dioxo-1H-1Λ6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one inhibitors of HCV polymerase
US7754759B2 (en) 2005-11-03 2010-07-13 Roche Palo Alto Llc Arylsulfonyl chromans as 5-HT6 inhibitors
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
WO2010100178A1 (fr) 2009-03-06 2010-09-10 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2010122082A1 (fr) 2009-04-25 2010-10-28 F. Hoffmann-La Roche Ag Composes antiviraux heterocycliques
WO2010149598A2 (fr) 2009-06-24 2010-12-29 F. Hoffmann-La Roche Ag Compose antiviral heterocyclique
US7902203B2 (en) 2002-11-01 2011-03-08 Abbott Laboratories, Inc. Anti-infective agents
WO2011033045A1 (fr) 2009-09-21 2011-03-24 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2011061243A1 (fr) 2009-11-21 2011-05-26 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
EP2361922A1 (fr) 2006-10-10 2011-08-31 Medivir AB Intermediaire pour la synthèse d'inhibiteurs nucleosidique du HCV
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
TWI395749B (zh) * 2006-06-22 2013-05-11 Anadys Pharmaceuticals Inc 吡咯并〔１，２-ｂ〕嗒酮化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098424A1 (fr) * 2001-06-07 2002-12-12 Smithkline Beecham Corporation Nouveaux anti-infectieux

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098424A1 (fr) * 2001-06-07 2002-12-12 Smithkline Beecham Corporation Nouveaux anti-infectieux

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7902203B2 (en) 2002-11-01 2011-03-08 Abbott Laboratories, Inc. Anti-infective agents
US7538105B2 (en) 2003-08-25 2009-05-26 Abbott Laboratories Anti-infective agents
US7479489B2 (en) 2004-08-23 2009-01-20 Roche Palo Alto Llc Heterocyclic antiviral compounds
US7576103B2 (en) 2004-12-21 2009-08-18 Roche Palo Alto Llc Tetralin and indane derivatives and uses thereof
WO2006093801A1 (fr) * 2005-02-25 2006-09-08 Abbott Laboratories Derives de thiadiazine utiles en tant qu’agents anti-infectieux
US7517876B2 (en) 2005-02-25 2009-04-14 Abbott Laboratories Anti-infective agents
US7674810B2 (en) 2005-05-04 2010-03-09 Roche Palo Alto Llc 1,1-dioxo-1H-1Λ6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one inhibitors of HCV polymerase
US7754759B2 (en) 2005-11-03 2010-07-13 Roche Palo Alto Llc Arylsulfonyl chromans as 5-HT6 inhibitors
TWI395749B (zh) * 2006-06-22 2013-05-11 Anadys Pharmaceuticals Inc 吡咯并〔１，２-ｂ〕嗒酮化合物
US7662958B2 (en) 2006-07-19 2010-02-16 Rolf Wagner Anti-infective agents
US7951800B2 (en) 2006-07-19 2011-05-31 Abbott Laboratories, Inc. Anti-infective agents
EP2361922A1 (fr) 2006-10-10 2011-08-31 Medivir AB Intermediaire pour la synthèse d'inhibiteurs nucleosidique du HCV
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
WO2010100178A1 (fr) 2009-03-06 2010-09-10 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2010122082A1 (fr) 2009-04-25 2010-10-28 F. Hoffmann-La Roche Ag Composes antiviraux heterocycliques
WO2010149598A2 (fr) 2009-06-24 2010-12-29 F. Hoffmann-La Roche Ag Compose antiviral heterocyclique
WO2011033045A1 (fr) 2009-09-21 2011-03-24 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2011061243A1 (fr) 2009-11-21 2011-05-26 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques

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