WO2003099801A1 - Nouveaux anti-infectieux - Google Patents

Nouveaux anti-infectieux Download PDF

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Publication number
WO2003099801A1
WO2003099801A1 PCT/US2003/016374 US0316374W WO03099801A1 WO 2003099801 A1 WO2003099801 A1 WO 2003099801A1 US 0316374 W US0316374 W US 0316374W WO 03099801 A1 WO03099801 A1 WO 03099801A1
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dihydro
hydroxy
alkyl
thiadiazin
dioxo
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PCT/US2003/016374
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English (en)
Inventor
Kevin J. Duffy
Karen A. Evans
Duke M. Fitch
Adam T. Gates
Victor K. Johnston
Robert T. Sarisky
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Smithkline Beecham Corporation
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Priority to AU2003248566A priority Critical patent/AU2003248566A1/en
Publication of WO2003099801A1 publication Critical patent/WO2003099801A1/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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6851—Quantitative amplification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D

Definitions

  • the present invention relates to compounds that inhibit an RNA-containing virus and methods of making and using the same. Specifically, the present invention relates to inhibitors of hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/yr. by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu- like symptoms, leukopenia, thrombocytopenia, and depression from interferon, as well as hemolytic anemia induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (Suppl. 1):71S-77S).
  • HCV post- transfusion non A, non-B hepatitis
  • HCV is an enveloped virus containing a single strand RNA molecule of positive polarity.
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang, C.Y., Le, S.Y., Ali, N., Siddiqui, A., Rna-A Publication of the Rna Society. 1(5): 526-537, 1995 Jul). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • the HCV-RNA Upon entry into the cytoplasm of the cell, the HCV-RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (Eds.) Virology, 2nd Edition, p931- 960, Raven Press, NY).
  • 3' NTR which roughly consists of three regions: an ⁇ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3'X-tail" (Kolykhalov, A. et al., (1996) J. Virology 70:3363-3371; Tanaka, T. et al., (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al, (1996) J. Virology 70:3307-3312; Yamada, N. et al, (1996) Virology 223:255-261).
  • the 3' NTR is predicted to form a stable secondary structure that is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E., et al, (1996) EMBO J. 15: 12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • RdRp RNA-dependent RNA polymerase
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across lb isolates) and inter-typically (-85% aa identity between genotype la and lb isolates).
  • HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (Kolykhalov, A.A., et al., (2000) J. Virology 74:2046-2051).
  • inhibition of NS5B RdRp activity is predicted to cure HCV infection.
  • Positive strand hepatitis C viral RNA is the nucleic acid strand that is translated and initially copied upon entry of the HCV-RNA into the cell. Once in the cell, positive strand viral RNA generates a negative strand replicative intermediate.
  • Negative strand RNA is the template used to generate the positive strand message that is generally packaged into productive virions.
  • HCV inhibitor compounds are only evaluated for their ability to inhibit positive strand HCV-RNA. However, it would be desirable to develop inhibitor compounds having the ability to inhibit both positive and negative strand replication to obtain complete clearance of the HCV virus.
  • R' is -C(0)OR 8 , Ci-Cio alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -(CpC ⁇ alkyl)-(C 3 -C 6 cycloalkyl), -(C 2 -C 6 alkenyl)-(C 3 -C 6 cycloalkyl), -(C 2 -C 6 alkynyl)-(C 3 -C 6 cycloalkyl), -(Ci-C ⁇ alkyl)-heterocycloalkyl, -(C 2 -C6 alkenyl)-heterocycloalkyl, -(C 2 -C 6 alkynyl)-heterocycloalkyl, -(C,-C 6 alkyl)-aryl, (C 2 -C 6 alken
  • R 4 and R 5 are each independently selected from: hydrogen, halogen, cyano, C,-C 6 alkyl, -OH, and -OC,-C 4 alkyl;
  • R 6 is hydrogen, C,-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 5 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, nitro, cyano, halogen, -C(0)OR 8 , -C(0)R 8 , -C(0)NR 8 R 9 , -OR 8 , -SR 8 , -S(0)R", -S(0) 2 R", -NR 8 R 9 , protected -OH, -N(R 9 )C(0)R 8 , -OC(0)NR 8 R 9 , -N(R 9 )C(0)NR 8 R 9 , -P(0)(OR 8 ) 2 , -S0 2 NR 8 R 9 , -S
  • R 7 is hydrogen, halogen, hydroxyl or Q- alkyl; or R 4 and R 5 or R 5 and R 6 or R 6 and R 7 taken together are alky lenedi oxy; wherein each R 8 is independently selected from: hydrogen, C C 8 alkyl,
  • -alkylheterocycloalkyl, -alkylaryl or -alkylheteroaryl is unsubstituted or substituted with one or more substituents independently selected from: Ci-C ⁇ alkyl, C C6 haloalkyl, halogen -OC,-C 6 alkyl, -OC,-C 6 haloalkyl, cyano, -N(C,-C 6 alkyl)(C,-C 6 alkyl), -NH(C,-C 6 alkyl), -NH 2 , -C0 2 CrC 6 alkyl, -C0 2 H, -CON(C,-C 6 alkyl)(C,-C 6 alkyl), -CONH(C,-C 6 alkyl), and -CONH 2 ; or, when present in any NR 8 R 9 or NR 9 R 10 , each R 8 and R 9 or each R 9 and R 10 , independently, taken together with the nitrogen to which they are attached
  • C C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, -OR 12 , -NR 9 R 12 , cyano, nitro, -C0 2 R 12 , -CONR 9 R 12 , -NR 9 CONR 9 R 12 , -OCONR 9 R 12 , -S0 2 NR 9 R 12 , and -COR 12 , and where any of said cycloalkyl, heterocycloalkyl, aryl or heteroaryl (including the cycloalkyl, heterocycloalkyl, aryl or heteroaryl moieties of said -
  • This invention is also directed to a prodrug of a compound according to Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • this invention is directed to pharmaceutical compositions comprising a compound according to Formula I, or a tautomer thereof, or a pharmaceutically acceptable prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.
  • this invention is directed to a method of inhibiting an RNA-containing virus comprising contacting the virus with an effective amount of a compound of Formula I.
  • this invention is directed to a method of treating infection or disease caused by an RNA-containing virus which comprises administering to a subject in need thereof, an effective amount of a compound according to Formula I.
  • This invention is particularly directed to methods of inhibiting hepatitis C virus.
  • This invention is also directed to a method for inhibiting replication of hepatitis C virus which comprises inhibiting replication of both positive and negative strand HCV-RNA.
  • alkyl represents a straight-or branched-chain saturated hydrocarbon, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • alkyls include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
  • lower alkyl refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl or alkenyl or alkynyl
  • haloalkyl or "arylalkyl”
  • alkyl is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • cycloalkylalkyl is intended to mean the radical -alkyl-cycloalkyl, wherein the alkyl moiety thereof is a divalent straight or branched-chain hydrocarbon radical and the cycloalkyl moiety thereof is as defined herein, and is represented by the bonding arrangement present in the groups -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, or -CH 2 CH(CH 3 )CH 2 -cyclopentenyl.
  • Arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH 2 -phenyl).
  • alkenyl represents a straight-or branched-chain hydrocarbon containing one or more carbon-carbon double bonds.
  • An alkenyl may be unsubstituted or substituted by one or more of the substituents defined herein.
  • Exemplary alkenyls include, but are not limited ethenyl, propenyl, butenyl, isobutenyl and pentenyl.
  • alkynyl represents a straight-or branched-chain hydrocarbon containing one or more carbon-carbon triple bonds and, optionally, one or more carbon-carbon double bonds.
  • An alkynyl may be unsubstituted or substituted by one or more of the substituents defined herein.
  • Exemplary alkynyls include, but are not limited ethynyl, butynyl, propynyl (propargyl, isopropynyl), pentynyl and hexynyl.
  • Cycloalkyl represents a group or moiety comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents defined herein and may be saturated or partially unsaturated.
  • exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl and cycloheptyl.
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or partially unsaturated, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-l ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1,3- dioxolanyl, 1 ,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[
  • heterocycloalkyl is a monocyclic heterocycloalkyl, such as azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydro-2H-l,4- thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,3-dithianyl, oxazolinyl, thiazolinyl and pyrazolinyl.
  • azetidinyl such as azetidinyl, pyrrolidyl (or
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be unsubstituted or substituted by one or more substituents defined herein.
  • aryl is phenyl.
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • This term also encompasses bicyclic or tricyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 16 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl, chromanyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl
  • heteroaryl is a monocyclic heteroaryl, such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl and tetrazolyl.
  • halogen and “halo” represent chloro, fluoro, bromo or iodo substituents.
  • Halroxy is intended to mean the radical -OH.
  • Alkoxy is intended to mean the radical -OR a , where R a is an optionally substituted alkyl group. Exemplary alkoxy include methoxy, ethoxy, propoxy, and the like.
  • Lower alkoxy groups have optionally substituted alkyl moieties from 1 to 4 carbons.
  • Alkylenedioxy is intended to mean the divalent radical -OR a O- which is bonded to adjacent atoms (e.g., adjacent atoms on a phenyl or naphthyl ring), wherein R a is a C ⁇ -C 2 alkyl group.
  • alkylenedioxy-substituted phenyls include benzo[l,3]dioxyl and 2,3-dihydro-benzo[l,4]dioxyl.
  • R 1 is C 3 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C r C 6 cycloalkyl-C,-C 4 -alkyl-, heterocycloalkyl-C C 4 -alkyl-, C 6 aryl-C C 4 alkyl-, or heteroaryl-C]-C 4 alkyl-, wherein said alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, cyano, -OH, -0(CpC alkyl), -NH 2 , -N(C,-C 4 alkylXC-G, alkyl), -NH(C C 4 alkyl), SH, and -S(C,-C 4 alkyl), and the heterocycloalkyl, aryl or heteroaryl moiety of said heterocycloalkyl-C C 4 -al
  • R 3 is H, C C 4 alkyl or C C 4 haloalkyl, wherein said C ⁇ -C 4 alkyl is unsubstituted or substituted with an aryl or heteroaryl group; or R 2 and R 3 taken together with the carbon to which they are attached represent a 3-, 4-, 5- or 6-membered saturated ring optionally containing one or two heteroatoms selected from: oxygen, sulfur, and nitrogen, where said 3-, 4-, 5- or 6-membered ring is unsubstituted or substituted with one or more substituents independently selected from: halogen, -CN, -OH, -NH 2 , -0(C,-C 4 alkyl), -C(0)0(C,-C 4 alkyl), -C(0)OH,
  • R 4 , R 5 and R 7 are each independently selected from: H, halogen, C C 4 alkyl and
  • R 6 is H, C r C 4 alkyl, halogen, N0 2 , -CN, -N(C,-C 4 alkyl)(C,-C 4 alkyl), -NH(C ⁇ -C 4 alkyl), -NH 2 , -OH, -0(C C 4 alkyl) or -0(C,-C 4 alkyl)phenyl wherein the alkyl moiety of said -C,-C 4 alkyl, -0(C,-C 4 alkyl), -0(C,-C 4 alkyl)phenyl, -N(C,-C 4 alkyl)(C,-C 4 alkyl) or -NH(C,-C 4 alkyl) is unsubstituted or substituted by -OH, -0(C,-C 4 alkyl), -CN, -C0 2 (C,-C 4 alkyl), -C0 2 H, -CON(C,-C 4 alky
  • R 1 is C 3 -C 8 alkyl, C 3 -C 6 cycloalkyl-C ⁇ -C 4 alkyl-, C 6 aryl-C C 4 alkyl-, heterocycloalkyl-C C 4 alkyl- or heteroaryl-C ⁇ -C 4 alkyl-, wherein the aryl or heteroaryl moiety is unsubstituted or substituted with one or more substituents independently selected from: C C 4 alkyl, C C 4 haloalkyl, -OH, -0(C
  • R 1 is -CH 2 -phenyl, -CH 2 -(2-chloro-phenyl), -CH 2 -(3-chloro-phenyl), -CH 2 -(4-chloro-phenyl), -CH 2 -(2-bromo-phenyl), -CH 2 -(3-bromo-phenyl), -CH 2 -(4-bromo-phenyl), -CH 2 -(2-fluoro-phenyl), -CH 2 -(3-fluoro-phenyl), -CH 2 -(4-fluoro-phenyl), -CH 2 -(2-trifluoromethyl-phenyl), -CH 2 -(3-trifluoromethyl-phenyl), -CH 2 -(4-trifluoromethyl-phenyl), -CH 2 -(2-methoxy-phenyl), -CH 2 -(3-methoxy
  • R 2 is H, C C 6 alkyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 3 -C 6 cycloalkyl-C C alkyl-, C 6 aryl-C ⁇ -C 4 alkyl-, heterocycloalkyl-C ⁇ -C 4 alkyl- or heteroaryl-C ⁇ -C 4 alkyl-, where said C C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of said cycloalkylalkyl, heterocycloalkylalkyl, arylaryl or heteroarylalkyl is unsubstituted or substituted with one or more substituents independently selected from: C,-C 4 alkyl, halogen, -OH, -NH 2 , -CN, -CONH
  • R 2 is H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -(CH 2 ) 4 NH 2 , -(CH 2 ) 2 SCH 3 , -(CH 2 ) 2 SOCH 3 , -(CH 2 ) 4 NH 2 , -CH 2 C0 2 H, -(CH 2 ) 2 C0 2 H, -(CH 2 ) 3 C0 2 H, -(CH 2 ) 3 C0 2 CH 3 , -CH 2 OC(CH 3 ) 3 , -CH 2 cyclopropyl, cyclohexyl, phenyl, 4-fluoro-phenyl, benzyl, 4-hydroxybenzyl-, pyridin-4-yl-, pyridin-2-yl-, pyridin-3-yl-
  • R 3 is H, C r C 3 alkyl, C r C 3 haloalkyl, C 3 -C 6 cycloalkyl, phenyl-C C 2 alkyl- or heteroaryl-C C 2 alkyl-, where the heteroaryl moiety of said heteroaryl-C C 2 alkyl or the phenyl moiety of said phenyl-C r C 2 alkyl- is unsubstituted or substituted with one or more substituents independently selected from: -OH, - ⁇ H 2 , -0(C,-C 4 alkyl), -C(0)0(C,-C 4 alkyl), -C(0)OH, -C(0)(C,-C 4 alkyl), -CONH 2 , -CONH(C,-C 4 alkyl), -CON(C,-C 4 alkyl)(C,-C 4 alkyl), -N(C,-C 4 alkyl)(C,
  • R 3 is H or
  • R 2 and R 3 taken together with the carbon to which they are attached form a 3-, 5- or 6-membered saturated ring optionally containing one or two heteroatoms selected from: oxygen, sulfur, and nitrogen, where said 3-, 5- or 6-membered ring is unsubstituted or substituted with one or more substituents independently selected from: halogen, -CN, -OH, -NH 2 , -0(C,-C 4 alkyl), -C(0)0(C C 4 alkyl), -C(0)OH, -C(0)(C,-C 4 alkyl), -C(0)cycloalkyl, -C(0)heterocycloalkyl, -C(0)aryl, -C(0)heteroaryl, -CONH 2 , -CONH(C ⁇ -C 4 alkyl), -CON(C,-C 4 alkyl)(C,-C 4 alkyl), -N(C,-C 4 alkyl
  • R 2 and R 3 taken together with the carbon to which they are attached form a 3-membered saturated carbocyclic ring (a spiro-cyclopropyl group) or a 6-membered heterocycloalkyl ring (a spiro-piperidyl group), wherein the heterocycloalkyl ring is optionally unsubstituted or substituted with -C(0)Ofert-butyl or -C(0)CH 3 .
  • R 4 , R 5 and R 7 are each H.
  • R 6 is H, C C alkyl, -OH or -0(C C 4 alkyl), wherein said C r C 4 alkyl or -0(C C 4 alkyl) is unsubstituted or substituted by -NH 2 , -CN, -CONH 2 , -CON(C,-C 4 alkyl)(C r C 4 alkyl), -CONH(C,-C 4 alkyl), aryl or heteroaryl, wherein the aryl or heteroaryl is optionally unsubstituted or substituted by one or more substituents sleeted from: cyano, halogen, -C(0)0(C C 6 alkyl), -C(0)C C 6 alkyl, -OR 8 , -NR 9 R 10 and -CONR 9 R 10 .
  • R 6 is H, -OH, methoxy or -OCH 2 C(0)NH 2 .
  • R 1 is C 3 -C 6 alkyl or benzyl
  • R 2 is H, C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 3 is H or methyl
  • R 4 , R 5 and R 7 are each H;
  • R 6 is H, -OH, -0(C,-C 4 alkyl), or -0(C,-C 4 alkyl)-CONH 2 ; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. It is to be understood that the present invention encompasses all combinations of particular, specific and preferred groups described hereinabove. If a substituent described herein is not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety.
  • a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
  • various substituents may be a "protected -OH" group.
  • This term refers to a substituent represented as -OR p , where R p refers to a suitable protecting group for an -OH moiety.
  • Hydroxyl protecting groups are well known in the art and any hydroxyl protecting group that is useful in the methods of preparing the compounds of this invention may be used.
  • Exemplary hydroxyl protecting groups include benzyl, tetrahydropyranyl, silyl (trialkyl-silyl, diaryl-alkyl-silyl, etc.) and various carbonyl-containing protecting groups, as disclosed in T. Greene and P. Wuts, supra.
  • the compounds of this invention may contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers), mixtures of stereoisomers (e.g. any mixture or enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the broad scope of the present invention.
  • Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that are at least 90% enantiomerically pure. Where the stereochemistry of the chiral carbons 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.
  • Such compounds may be obtained synthetically, according to the procedures described herein using optically pure (enantiomerically pure) or substantially optically pure materials.
  • these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures.
  • Exemplary methods that may be useful for the resolution/separation of mixtures of stereoisomers include chromatography and crystallization/re-crystallization. Other useful methods may be found in "Enantiomers, Racemates, and Resolutions, " J. Jacques et al., 1981, John Wiley and Sons, New York, NY, the disclosure of which is incorporated herein by reference.
  • the compounds of this invention may possess one or more unsaturated carbon- carbon double bonds. All double bond isomers, both the cis (Z) and trans (E) isomers, and mixtures thereof are intended to be encompassed within the scope of the present invention.
  • pharmaceutically acceptable salt is intended to describe a salt that retains the biological effectiveness of the free acid or base of a specified compound and is not biologically or otherwise undesirable.
  • a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like.
  • an inorganic acid such
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne- 1 ,4-dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycollates, tartrates, mandelate
  • an inventive compound is an acid
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • Suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • Particular pharmaceutically acceptable salts of a compound of Formula I include the sodium salt and the potassium salt. Because the compounds of this invention may contain both acid and base moieties, pharmaceutically acceptable salts may be prepared by treating these compounds with an alkaline reagent or an acid reagent, respectively. Accordingly, this invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention, e.g., a hydrochloride salt, into another pharmaceutically acceptable salt of a compound of this invention, e.g., a sodium salt.
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • inventive compounds, salts, or solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas. Also included within the scope of this invention are prodrugs of the compounds of this invention.
  • prodrug is intended to mean a compound that is converted under physiological conditions, e.g., by solvolysis or metabolically, to a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • a prodrug may be a derivative of one of the compounds of this invention that contains, for example, a carboxylic acid ester or amide moiety or an enol- ester moiety that may be cleaved under physiological conditions.
  • a prodrug containing such a moiety may be prepared according to conventional procedures, for example, by treatment of a compound of Formula I, containing an amino, amido or hydroxyl moiety with a suitable derivatizing agent, for example, a carboxylic acid halide or acid anhydride, or by converting a compound of Formula I, containing a carboxyl moiety to an ester or amide or by converting a compound of Formula I, containing a carboxylic acid ester moiety to an enol-ester.
  • a suitable derivatizing agent for example, a carboxylic acid halide or acid anhydride
  • Prodrugs of the compounds of this invention may be determined using techniques known in the art, for example, through metabolic studies. See, e.g., "Design of Prodrugs," (H.
  • the present invention is directed to a method of inhibiting an RNA-containing virus which comprises contacting the virus with an effective amount of a compound of Formula I.
  • This invention is also directed to a method of treating infection or disease caused by an RNA-containing virus comprising administering to a subject in need thereof, an effective amount of the compound of Formula I.
  • this invention is directed to a method of inhibiting HCV activity, comprising contacting the virus with an effective amount of a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • HCV activity may be inhibited in mammalian tissue by administering to a subject in need thereof a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • a therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof is a quantity of an inventive agent that, when administered to a mammal in need thereof, is sufficient to modulate or inhibit the activity of HCV such that a disease condition which is mediated by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (IC 50 ), efficacy (EC 50 ), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (IC 50 ), efficacy (EC 50 ), and the biological half-life of the particular compound
  • disease condition and its severity e.g., the identity of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • this invention is directed to a method for inhibiting replication of hepatitis C virus comprising inhibiting replication of both positive and negative strand HCV-RNA, which method comprises contacting a cell infected with said virus with an effective amount of a compound of Formula I.
  • This invention is also directed to a method of treating infection or disease caused by hepatitis C virus comprising inhibiting replication of both positive and negative strand HCV-RNA, which method comprises administering to a subject in need thereof, an effective amount of a compound of Formula I. More specifically, this invention is directed to a method of inhibiting replication of both positive and negative strand HCV-RNA with a compound of Formula I, wherein the compounds demonstrate substantially equal inhibition of positive strand HCV-RNA replication and negative strand HCV-RNA replication.
  • the IC 50 for inhibition of positive strand HCV-RNA replication is not statistically different (less than a 2-fold difference) from the IC 50 for inhibition of negative strand HCV-RNA replication.
  • the compounds of this invention demonstrate an IC 50 for inhibition of positive strand HCV-RNA replication that is +30% the IC 50 for inhibition of negative strand HCV- RNA replication.
  • Treating is intended to mean at least the mitigation of a disease condition (acute, chronic, latent, etc.) in a subject (a mammal, such as a human), where the disease condition is caused by an infectious RNA-containing virus.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • the compounds of Formula I of this invention may be particularly useful for the treatment of acute, chronic or latent HCV diseases, such as acute and chronic hepatitis infection, hepatocellular carcinoma, liver fibrosis, or other
  • the compounds of Formula I of this invention may also be useful for treatment of diseases caused by infectious RNA-containing viruses other than HCV, including, but not limited to, Dengue, HIV or picornaviruses.
  • Chronic fatigue syndrome is another disease that may be treatable using the compounds of this invention.
  • An inventive compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be administered to a subject as a pharmaceutical composition in any pharmaceutical form that is recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
  • compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use or mode of administration.
  • Administration of a compound of the Formula I, or a tautomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be performed according to any of the generally accepted modes of administration available to those skilled in the art.
  • the compounds of this invention may be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration. For systemic administration, oral administration is preferred.
  • the compounds may be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection e.g., parenteral administration
  • the compounds of the invention may be formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds of the invention may also be formulated in liposome-containing preparations, particularly liposome-containing preparations useful for delivery of the compounds of this invention to the liver or potentially to nonhepatic reservoirs of infection.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated may be used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention may be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • compositions containing a compound of Formula I, or a tautomer thereof, or pharmaceutically acceptable salt therof, or a pharmaceutically acceptable solvate thereof, which are active when given orally may be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any routine encapsulation may be suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and may be incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt therof, or a pharmaceutically acceptable solvate thereof, which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is formulated and administered in a unit dosage form.
  • a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof).
  • the selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of HCV activity by any known or suitable method of administering the dose, including: topically, for example, as an ointment, or cream, orally, rectally, for example, as a suppository, parenterally by injection, or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
  • Treatment of all forms of infection or disease (acute, chronic, latent etc) or as prophylaxis with these compounds (or their salts etc.) may be achieved using the compounds of this invention as a monotherapy, in dual or multiple combination therapy, such as in combination with other antivirals, in combination with an interferon, in combination with an interferon and ribavirin or levovirin, or in combination with one or more agents which include but are not limited to: immunomodulatory agents (such as cytokines, suppressors of cytokines and/or cytokine signalling, or immune modifiers, adjuvants and the like), immunomodulatory agents that enhance the body's immune system (such as vitamins, nutritional supplements, antioxidant compositions, vaccines or immunostimulating complexes, such as vaccines comprising a multimeric presentation of an antigen and adjuvant), other direct antiviral agents, indirect antiviral agents or agents which target viral RNA and impair translation or replication or modulate signalling or cellular host factors, or host-viral interface, immunoglob
  • an interferon is intended to mean any form of interferon, which includes, but is not limited to, natural or recombinant forms of alpha, beta or gamma interferons, albumin-linked interferons, or pegylated interferons.
  • Representative compounds of this invention include the compouns of Examples
  • Preferred compounds of this invention include: (S)-l-benzyl-3-( 1,1 -dioxo- 1,4- dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-4-hydroxy-5-( 1 -methylpropyl)- 1 ,5-dihydropyrrol-2- one, (S)- 1 -benzyl-5-tert-butyl-3-( 1 , 1 -dioxo- 1 ,4-dihydro- l-benzo[ 1 ,2,4]thiadiazin-3-yl)-4- hydroxy- 1 ,5-dihydropyrrol-2-one, (S)- 1 -benzyl-5-tert-butyl-4-hydroxy-3-(7-hydroxy- 1,1- dioxo-1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)- 1 ,5-dihydropyrrol-2-one, (S)-4-
  • salt complexes are also included in the present invention.
  • Preferred are the ethylene diamine, sodium, potassium, calcium, ethanolamine, hydrochloride, hydrobromide, maleate and trifluoroacetate salts of the above-listed compounds.
  • This invention is also directed to methods for the synthesis of the compounds of Formula I and tautomers thereof. Included in the present invention is a process according to Scheme 1 for the synthesis of the compounds :
  • An appropriately substituted alpha-amino ester (a) with an ester substituent (R) such as methyl, ethyl, tert-butyl or an appropriate linkage to a polystyrene resin such as the Wang linker may be reductively alkylated with an appropriate aldehyde or ketone such as isovaleraldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in an appropriate solvent such as methanol, acetic acid or dichloromethane to afford the N-alkylated alpha-amino ester (c).
  • Compounds of Formula I are prepared by the coupling of N-alkylated amino esters (c) with an appropriate acid (d) such as (l,l-dioxo-l,4- dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-acetic acid, (7-methoxy- 1 , 1 -dioxo- 1 ,4-dihydro-l- benzo[l,2,4]thiadiazin-3-yl)-acetic acid or (7-hydroxy-l,l -dioxo-1, 4-dihydro-l- benzo[l,2,4]thiadiazin-3-yl)-acetic acid in the presence of an appropriate amide coupling reagent such as dicyclohexylcarbodiimide in an appropriate solvent such as dichloromethane or dimethylformamide followed by cyclization with an appropriate base such as triethylamine or potassium tert-butoxide in an appropriate solvent such as dichloromethane or 2-
  • the activity of the inventive compounds as inhibitors of HCV activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays.
  • the HCV NS5B inhibitory activity of the compounds of Formula I was determined using standard assay procedures described in Behrens et al., EMBO J. 15:12-22 (1996), Lohmann et al., Virology 249:108-118 (1998) and Ranjith- Kumar et al., J. Virology 75:8615-8623 (2001).
  • the compounds of this invention have demonstrated in vitro HCV NS5B inhibitory activity in such standard assays and have IC 50 's in the range of 0.0001 ⁇ M to 100 ⁇ M.
  • Representative compounds of Formula I, Examples 3, 7, 9, 1 1, 12, 15, 16, 18, 19, 21, 22, 25, 26, 28, 29, 34, 35, 46, 47, 49, 61, 72, 73, 78, 108, 112, 116, 117, 128, 130, 131 and 138 have all demonstrated in vitro HCV NS5B inhibitory activity and have IC 50 's in the range of 0.0005 ⁇ M to 1 ⁇ M.
  • Inhibition of recombinant purified HCV polymerase with compounds in in vitro biochemical assays may be validated using the replicon system whereby the polymerase exists within a replicase complex, associated with other viral and cellular polypeptides in appropriate stoichiometry. Demonstration of cell- based inhibition of HCV replication may be more predictive of in vivo function than demonstration of HCV NS5B inhibitory activity in in vitro biochemical assays.
  • the compounds of this invention inhibit both positive and negative strand HCV-RNA replication.
  • the following methods have been developed and used for determining the positive and negative strand HCV-RNA replication inhibition activity of the compounds of this invention.
  • Test Method 1 Method for positive strand replicon HCV-RNA detection in replicon cells
  • Buffer RLT Qiagen, Valencia, California, US
  • RNA purified according to manufacturer's recommendations Qiagen RNAeasy
  • Primers and probes specific for the positive strand RNA detection of neomycin gene were: neo-forward: 5'CCGGCTACCTGCCCATTC3' (SEQ ID NO 1); neo- reverse: 5'CCAGATCATCCTGATCGACAAG3' (SEQ ID NO 2); neo-probe: 5'FAM- ACATCGCATCGAGCGAGCACGTAC-TAMRA3' (SEQ ID NO 3).
  • the cDNA primer used was 5'ACA TGC GCG GCA TCT AGA CCG GCT ACC TGC CCA TTC3' (SEQ ID NO 4) whereby the first 18 bases represent SEQ ID NO 5 linked to neo sequences; neo-forward tag: 5'ACA TGC GCG GCA TCT AGA3' (SEQ ID NO 5); neo reverse 5'CCAGATCATCCTGATCGACAAG3' (SEQ ID NO 6); neo probe: 5'FAM-ACA TCG CAT CGA GCG AGC ACG TAC-TAMRA3' (SEQ ID NO 3).
  • Test Method 2 Method for negative strand replicon HCV-RNA detection in replicon cells To achieve strand-specific detection, a primer containing HCV RNA (or replicon
  • RNA sequences such as neomycin gene and an 18 base tag of nonrelated sequence at the 5' end was for the reverse transcription (RT) reaction,
  • neo-forward tag 5'ACA TGC GCG GCA TCT AGA3' (SEQ ID NO 5); neo reverse: 5'CCAGATCATCCTGATCGACAAG3' (SEQ ID NO 6); and neo probe: 5'FAM-ACA TCG CAT CGA GCG AGC ACG TAC-TAMRA3' (SEQ ID NO 3).
  • the title compound could be prepared according to the following method: A solution of the compound from example 1 (a) (0.052 g, 0.208 mmol) and the compound from example 1(b) (0.050 g, 0.208 mmol) in anhydrous methylene chloride (3.0 mL) and anhydrous dimethylformamide (0.5 mL) was treated with dicyclohexylcarbodiimide (1M solution in methylene chloride, 0.210 mL, 0.210 mmol). After stirring 30 min at ambient temperature, triethylamine (0.087 mL, 0.624 mmol) was added.
  • Example 11 4-[(S)-4-( 1 , 1 -Dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-3-hydroxy- 1 -(3-methyl- butyl)-5-oxo-2,5-dihydro- 1 -pyrrol-2-yl]-butyric acid During the preparation of the compound from example 10, partial hydrolysis of the methyl ester under the reaction conditions allowed the title compound to be obtained as a white solid. !
  • Example 13 6-( 1 , 1 -Dioxo- 1 ,4-dihydro-l-benzo[ 1 ,2,4]thiadiazin-3-yl)-7-hydroxy-4-(3-methyl-butyl)-4- aza-spiro[2.4]hept-6-en-5-one
  • Example 18 (S)-5-tert-butyl-4-hydroxy-3-(7-hydroxy-l, 1 -dioxo-1, 4-dihydro-l-benzo[l,2,4]thiadiazin-3- yl)- 1 -(3-methylbutyl)- 1 ,5-dihydropyrrol-2-one a) Ethyl (7-hydroxy- 1 , 1 -dioxo-1 ,4-dihydrobenzof 1 ,2,4]thiadiazin-3-yl)acetate
  • Example 21 2- ⁇ 3-[5-cyclohexyl-4-hydroxy- 1 -(3-methyl-butyl)-2-oxo-2,5-dihydro- 1 -pyrrol-3-yl]- 1, 1- dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-7-yloxy ⁇ -acetamide a) 5-cyclohexyl-4-hydroxy-3-(7-hydroxy-l,l-dioxo-l ,4-dihydro-l-benzo[l,2,4]thiadiazin-3- yl)- 1 -(3-methylbutyl)- 1 ,5-dihydropyrrol-2-one
  • Example 22 tert-butyl 3-( 1 , 1 -Dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-4-hydroxy- 1-(3- methylbutyl)-2-oxo-l,8-diaza-spiro[4.5]dec-3-ene-8-carboxylate a) 1 -tert-butyl 4-(3-methylbutylamino)-piperidine-l ,4-dicarboxylate
  • Example 24 8-acetyl-3-( 1 , 1 -Dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-y l)-4-hydroxy- 1 -(3- methylbutyl)-l,8-diaza-spiro[4.5]dec-3-en-2-one
  • Example 26 2- ⁇ 3-[(S)-4-Hydroxy-5-methy 1- 1 -(3-methylbutyl)-5-( 1 -methylethy l)-2-oxo-2,5-dihydro- 1 H- pyrrol-3-yl]-l , 1 -dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-7-yloxy ⁇ -acetamide
  • Example 30 1 -benzyl-3-( 1 , 1 -dioxo- 1 ,4-dihydro-l -benzofl ,2,4]thiadiazin-3-yl)-4-hydroxy-5-(pyridin-2- yl)- 1 ,5-dihydropyrrol-2-one a) methyl 2-(benzyl)amino-2-(pyridin-2-yl)acetate A solution of methyl 2-bromo-2-(pyridin-2-yl)acetate (prepared by the method of
  • Example 35 2- ⁇ 3-[(S)-(5-tert-butyl-l-(3,3-dimethylbutyl)-4-Hydroxy-2-oxo-2,5-dihydro-lH-pyrrol-3- yl]-l , 1 -dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-7-yloxy ⁇ -acetamide Following the procedure of example 19, except substituting the compound from example 34 for the compound from example 18, the title compound was obtained as a white solid.
  • Example 36 2-[3-( 1 -benzyl-4-Hydroxy-5-methyl-2-oxo-5-(pyridin-2-yl)-2,5-dihydro- 1 H-pyrrol-3-yl)- 1 , 1-dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-7-yloxy]-acetamide a) 2-(benzyl)amino-2-(pyridin-2-yl)propanenitrile
  • Example 37 1 -benzyl-3-( 1 , 1 -dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-4-hydroxy-5-(pyridin-3- yl)-l ,5-dihydropyrrol-2-one Following the procedures of examples 30(a) and 30(b), except substituting methyl
  • Example 38 2-[3-( 1 -benzyl-4-Hydroxy-2-oxo-5-(pyridin-2-yl)-2,5-dihydro- 1 H-pyrrol-3-yl)-l , 1 -dioxo- 1 ,4-dihydro-l -benzof 1 ,2,4]thiadiazin-7-yloxy]-acetamide a) 1 -benzyl-3-(7 -hydroxy- 1 , 1 -dioxo- 1 ,4-dihydro- 1 -benzof 1 ,2,4]thiadiazin-3-yl)-4-hydroxy- 5-(pyridin-2-yl)- 1 ,5-dihydropyrrol-2-one
  • Examples 39- 166 The title compounds were prepared as part of a solid-phase array according to the following general procedure: a) To the appropriate Fmoc-protected alpha-amino acid on Wang resin (-0.1 g., 150-300 ⁇ m bead diameter) was added 20% piperidine/dimethylformamide solution (1 .5 mL). The slurry was orbitally mixed at ambient temperature for 30 min and filtered. The resin was washed with dimethylformamide, methanol, methylene chloride, and methanol (3 x 2-3 mL each). The resin was dried in vacuo.
  • the reaction was vigorously mixed for an additional 3 h at ambient temperature and filtered.
  • the resin was washed with dimethylformamide, methanol, 10% triethylamine/methylene chloride, methanol, methylene chloride, methanol, and diethyl ether (3 x 2-3 mL each).
  • the resin was dried in vacuo.

Abstract

Cette invention concerne des composés utiles comme anti-infectieux contre le virus de l'hépatite C, ainsi que des méthodes de fabrication et d'utilisation de ces composés.
PCT/US2003/016374 2002-05-24 2003-05-23 Nouveaux anti-infectieux WO2003099801A1 (fr)

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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
WO2011058084A1 (fr) 2009-11-14 2011-05-19 F. Hoffmann-La Roche Ag Marqueurs biologiques destinés à prédire une réaction rapide au traitement du virus de l'hépatite c (hcv)
WO2011061243A1 (fr) 2009-11-21 2011-05-26 F. Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2011067195A1 (fr) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarqueurs pour prédire une réponse soutenue à un traitement du vhc
EP2361922A1 (fr) 2006-10-10 2011-08-31 Medivir AB Intermediaire pour la synthèse d'inhibiteurs nucleosidique du HCV
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EP2361922A1 (fr) 2006-10-10 2011-08-31 Medivir AB Intermediaire pour la synthèse d'inhibiteurs nucleosidique du HCV
JP2010537986A (ja) * 2007-08-31 2010-12-09 イデニク プハルマセウティカルス，インコーポレイテッド ホスファジアジンｈｃｖポリメラーゼ阻害剤ｉｖ
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