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WO2009000818A1 - Acides 3-carbonylaminothiophène-2-carboxyliques en tant qu'inhibiteurs du virus de l'hépatite c - Google Patents

Acides 3-carbonylaminothiophène-2-carboxyliques en tant qu'inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2009000818A1
WO2009000818A1 PCT/EP2008/057984 EP2008057984W WO2009000818A1 WO 2009000818 A1 WO2009000818 A1 WO 2009000818A1 EP 2008057984 W EP2008057984 W EP 2008057984W WO 2009000818 A1 WO2009000818 A1 WO 2009000818A1
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compound
optionally substituted
formula
amino
pyrazolo
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David Harrison
Charles David Hartley
Jacqueline Elizabeth Mordaunt
Martin John Slater
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings

Definitions

  • the present invention relates to novel 2-carboxy thiophene derivatives useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication.
  • HCV Hepatitis C Virus
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year 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, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S).
  • HCV post-transfusion non A, non-B hepatitis
  • NANBH non-B hepatitis
  • this virus was assigned as a new genus in the Flaviviridae family.
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • 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 CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' 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
  • this RNA Upon entry into the cytoplasm of the cell, this 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 2 nd Edition, p931-960; Raven Press, N.Y.).
  • 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 which 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.
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1 a and 1 b isolates).
  • the essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051 ).
  • inhibition of NS5B RdRp activity is predicted to be useful to treat HCV infection.
  • genotype 1 Although the predominant HCV genotype worldwide is genotype 1 , this itself has two main subtypes, denoted 1a and 1 b. As seen from entries into the Los Alamos HCV database
  • genotype 1 a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1 b.
  • X is chosen from -N(R J )M(Fr) or -JN(FT)(R 3 ⁇ ).
  • M is chosen from -SO 2 -, -SO-, -S-, -C(O)-, -C(S)-, -CH 2 C(O)N(R 4 )-, -CH 2 C(S)N(R 15 )-, -
  • R 4 is Ci -6 alkyl
  • R 8 is chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6 -i 4 aryl, C 3-12 heterocycle, C 3- i 2 heteroaralkyl, C 6- i 6 aralkyl;
  • R 15 is chosen from H or Ci -6 alkyl
  • J is chosen from -C(W)-, -C(R 6 )-, -S-, -S(O)-, or -SO 2 -;
  • W is chosen from O, S or NR 7 ;
  • R 7 is chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6 -i 4 aryl, C 3- i 2 heterocycle, C 3-
  • R 6 is chosen from H, Ci_i 2 alkyl, C 6 -i 4 aryl, or C 6- i 6 aralkyl;
  • Y 1 is chosen from a bond, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
  • Y is chosen from COOR 16 , COCOOR 5 , P(0)0ROR b , S(O)OR 5 , S(O) 2 OR 5 , tetrazole,
  • R , R ,R 5 10 and R are each independently chosen from H, C 2- i 2 alkenyl, C 2- 12 alkynyl, C 3-12 heterocycle, C 3-18 heteroaralkyl, C 6- i 8 aralkyl; or R 10 and R 11 are taken together with the nitrogen to form a 3 to 10 membered heterocycle;
  • R a and R b are each independently chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6- 14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, C 6- i 8 aralkyl; or R a and R b are taken together with the oxygens to form a 5 to 10 membered heterocycle;
  • R 16 is chosen from H, Ci.-i 2 al
  • R 2 is chosen from C 1-12 alkyl, C 2- i 2 alkynyl, C 6- i 4 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, C 6- i ⁇ aralkyl;
  • R 3 is chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6 -i 4 aryl, C 3- i 2 heterocycle, C 3- 18 heteroaralkyl, C 6- i 8 aralkyl; Z is chosen from H, halogen, or C h alky!.
  • the present invention involves novel 2-carboxy thiophene compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides a compound of Formula (I) :
  • A represents hydroxy
  • R 1 represents -R x R y ;
  • R :>X represents phenyl (optionally substituted at one of the mef ⁇ -positions to the thiophene by chloro, fluoro, methyl, ethyl, -CF 3 , -OMe, -NH 2 or -OH); thienyl (optionally substituted by chloro, fluoro, methyl, ethyl, -CF 3 or -OMe) bonded through a ring carbon atom to the carbon atom of the thiophene; or pyridyl wherein the N atom is positioned at the mef ⁇ -position to the thiophene (optionally substituted at the other mef ⁇ -position to the thiophene by chloro, fluoro, methyl, ethyl, -CF 3 , -OMe, -NH 2 or -OH);
  • R ⁇ represents optionally substituted 8-, 9- or 10-membered bicyclic heteroaryl, bonded such tthhaatt wwhheenn I
  • R x is phenyl or pyridyl, the R ⁇ group is attached to R x in the para-position to the thiophene;
  • R 2 represents -C 5-7 cycloalkyl (optionally substituted by one or more substituents independently selected from -C 1-2 alkyl (optionally substituted with one or more fluoro substituents), and -OH) or C 6 cycloalkenyl;
  • R 3 represents linear or branched -C 2-6 alkyl substituted by one or more fluoro substituents, or -(CH 2 ) m C 3- 6cycloalkyl substituted by one or more fluoro substituents;
  • n 0 or 1 ;
  • the compounds of the present invention exhibit improved potency against the replication of HCV (1a and 1 b genotypes), and therefore have the potential to achieve greater efficacy in man. High potency in both genotypes is considered to be advantageous.
  • a compound chosen from compounds of Formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly flavivirus infection, for example HCV infection.
  • references herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a method for the treatment of a human or animal subject with viral infection, particularly HCV infection comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention.
  • R x represents unsubstituted phenyl or unsubstituted thienyl.
  • R ⁇ represents optionally substituted 8- or 9-membered bicyclic heteroaryl.
  • R ⁇ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo[2,1-b][1 ,3]thiazol-6-yl, 7-amino-5-methylpyrazolo[1 ,5- a]pyrimidin-2-yl, 5-methylpyrazolo-[1 ,5-a]pyrimidin-2-yl, 7-aminopyrazolo[1 ,5-a]pyrimidin-2-yl, [1 ,3]oxazolo[4,5-b]pyridin-2-yl, furo[2,3-b]pyridin-5-yl, 5-amino-1 ,3-benzoxazol-2-yl, [1 ,3
  • R ⁇ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo[2,1-b][1 ,3]thiazol-6-yl or 7-aminopyrazolo[1 ,5-a]pyrimidin- 2-yl, all of which may be optionally substituted.
  • R ⁇ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl or imidazo[1 ,2-a]pyridin-2-yl, all of which may be optionally substituted.
  • R ⁇ represents optionally substituted pyrazolo[1 ,5-a]pyrimidinyl.
  • R ⁇ represents unsubstituted pyrazolo[1 ,5-a]pyrimidinyl.
  • R 2 represents C 6 cycloalkyl (optionally substituted by one or more substituents selected from -Ci -2 alkyl optionally substituted with one or more fluoro groups) or cyclohex-3- en-1-yl.
  • R 2 represents -C 6 cycloalkyl (optionally substituted by methyl or trifluoromethyl).
  • R 2 represents frans-4-methylcyclohexyl.
  • R 3 represents -CH 2 CHF 2 or -CH 2 CF 3 .
  • R x represents unsubstituted phenyl or unsubstituted thienyl;
  • R ⁇ represents optionally substituted 8- or 9-membered bicyclic heteroaryl group;
  • R 2 represents - C 6 cycloalkyl (optionally substituted by one or more substituents selected from -Ci -2 alkyl ooppttiioonnaallllyy substituted with one or more fluoro groups); and
  • R 3 represents -CH 2 CHF 2 or- CH 2 CF 3 .
  • R x represents unsubstituted phenyl or unsubstituted thienyl
  • R ⁇ represents unsubstituted pyrazolo[1 ,5-a]pyrimidinyl
  • R 2 represents frans-4-methylcyclohexyl
  • R 3 represents -CH 2 CHF 2 or -CH 2 CF 3 .
  • acetyl refers to -C(O)CH 3 .
  • alkyl' refers to a linear or branched saturated hydrocarbon group having the stated number of carbon atoms.
  • 'Ci-salkyl' has from 1 to 6 carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • alkyl moieties are -C 1-4 alkyl.
  • 'alkenyl' refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and having the stated number of carbon atoms.
  • 'C 2-6 alkenyr has from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • 'alkynyl' refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and having the stated number of carbon atoms.
  • 'C 2-6 alkenyr has from 2 to 6 carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.
  • 'cycloalkyl' refers to a saturated monocyclic hydrocarbon ring having the stated number of carbon atoms.
  • 'C 3- ⁇ cycloalkyl' has from 3 to 8 carbon atoms.
  • examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • 'cycloalkenyl' refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms containing one or more carbon-carbon double bonds and having the stated number of carbon atoms.
  • 'Cs-scycloalkyl' has from 3 to 8 carbon atoms. Examples of such groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • alkoxy' refers to an -O-alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • 'aryl' refers to a C 6- i 2 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like. In one aspect, 'aryl' moieties contain 6-10 carbon atoms. In one aspect, 'aryl' moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • the aryl group may be substituted by one or more optional substituents independently selected from the group consisting of -Ci -6 alkyl unsubstituted), halo, -OR E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , - NR A C(O)R°, -NR A CO 2 R°, -NR A C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, optionally substituted heterocyclyl, -CF 3 , -OCF 3 and optionally substituted phenyl, wherein R A -R G are as defined below.
  • the 'aryl' group may be substituted by -C 1-6 alkyl (unsubstituted), halo, -0R E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , - NR A C(0)R°, -NR A C0 2 R°, -NR A C(0)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl (unsubstituted), -CF 3 , -OCF 3 and phenyl (unsubstituted), wherein R A -R G are as defined below.
  • the 'aryl' group is unsubstituted.
  • 'carbonyl' refers to -C(O)-.
  • 'cyano' refers to -CN.
  • 'halogen', hal or 'halo' refer to a fluorine, chlorine, bromine or iodine atom. References to 'fluoro', 'chloro', 'bromo' or 'iodo' should be construed accordingly.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • 'bicyclic heteroaryl' refers to a fused 8-10 membered bicyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • heteroaryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted (where applicable) pyridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, pyrimidine, pyridazine, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, benzotriazole, furopyridine, furopyrimidine, furopyridazine, furopyrazine, furotriazine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, pyrrolopyra
  • Each heteroaryl group may be attached at any ring carbon or may be attached through nitrogen when the nitrogen is part of a 5-membered ring.
  • 'heteroaryl' substituents including 'bicyclic heteroaryl' substituents, are independently selected from the group consisting of -C ⁇ alkyl (unsubstituted), halo, -OR E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 R 0 , - NR B R C , -NR A C(O)R°, -NR A CO 2 R D , -NR A C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, optionally substituted heterocyclyl, -CF 3 and optionally substituted
  • 'heteroaryl' subsituents including 'bicyclic heteroaryl' substituents are independently selected from the group consisting of -C 1-6 alkyl (unsubstituted), halo, -OR E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 R 0 , -NR B R C , -NR A C(O)R°, - NR A CO 2 R°, -NR A C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, heterocyclyl (unsubstituted), -CF 3 and phenyl (unsubstituted), wherein R A -R G are as defined below.
  • 'heteroaryl' including 'bicyclic heteroaryl' is unsubstituted.
  • heterocyclyl refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring, each of which may be saturated or partially unsaturated containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, wherein N atoms may be optionally substituted by hydrogen, -C 1-6 alkyl, -C(O)R 0 , -C(O)NR B R C , -C(O)OH, -SO 2 R 0 , aryl or heteroaryl and S atoms may be optionally substituted by one or two oxygen atoms.
  • Ring carbon atoms may be optionally substituted by -Ci -6 alkyl, -OR A , -C(O)R 0 , or -SO 2 R 0 .
  • monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetra
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1 H-3-benzazepine, tetrahydroisoquinolinyl and the like.
  • the term 'heterocyclyl' refers to a 4-7 membered monocyclic ring or a fused 8- 12 membered bicyclic ring, each of which may be saturated or partially unsaturated containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, wherein N atoms may be optionally substituted by hydrogen, -C 1-6 alkyl (unsubstituted), -C(O)R 0 , -C(O)NR B R C , -C(O)OH, -SO 2 R 0 , aryl (unsubstituted) or heteroaryl (unsubstituted) and S atoms may be optionally substituted by one or two oxygen atoms.
  • Ring carbon atoms may be optionally substituted by -C 1-6 alkyl (unsubstituted), -OR A , -C(O)R 0 , or -SO 2 R 0 .
  • monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidiny
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and the like.
  • 'nitro' refers to -NO 2 .
  • 'Et' refers to 'ethyl'
  • 'iPr' refers to 'isopropyl'
  • 'Me' refers to 'methyl'
  • 'OBn' refers to 'benzyloxy'
  • 'Ph' refers to 'phenyl'.
  • R A is selected from the group consisting of hydrogen or optionally substituted -C 1-6 alkyl. In one aspect, R A is selected from the group consisting of hydrogen or -C h alky!.
  • R B and R c are independently selected from the group consisting of hydrogen and -C 1-6 alkyl, aryl, heterocyclyl and heteroaryl, all of which may be optionally substituted; or R B and R c together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group, for example piperidine, piperazine, morpholine or pyrrolidine.
  • R B and R c are independently selected from the group consisting of hydrogen and - Ci -6 alkyl, aryl, heterocyclyl and heteroaryl; or R B and R c together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group, for example piperidine, piperazine, morpholine or pyrrolidine.
  • R D is selected from the group consisting of -C 1-6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl, all of which may be optionally substituted. In one, aspect R D is selected from the group consisting of -Ci -6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • R E is selected from the group consisting of hydrogen, -Ci -6 alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl and heteroaryl, all of which may be optionally substituted. In one aspect, R E is selected from the group consisting of hydrogen, -d- ⁇ alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl and heteroaryl.
  • R F and R G are independently selected from the group consisting of hydrogen and -Ci- ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, all of which may be optionally substituted; or
  • R F and R G together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated cyclic group.
  • R F and R G are independently selected from the group consisting of hydrogen and -Ci -6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group.
  • the present invention provides a compound chosen from the group consisting of:
  • Suitable pharmaceutically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluen
  • the present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
  • the present invention also relates to solvates of the salts of compounds of the Formula (I).
  • Solvates of the compounds of Formula (I) and solvates of the salts of the compounds of Formula (I) are included within the scope of the present invention.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • the solvent used is water and the solvate may also be referred to as a hydrate.
  • Solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the solvent is pharmaceutically acceptable.
  • solvates having non- pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
  • the present invention also relates to esters of the compounds of Formula (I). Esters of the compounds of Formula (I) are included within the scope of the present invention.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of
  • any alkyl moiety present in such esters suitably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety present in such esters suitably comprises a phenyl group.
  • the term "pharmaceutically acceptable” used in relation to an ingredient (active ingredient such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • A is a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy group and R 1 , R 2 , and R 3 are as defined above for Formula (I).
  • R 1 , R 2 , and R 3 are as defined above for Formula (I)
  • an appropriate base for example aqueous sodium hydroxide or lithium hydroxide, optionally in a solvent such as methanol, ethanol, tetrahydrofuran or combinations thereof.
  • the temperature is in the range 20 to 100 0 C.
  • A is te/t-butoxy
  • R 1 , R 2 and R 3 are as defined above for Formula (I)
  • an appropriate acid for example trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 0 to 50 0 C, for example 15 to 30 0 C.
  • A is silyloxy
  • R 1 , R 2 and R 3 are as defined above for Formula (I)
  • a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • the temperature is in the range 0 to 50 0 C, for example 15 to 30 0 C.
  • A is hydroxy or an alkoxy, benzyloxy or silyloxy group, R 2 and R 3 are as defined above for Formula (I), and X is a halogen such as bromide or iodide; with a suitable boronic acid R 1 -B(OH) 2 or boronate ester R 1 -B(OR')(OR"), in which R 1 is as defined above for Formula (I) and R' and R" are independently C 1-6 alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by Ci -6 alkyl, such as a pinacol ester, in the presence of a palladium catalyst such as tetrakistriphenyl phosphine palladium(O) or bis-[(diphenylphosphino)-ferrocene]-palladium(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF,
  • A is hydroxy or an alkoxy, benzyloxy or silyloxy group
  • R 2 and R 3 are as defined above for Formula (I)
  • X is a suitable boronic acid -B(OH) 2 or boronate ester -
  • R' and R" are independently C 1-6 alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by Ci -6 alkyl, such as a pinacol ester, with R 1 -Hal wherein R 1 is as defined above for Formula (I) and Hal is a halogen such as bromide or iodide, in the presence of a palladium catalyst such as tetrakistriphenyl phosphine palladium(O) or bis-[(diphenylphosphino)-ferrocene]-palladium(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, dioxane or dimethyoxyethane, or combinations thereof, optionally in the presence of water, at a temperature in the range 50-100 0 C, optionally under an inert atmosphere.
  • a palladium catalyst such as tetrakistripheny
  • A is an alkoxy, benzyloxy or silyloxy, and R 2 and R 3 are as defined above for Formula (I)
  • a suitable base such as lithium diisopropylamide and a halogen source such as iodine in a suitable solvent such as tetrahydrofuran, heptane, ethylbenzene or combinations thereof and at a temperature in the range -78°C to -20 0 C.
  • A is an alkoxy, benzyloxy or silyloxy, and R 2 and R 3 are as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a boronate such as B(OR) 3 wherein R is an alkyl group, for example methyl, in a suitable solvent such as tetrahydrofuran, heptane, ethylbenzene or combinations thereof, and at a temperature in the range -78°C to -20 0 C.
  • a suitable base such as lithium diisopropylamide and a boronate such as B(OR) 3 wherein R is an alkyl group, for example methyl
  • a suitable solvent such as tetrahydrofuran, heptane, ethylbenzene or combinations thereof, and at a temperature in the range -78°C to -20 0 C.
  • Compounds of Formula (III) in which A is hydroxy, R 2 and R 3 are as defined above for Formula (I), and X is a halogen such as bromide or iodide may be prepared from compounds of Formula (III) in which A is an alkoxy, benyloxy or silyloxy group, R 2 and R 3 are as defined above for Formula (I), and X is a halogen such as bromide or iodide, for example by treatment with an appropriate base, acid or fluoride source as described in relation to the preparation of compounds of Formula (I) from compounds of Formula (II).
  • a an alkoxy, benzyloxy or silyloxy group, and R 3 is as defined above for Formula (I), with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane or dichloroethane, and optionally in the presence of a suitable base, for example pyridine or triethylamine.
  • the reaction may be carried out at a suitable temperature, for example in the range 20 0 C to 80 0 C and optionally under an inert atmosphere.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • a an alkoxy, benzyloxy or silyloxy group by treatment with a suitable vinyl ether, or a suitable aldehyde or a suitable ketone in the presence of a suitable acid, such as acetic acid, and a suitable reducing agent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane.
  • a suitable acid such as acetic acid
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • compounds of Formula (V), in which A is an alkoxy, benzyloxy or silyloxy group and R 3 is as defined above for Formula (I) may be prepared from compounds of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy are as defined above for Formula (I), by treatment with a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulfonate or trifluoromethanesulphonate, in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulfonate or trifluoromethan
  • R 3 is a suitable alkylating agent R 3 -X' in which X' is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate or trifluoromethanesulphonate, and R 3 is as defined above for Formula (I), in a suitable solvent such as dimethylformamide, in the presence of a suitable base such as sodium hydride optionally in the presence of triethylamine.
  • Compounds of Formula (VIII), in which A is an alkoxy, benzyloxy or silyloxy group and R 2 is as defined above for Formula (I), may be prepared by reaction of a compound of Formula (Vl) in which A an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, optionally in the presence of a suitable base, for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • a an alkoxy, benzyloxy or silyloxy group, and R 1 and R 3 are as defined above for Formula (I), with a suitable acylating agent, for example R 2 -C(0)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane or dichloroethane, optionally in the presence of a suitable base, for example pyridine or triethylamine.
  • the reaction may be carried out at a suitable temperature, for example in the range 20 0 C to 100 0 C.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • Compounds of Formula (IX) in which A is an alkoxy, benzyloxy or silyloxy group and R 1 and R 3 are as defined above for Formula (I), may also be prepared by reaction of a compound of Formula (X)
  • X is a halogen such as bromide or iodide
  • A is an alkoxy, benzyloxy or silyloxy group and R 3 is as defined above for Formula (I)
  • a suitable boronic acid R 1 -B(OH) 2 or boronate ester R 1 -B(OR')(OR"), in which R' and R" are independently C 1-6 alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by Ci -6 alkyl, such as a pinacol ester, in the presence of a palladium catalyst such as tetrakistriphenyl phosphine palladium(O) or bis-[(diphenylphosphino)-ferrocene]-palladium(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, dioxane or dimethyoxyethane, or combinations thereof
  • A is an alkoxy, benzyloxy or silyloxy group and X is a halogen such as bromide or iodide
  • X is a halogen such as bromide or iodide
  • compounds of Formula (X), in which A is an alkoxy, benzyloxy or silyloxy group and X is a halogen such as bromide or iodide may be prepared from compounds of Formula (Xl) in which A is an alkoxy, benzyloxy or silyloxy, and X is a halogen such as bromide or iodide, by treatment with a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulfonate or trifluoromethanesulphonate, and R 3 is as defined above for Formula (I), in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • Compounds of Formula (X) in which A is an alkoxy, benzyloxy or silyloxy group, R 3 is as defined above for Formula (I) and X is a halogen such as bromide or iodide may be prepared by reaction of a compound of Formula (Xl)' wherein P is -COCF 3 or -CO 2 1 Bu and R 3 is as defined above for Formula (I), by treatment with a halogen source, for example iodine, in a suitable solvent such as THF, heptane, ethylbenzene, or combinations thereof, in the presence of a suitable base such as LDA, at a suitable temperature for example -78 to -20 0 C, optionally in an inert atmosphere, and thereafter removing the protecting group P, for example with hydrochloric acid when P is CO 2 1 Bu or with aqueous sodium carbonate solution when P is COCF 3 .
  • a halogen source for example iodine
  • a suitable solvent such
  • Compounds of Formula (Xl)' in which P is C0 2 tBu and R 3 is as defined above for Formula (I), may be prepared from a compound of Formula (V), by treatment with di-tert-butyl dicarbonate in a suitable solvent such as ether, acetonitrile or acetone, optionally in the presence of a catalyst such as DMAP and a base such as triethylamine.
  • P is a suitable protecting group such as -COCF 3 or -CO 2 1 Bu and P' is hydrogen or a suitable protecting group such as -CO 2 1 Bu.
  • a suitable base such as aqueous potassium carbonate optionally in the presence of an alcohol such as methanol
  • a suitable acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as dioxane or dichloromethane.
  • A is an alkoxy, benzyloxy or silyloxy group
  • P is a suitable protecting group such as -COCF 3 and P' is hydrogen
  • P is -CO 2 1 Bu and P' is hydrogen or -CO 2 1 Bu
  • a suitable base such as lithium diisopropylamide and a halogen source such as iodine
  • a suitable solvent such as tetrahydrofuran
  • Compounds of Formula (XIII), in which A is an alkoxy, benzyloxy or silyloxy group and P and P' are as described above for Formula (XII), may be prepared by treating compounds of Formula (Vl) with trifluoroacetic anhydride or di-tert-butyl dicarbonate in a suitable solvent such as ether, acetonitrile or acetone, optionally in the presence of a catalyst such as DMAP and a base such as triethylamine.
  • a suitable solvent such as ether, acetonitrile or acetone
  • A is an alkoxy, benzyloxy or silyloxy group
  • X is a halogen such as bromide or iodide
  • Rw is -CF 3 , -CF 2 H or -CH 2 F
  • a reducing agent such as sodium borohydride in the presence of an acid such as acetic acid, in a suitable solvent such as dioxane and at a temperature in the range 0-25 0 C.
  • A is an alkoxy, benzyloxy or silyloxy group
  • X is a halogen such as bromide or iodide
  • Rw is -CF 3 , -CF 2 H or -CH 2 F
  • a reducing agent such as sodium borohydride in the presence of an acid such as acetic acid, in a suitable solvent such as dioxane and at a temperature in the range 0-25°C.
  • A is an alkoxy, benzyloxy or silyloxy
  • R 1 and R 2 are as defined above for Formula (I)
  • a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulfonate or trifluoromethylsulphonate, and R 3 is as defined above for Formula (I), in a suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine or sodium hydride or combinations thereof.
  • A is an alkoxy, benzyloxy or silyloxy
  • R 2 is as defined above for Formula (I) and X is a halogen such as bromide or iodide
  • a suitable boronic acid R 1 -B(OH) 2 or boronate ester R 1 -B(OR')(OR")
  • R' and R" are independently C 1-6 alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by C 1-6 alkyl, such as a pinacol ester
  • a palladium catalyst such as tetrakistriphenyl phosphine palladium(O) or bis-[(diphenylphosphino)-ferrocene]-palladium(ll) chloride
  • a suitable base such as sodium carbonate
  • a suitable solvent such as DMF, dioxane or dimethyoxyethane, or combinations
  • Compounds of Formula (XVI), in which A is an alkoxy, benzyloxy or silyloxy group, R 2 is as defined above for Formula (I) and X is a halogen such as bromide or iodide, may be prepared from compounds of Formula (Xl) in which A is an alkoxy, benzyloxy or silyloxy, and X is a halogen such as bromide or iodide, by treatment with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable acylating agent for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane or dichloroethane, optionally in the presence of a suitable base, for example pyridine or triethylamine.
  • a suitable base for example pyridine or triethylamine.
  • the reaction may be carried out at a suitable temperature, for example in the range 20 0 C to 100 0 C.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • A is an alkoxy, benzyloxy or silyloxy
  • X is a halogen such as bromide or iodide
  • R 2 is as defined above for Formula (I)
  • a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulphonate or trifluoromethanesulphonate, and R 3 is as defined above for Formula (I), in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine or sodium hydride or combinations thereof.
  • Compounds of Formula (III) in which A is an alkoxy, benzyloxy or silyloxy group, X is a halogen such as bromide or iodide and R 2 and R 3 are as defined above for Formula (I), may also be prepared by reaction of a compound of Formula (X), in which A an alkoxy, benzyloxy or silyloxy group, R 3 is as defined above for Formula (I) and X is a halogen such as bromide or iodide, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable acylating agent for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a suitable base for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • Compounds of Formula (X), in which A is an alkoxy, benzyloxy or silyloxy group, R 3 is as defined above and X is a suitable halogen such as bromide or iodide, may also be prepared by reaction of a compound of Formula (V) in which A an alkoxy, benzyloxy or silyloxy group, and R 3 is as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a halogen source such as iodine in a suitable solvent such as tetrahydrofuran, heptane, ethylbenzene or mixtures thereof and at a temperature in the range -78°C to -20 0 C.
  • a suitable base such as lithium diisopropylamide
  • a halogen source such as iodine
  • a suitable solvent such as tetrahydrofuran, heptane, ethylbenzene or mixtures
  • Ci -6 alkyl such as a pinacol ester
  • a suitable acylating agent for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • a an alkoxy, benzyloxy or silyloxy group, and R 3 is as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a boronate source such as B(OR) 3 wherein R is an alkyl group, for example methyl, in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78°C to -20 0 C.
  • Compounds of Formula (I) in which A is hydroxy, or compounds of Formula (II) in which A is an alkoxy, benzyloxy or silyloxy group, and R 1 , R 2 and R 3 are as defined above for Formula (I), may be prepared by reaction of a compound of Formula (II)' in which Z represents a halo substituent, and R x , R 2 , R 3 , and A are as defined for Formula (II), by reaction with a suitable heteroaryl boronic acid R ⁇ -boronic acid wherein R ⁇ is as defined above for Formula (I), in the presence of a palladium catalyst such as palladium (II) acetate, a reagent such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl, and an additional reagent such as caesium fluoride, in a suitable solvent such as dioxane.
  • a palladium catalyst such as pal
  • Z represents B(OH) 2 , and R x , R 2 , R 3 and A are as defined for Formula (II), by reaction with a suitable heteroaryl halide R ⁇ -hal, in which suitably the halide is bromo or iodo, in the presence of a palladium catalyst such as palladium (II) acetate, a reagent such as 2- dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl, and an additional reagent such as caesium fluoride, in a suitable solvent such as dioxane.
  • a suitable heteroaryl halide R ⁇ -hal in which suitably the halide is bromo or iodo
  • a palladium catalyst such as palladium (II) acetate
  • a reagent such as 2- dicyclohexylphosphino-2'(N,N-dimethylamino)-b
  • Compounds of Formula (II)' in which Z is halo and R x , R 2 , R 3 and A are as defined for Formula (II), may be prepared by reaction of a compound of Formula (III) wherein A is an alkoxy, benzyloxy or silyloxy group, R 2 and R 3 are as defined above for Formula (I), and X is halo such as bromo or iodo, with a boronic acid of Formula Z-R x -boronic acid wherein Z is halo and R x is as defined above for Formula (I) under the conditions described above for the preparation of compounds of Formula (I) and (II) from compounds of Formula (III) and R ⁇ -R x - boronic acid.
  • Compounds of Formula (II)', in which Z is -B(OH) 2 may be prepared by reaction of a compound of Formula (III), in which A is an alkoxy, benzyloxy or silyloxy group, R 2 and R 3 are as defined above for Formula (I) and X is halo such as bromo or iodo, with a compound of Formula Z-R X -B(OH) 2 , wherein R x is as described above for Formula (I) and Z is -B(OH) 2 , under the conditions described above for the preparation of compounds of Formula (I) and (II) from (III) and R 1 -boronic acid.
  • a compound of Formula (III) in which A is an alkoxy, benzyloxy or silyloxy group, R 2 and R 3 are as defined above for Formula (I) and X is halo such as bromo or iodo
  • R 1 represents a 4-ethynylphenyl derivative
  • R 2 , R 3 and A are as defined above for Formula (II)
  • a suitable pyridine the pyridine being substituted with adjacent hydroxy and iodo groups
  • a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide
  • a suitable solvent such as triethylamine or DMF.
  • the temperature is in the range 50-80 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(pyrrolopyridine)phenyl and R 2 , R 3 and A are as defined above for Formula (II), may be prepared by treatment of a compound of Formula (II)" in which R 1 represents 4-ethynylphenyl and R 2 , R 3 and A are as defined above for Formula (II) with an appropriate pyridine (the pyridine being substituted by adjacent amino and iodo groups), in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, in a suitable solvent such as triethylamine.
  • a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide
  • a suitable solvent such as triethylamine.
  • the temperature is in the range 50-80 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 5-(pyrazolopyrimidine)-2-thienyl and R 2 , R 3 and A are as defined above for Formula (II), may be prepared by treating a compound of Formula (II)" in which R 1 represents 3-(thienyl)-1 H-pyrazole-5-amine and R 2 , R 3 and A are as defined above for Formula (II) with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid; suitably the temperature is in the range 90-110 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(pyrazolopyrimidine)phenyl and R 2 , R 3 and A are as defined above for Formula (II), may be prepared by treating a compound of Formula (II)" in which R 1 represents 4-(phenyl)-1 H-pyrazole-5-amine and R 2 , R 3 and A are as defined above for Formula (II) with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid; suitably the temperature is in the range 90-1 10 0 C.
  • a 2-(4-bromophenyl)imidazo[1 ,2-a]pyridine derivative may be prepared by analogy to methods described in Tetrahedron Letters (2001 ) 42, 3077.
  • a 4-(furopyridine)phenyl bromide may be prepared by treatment of a 4-ethynylphenyl bromide with a suitable pyridine (the pyridine being substituted with adjacent hydroxy and iodo groups), with a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, in a suitable solvent such as triethylamine or DMF.
  • a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide
  • a suitable solvent such as triethylamine or DMF.
  • the temperature is in the range 50-80°C.
  • a 4-(pyrazolopyrimidine)phenyl bromide may be prepared by treating a 3-(4-bromophenyl)- 1 H-pyrazole-5-amine with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-110 0 C.
  • a 2-(5-bromo-2-thienyl)pyrazolo[1 ,5-a]pyrimidine may be prepared by treating a 3-(5-bromo- 2-thienyl)-1 H-pyrazol-5-amine with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-1 10°C.
  • Esters of compounds of Formula (I), in which A is -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl may also be prepared by esterification of a compound of Formula (I) in which A is hydroxy by standard literature procedures for esterification.
  • compounds of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and (XVI) which exist as diastereoisomers may optionally be separated by techniques well known in the art, for example by column chromatography or recrystallisation. For example, the formation of an ester using a chiral alcohol, separation of the resulting diastereoisomers, and subsequent hydrolysis of the ester to yield the individual enantiomeric acid of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and (XVI).
  • racemic compounds of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and (XVI) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and (XVI) may be resolved by chiral preparative HPLC.
  • racemic compounds of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and (XVI) which contain an appropriate acidic or basic group, such as a carboxylic acid group or amine group may be resolved by standard diastereoisomeric salt formation with a chiral base or acid reagent respectively as appropriate. Such techniques are well established in the art.
  • a racemic compound may be resolved by treatment with a chiral acid such as (R)-(-)-1 ,1 '- binaphthyl-2,2'-diyl-hydrogen phosphate or (-)-di-O,O'-p-tolyl-L-tartaric acid, in a suitable solvent, for example isopropanol.
  • a suitable solvent for example isopropanol.
  • the free enantiomer may then be obtained by treating the salt with a suitable base, for example triethylamine, in a suitable solvent, for example methyl tert-butyl ether.
  • racemic acid compounds may be resolved using a chiral base, for example (S)-alpha methylbenzylamine, (S)-alpha phenylethylamine, (1 S, 2S)-(+)-2- amino-1-phenyl-1 ,3-propane-diol, (-) ephidrine, quinine, brucine.
  • Individual enantiomers of Formula (I), (II), (III), (III)', (IV), (V), (VIII), (IX), (X), (XV) and/or (XVI) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds.
  • the crude material was purified by ISCO Companion silica chromatography, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to give the title compound. Further quantities were obtained by collecting the early eluting fractions and further purification by ISCO Companion silica chromatography, eluting with a gradient 0-
  • n-Butyllithium (3.49 ml_, 1.6M solution in hexanes) was added dropwise to a solution of diisopropylamine (0.781 ml.) in THF (5 ml.) at O 0 C under nitrogen. The solution was cooled to -78 0 C and a solution of methyl 3-[[(2,4-dichlorophenyl)carbonyl](1-methylethyl)amino]-2- thiophenecarboxylate (Intermediate 22) (1.036 g) in THF (5 ml.) was added dropwise, maintaining an internal temperature below -65 0 C. The reaction was left to stir for 30 mins.
  • n-Butyl lithium (2.94 ml_, 1.6M solution in hexanes) was added dropwise to a solution of 5-(4- bromophenyl)-2-(triphenylmethyl)-2H-tetrazole (2.0 g, a synthesis of which is described as Intermediate 24) in THF (25 ml.) at -78 0 C under nitrogen. The mixture was stirred at -78 0 C under nitrogen for 45 mins. Trimethoxyborate (0.669 ml.) in THF (3 ml.) was added dropwise, maintaining the internal temp at -78 0 C. This was stirred at -78 0 C for 30 mins then allowed to warm to room temperature and stirred for a further 45 mins.
  • Tetrakis(triphenylphosphine)palladium (0) (23 mg) was added to a mixture of methyl 3-[[(2,4-dichlorophenyl)carbonyl](1-methylethyl)amino]-5-iodo-2- thiophenecarboxylate (200 mg, a synthesis of which is described as Intermediate 23) and the solid (prepared above) (185 mg) in dioxane (3 ml.) and 2N sodium carbonate solution (1 ml_). The mixture was heated to 100°C under nitrogen for 4 hours. The reaction was allowed to cool and the solvent evaporated, acidified with 2N HCI and the phases separated using a hydrophobic frit.
  • the compounds of Formula (I) may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.
  • the compounds of Formula (I) can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is convenient.
  • the compounds of Formula (I) can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • parenteral administration e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous.
  • the compounds of Formula (I) are formulated in liquid solutions, for example, in pharmaceutically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • 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 are used in the formulation.
  • 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 Formula (I) can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds of Formula (I) to be administered can be determined by standard procedures taking into account factors such as the compound (IC 5 o) potency, (EC 5 o) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds of Formula (I) with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a convenient method of administration of the compounds of Formula (I).
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, 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.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, for example from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 3 times per day, suitably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • 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 flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a sterile aqueous or nonaqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • Typical 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 non- CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt 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.
  • 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 nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • Reaction Conditions were 0.5 ⁇ M [ 33 P]-GTP (20 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI 2 , 5mM MnCI 2, 20 mM Tris-HCI, pH7.5, 1.6 ⁇ g/mL polyC/0.256 ⁇ M biotinylated oligoG13, 10% glycerol, 0.01% NP-40, 0.2 u/ ⁇ L RNasin and 50 mM NaCI.
  • HCV RNA Polymerase Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11 ), 1997, 8416. 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 4 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1 M MnCI 2 (0.25 ml_), glycerol (2.5ml_), 10% NP-40 (0.025 ml.) and Water (7.225 ml_), Total 10 ml_.
  • 2x concentrated enzyme buffer contained 1 M-Tris-HCI, pH7.5 (0.4 ml_), 5M NaCI (0.2 ml_), 1 M-MgCI 2 (0.4 ml_), glycerol (1 ml_), 10% NP-40 (10 ⁇ L), 1 M DTT (20 ⁇ L) and water (7.97 ml_), Tote/ 1O mL Substrate Mix was prepared using 5x Concentrated assay Buffer mix (4 ⁇ l_), [ 33 P]-GTP (10 ⁇ Ci/ ⁇ L, 0.02 ⁇ l_), 25 ⁇ M GTP (0.4 ⁇ l_), 40 u/ ⁇ L RNasin (0.1 ⁇ L), 20 ⁇ g/mL polyrC/biotinylated- oligorG (1.6 ⁇ L), and Water (3.94 ⁇ L), Total 10 ⁇ L.
  • Enzyme Mix was prepared by adding 1 mg/ml full-length NS5B polymerase (1.5 ⁇ L) to 2.81 mL 2x-concentrated enzyme buffer.
  • the Assay was set up using compound (1 ⁇ L), Substrate Mix (10 ⁇ L), and Enzyme Mix (added last to start reaction) (10 ⁇ L), Tota/ 21 ⁇ L.
  • the reaction was performed in a U-bottomed, white, 96-well plate.
  • the reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1 h at 22°C. After this time, the reaction was stopped by addition of 40 ⁇ L 1.875 mg/ml streptavidin SPA beads in 0.1 M EDTA.
  • the beads were incubated with the reaction mixture for 1 h at 22°C after which 120 ⁇ L 0.1 M EDTA in PBS was added.
  • the plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.
  • genotype 1 a and genotype 1 b may be demonstrated, for example, using the following cell based assay:
  • a 4OmM stock solution in DMSO of each test compound was further diluted into 50 ⁇ L of DMSO in the first row of a 96 well, V-bottom microplate, to give 100 times the top concentration of the required dilution series. Aliquots of 25 ⁇ L of DMSO were added to each well of the remaining rows, and doubling dilutions of compound were prepared by the serial transfer of 25 ⁇ L volumes from the first row onwards.
  • a Plate-mate robot was used to transfer 1 ⁇ L volumes from each dilution well into duplicate wells of a clear bottom, black walled, 96 well assay plate (COSTAR #3603). Control wells received 1 ⁇ L of DMSO alone.
  • Suspensions were prepared from cultures of Huh-7 cells stably transfected with sub-genomic HCV NS3-NS5B replicons of either genotype 1 b (the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021 ) or genotype 1a (subline 1.19 constructed in-house) linked to a firefly luciferase reporter gene.
  • genotype 1 b the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021
  • genotype 1a subline 1.19 constructed in-house linked to a firefly
  • Monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells re- suspended in assay medium comprising DMEM (Invitrogen #41965-039) supplemented with 5% v/v foetal calf serum, 1% v/v non-essential amino acids solution, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin and 2mM L-glutamine.
  • DMEM Invitrogen #41965-039
  • 100 ⁇ l_ of suspension containing either 15,000 cells (genotype 1 b luciferase replicon) or 20,000 cells (genotype 1a luciferase replicon) were added to all wells, except medium controls, of the assay plate and the plate incubated for 48 hours at 37°C in a 5% CO 2 atmosphere.
  • Resazurin (Fisher #R/0040/79) was dissolved in 5OmL of phosphate buffered saline and 100 ⁇ l_ of solution added to all wells. The plate was re-incubated at 37°C for a further 2 to 4 hours, wrapped in aluminium foil, before reading in a FluoStar Optima at 595nm. All growth medium and Resazurin was removed by aspiration, and an opaque mask applied to the bottom of the plate. A solution of SteadyLite cytolytic buffer/luciferase substrate (Perkin-Elmer #6016987) was prepared according to the manufacturer's instructions, and 25 ⁇ l_ added to each well. The plate was then read for luminescence on a TopCount NXT.
  • Toxicity The Resazurin absorbance values from duplicate wells were averaged and expressed as a percentage of the mean absorbance of compound free control wells to determine comparative cell viability. Compound cytotoxicity was expressed either as the lowest concentration at which a significant reduction in viability was observed or a 50% toxic concentration (CCID 50 ) was determined by plotting percentage cytotoxicity against compound concentration using Grafit software (Erithacus Software Ltd.).
  • Potency The luminescence values from all compound-free wells containing cells were averaged to obtain a positive control value. The mean luminescence value from the compound-free wells that had received no cells was used to provide the negative (background) control value. The readings from the duplicate wells at each compound concentration were averaged and, after the subtraction of the mean background from all values, were expressed as a percentage of the positive control signal. The quantifiable and specific reduction of luciferase signal in the presence of a drug is a direct measure of replicon inhibition. GraFit software was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC 50 ) for the compound.
  • Genotype 1a Genotype 1 b
  • Compound A corresponds to the compound disclosed as Example 317 in WO2002/100851,
  • Compound B corresponds to the compound disclosed as Example 576 in WO2002/100851,
  • Compounds A, B, C and D may be made according to the processes described in WO2002/100851 or as described hereinabove.
  • the compounds of Formula (I) which have been tested demonstrate a surprisingly superior potency as HCV polymerase inhibitors, as shown by the IC 5 O values in the cell-based assays across both of the 1 a and 1 b genotypes of HCV, compared to Compounds A, B, C and D. Accordingly, the compounds of Formula (I) are of great potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions comprising compounds of Formula (I) may also be used in combination with other therapeutic agents, for example immune therapies (e.g. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche)), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g.
  • Interferon such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon al
  • HCV NS3 protease inhibitors for example HCV NS3 protease inhibitors, e.g.
  • compositions comprising compounds of Formula (I) may also be used in combination with gene replacement therapy.
  • the invention thus provides, in a further aspect, a combination comprising at least one compound of Formula (I) or pharmaceutically acceptable salt thereof together with at least one other therapeutically active agent, especially Interferon, ribavirin and/or an additional anti-HCV agent.

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Abstract

La présente invention concerne de nouveaux composés 2-carboxythiophène de formule (I) : et leurs sels, des compositions pharmaceutiques les contenant et leur utilisation en médecine, comme agents antiviraux. Spécifiquement, la présente invention concerne des composés en tant qu'inhibiteurs de la réplication du virus de l'hépatite C (HCV).
PCT/EP2008/057984 2007-06-26 2008-06-24 Acides 3-carbonylaminothiophène-2-carboxyliques en tant qu'inhibiteurs du virus de l'hépatite c Ceased WO2009000818A1 (fr)

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WO2011034962A3 (fr) * 2009-09-16 2011-07-28 Calcimedica Inc. Composés qui modulent le calcium intracellulaire
US8771665B2 (en) 2010-12-17 2014-07-08 Cocrystal Discovery, Inc. Inhibitors of hepatitis C virus polymerase
WO2016154241A1 (fr) 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibiteurs de polymérase du virus de l'hépatite c
US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
WO2019217643A1 (fr) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Polythérapie pour le traitement du virus de l'hépatite c

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WO2008043791A2 (fr) * 2006-10-13 2008-04-17 Smithkline Beecham Corporation Composés
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WO2002100851A2 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et procedes destines au traitement des infections par flavivirus
WO2002100846A1 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et methodes de traitement ou de prevention d'infections a flavivirus
WO2004052885A1 (fr) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Composes et procedes de traitement ou de prevention d'infections a flavivirus
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Cited By (10)

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WO2011034962A3 (fr) * 2009-09-16 2011-07-28 Calcimedica Inc. Composés qui modulent le calcium intracellulaire
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US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
US10426762B2 (en) 2012-06-20 2019-10-01 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
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US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US10947210B2 (en) 2015-03-23 2021-03-16 Cocrystal Pharma, Inc. Inhibitors of Hepatitis C virus polymerase
WO2019217643A1 (fr) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Polythérapie pour le traitement du virus de l'hépatite c
US11752166B2 (en) 2018-05-09 2023-09-12 Cocrystal Pharma, Inc. Combination therapy for treatment of HCV

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