WO2007147794A1 - Dérivés du furanne et leur utilisation comme agents antiviraux - Google Patents

Dérivés du furanne et leur utilisation comme agents antiviraux Download PDF

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Publication number
WO2007147794A1
WO2007147794A1 PCT/EP2007/055991 EP2007055991W WO2007147794A1 WO 2007147794 A1 WO2007147794 A1 WO 2007147794A1 EP 2007055991 W EP2007055991 W EP 2007055991W WO 2007147794 A1 WO2007147794 A1 WO 2007147794A1
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optionally substituted
phenyl
alkyl
compound
amino
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PCT/EP2007/055991
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English (en)
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Richard Martin Grimes
Pritom Shah
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Smithkline Beecham Corporation
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Priority claimed from GB0612134A external-priority patent/GB0612134D0/en
Priority claimed from GB0706929A external-priority patent/GB0706929D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2007147794A1 publication Critical patent/WO2007147794A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 3-carboxy furan 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 1 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 1a and 1b 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.
  • X is an optionally substituted phenyl, 4H-[1 ,2,4]triazol-4-yl, pyridyl or indolizinyl;
  • Y is an optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl;
  • each Z is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl, each optionally substituted; or a haloalkyl, -C(O)NR 1 R 2 , -NR 4 C(O)R 5 , halo, -OR 4 , cyano, nitro, haloalkyl, -
  • L is a linker selected from a covalent bond, -NRCH 2 -, CH 2 NR-, -C(O)-, -NR-C(O)-, -C(O)-NR- , -OC(O)-, -C(O)O-, -C(S)-, -NR-C(S)-, -C(S)-NR-; each R is independently selected from -H, an alkyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl;
  • R 1 and R 2 are independently H 1 or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl, each optionally substituted; or R 1 and R 2 together with the nitrogen to which they are attached is optionally substituted heterocyclyl or heteroaryl;
  • R 4 and R5 are independently H 1 or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl, each optionally substituted; n is O or an integer from 1 to 4; and p is 0, 1 or 2.
  • PCT publication number WO2004/110357 generically discloses a range of compounds, including certain 3-carboxy furan compounds, having phosphodiesterase 6 delta (PDE6D) modulating activity.
  • the compounds disclosed have the formula (III)
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, NR 5 C(O)R 7 , C(O)NR 5 R 6 , C(O)R 7 and C(O)OR 7 , wherein R 5 , R 6 and R 7 are independently selected to be hydrogen, lower alkyl, cycloalkyl or aryl, and where R 5 , R 6 , and R 7 together can optionally form a 3, 4, 5, 6 or 7 membered ring optionally having one or more degrees of substitution.
  • the present invention involves novel 3-carboxy furan compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides the use of a compound of Formula (I) :
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or a 5- or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents H, halo, or heteroaryl (optionally substituted by one or more substituents selected from -Ci -4 alkyl, halo, hydroxy and -NH 2 ), wherein when R x is phenyl or a 6- membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents -C 5 - 7 cycloalkyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl (unsubstituted), -CF 3 , -CF 2 H, -CFH 2 , hydroxy and lluoro) or phenyl (optionally substituted by one or more substituents selected from -Ci -2 alkyl, -CF 3 and halo);
  • R 3 represents linear or branched -C 1-6 alkyl (optionally substituted by one or more substituents selected from 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl), linear or branched -C 2 . 6 alkyl (optionally substituted by one or more substituents selected from methoxy, ethoxy and fluoro), or -Cs- ⁇ cycloalkyl, pyranyl or tetrahydrofuranyl (each of which may be optionally substituted by one or more substituents selected from -C ⁇ alkyl, fluoro and methoxy), or -CH 2 CF 3 , or -CH ⁇ yclopropyl; or salts, solvates or esters thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • the present invention also provides a compound of Formula (I) represented by Formula (Ia) :
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or 5- or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents heteroaryl (optionally substituted by one or more substituents selected from halo, hydroxy and -NH 2 ), wherein when R x is phenyl or 6-membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents -Cs-rcycloalkyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl, -CF 3 , -CF 2 H, -CFH 2 , hydroxy and fluoro) or phenyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl, -CF 3 and halo);
  • R 3 represents linear or branched -Ci -6 alkyl (optionally substituted by one or more substituents selected from 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl), linear or branched -C 2-6 alkyl (optionally substituted by one or more substituents selected from methoxy, ethoxy and fluoro), or -Cs-scycloalkyl, pyranyl or tetrahydrofuranyl (each of which may be optionally substituted by one or more substituents selected from -C ⁇ alkyl, fluoro and methoxy), or -CH 2 CF 3 or -CH 2 cyclopropyl;
  • the present invention also provides the use of a compound of Formula (Ib) : wherein:
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or a 5- or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents H, halo, or heteroaryl (optionally substituted by one or more substituents selected from -C 1-4 alkyl, halo, hydroxy and -NH 2 ), wherein when R x is phenyl or a 6- membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents -Cs-ycycloalkyl (optionally substituted by one or more substituents selected from -Ci. ⁇ alkyI (unsubstituted), -CF 3 , -CF 2 H, -CFH 2 , hydroxy and fluoro) or phenyl (optionally substituted by one or more substituents selected from -Ci -2 alkyl, -CF 3 and halo);
  • R 3 represents linear or branched -Ci- ⁇ alkyl (optionally substituted by one or more substituents selected from -C 2 -C 6 alkoxy, 5- or 6-membered heteroaryl and 5- or 6- membered heterocyclyl), or -Cs-ecycloalkyl, pyranyl or tetrahydrofuranyl (each of which may be optionally substituted by one or more substituents selected from -C 1-2 alkyl, fluoro and methoxy), Or -CH 2 CF 3 , or -CH 2 cyclopropyl;
  • the present invention also provides a compound of Formula (I) represented by Formula (Ic) :
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or 5- or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents heteroaryl (optionally substituted by one or more substituents selected from -Ci -4 alkyl, halo, hydroxy and -NH 2 ), wherein when R x is phenyl or 6-membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents -Cs ⁇ cycloalkyl (optionally substituted by one or more substituents selected from -CF 3 , -CF 2 H, -CFH 2 , hydroxy and fluoro) or phenyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl, -CF 3 and halo);
  • R 3 represents linear or branched -C 1-6 alkyl (optionally substituted by one or more substituents selected from -C 2 -C 6 alkoxy, 5- or 6-membered heteroaryl and 5- or 6- membered heterocyclyl), or -C 3-6 cycloalkyl, pyranyl or tetrahydrofuranyl (each of which may be optionally substituted by one or more substituents selected from -Ci. 2 alkyl, fluoro and methoxy), or -CH 2 CF 3 Or -CH ⁇ yclopropyl;
  • the present invention provides the use of a compound of Formula (Id)
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or a 5 or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents H, halo, or heteroaryl optionally substituted by one or more substituents selected from -C h alky!, halo, hydroxy or -NH 2 , wherein when R x is phenyl or a 6-membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents C 5 . 7 cycloalkyl (optionally substituted by one or more substituents selected from CF 3 , hydroxy or halo) or phenyl (optionally substituted by one or more substituents selected from -d ⁇ alkyl, CF 3 or halo);
  • R 3 represents linear or branched -C h alky! (optionally substituted by one or more substituents selected from methoxy, ethoxy, or a 5 or 6-membered heteroaryl or heterocyclyl), or -Cs- ⁇ cycloalkyl, pyranyl or furanyl (each of which may be optionally substituted by one or more substituents selected from -C 1-2 alkyl, fluoro or methoxy);
  • the present invention also provides a compound of Formula (I) represented by Formula (Ie) :
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or a 5 or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the furan;
  • R ⁇ represents heteroaryl optionally substituted by one or more substituents selected from -Ci -4 alkyl, halo, hydroxy or -NH 2 , wherein when R x is phenyl or a 6-membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents C 5 . 7 cycloalkyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl, CF 3 , hydroxy or halo) or phenyl (optionally substituted by one or more substituents selected from -C 1-2 alkyl, CF 3 or halo);
  • R 3 represents linear or branched -C 1-6 alkyl (optionally substituted by one or more substituents selected from methoxy, ethoxy, or a 5 or 6-membered heteroaryl or heterocyclyl), or -C 3-6 cycloalkyl, pyranyl or furanyl (each of which may be optionally substituted by one or more substituents selected from -Ci. 2 alkyl, fluoro or methoxy);
  • a compound of Formula (I) or pharmaceutically acceptable salts, solvates or esters 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 pharmaceutically acceptable salts, solvates or esters thereof.
  • a compound of Formula (I) or pharmaceutically acceptable salts, solvates or esters 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 phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl. In a further aspect, R x represents phenyl optionally substituted by halo or methyl. In a further aspect, R x represents unsubstituted phenyl.
  • R ⁇ represents bicyclic heteroaryl optionally substituted by one or more substituents selected from -Ci -4 alkyl, halo, hydroxy or -NH 2 , wherein when R x is phenyl or a 6-membered heteroaryl, then R ⁇ is bonded in the para-position.
  • R ⁇ represents unsubstituted 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 - ⁇ >][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, 1 ,3-benzoxazol-2-yl, 5-amino-1 ,3- benzoxazol-2-yl, [1 ,3]oxazolo[5,4
  • R ⁇ represents furo[3,2- ⁇ ]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl, imidazo[1 ,2-a]pyhdin-2-yl, imidazo[2, 1 -6][1 ,3]thiazol-6-yl, [1 ,3]oxazolo[4,5-b]pyridin-2-yl or 1 ,3-benzoxazol-2-yl.
  • R ⁇ represents furo[3,2-/b]pyridin-2-yl or pyrazolo[1 ,5-a]pyrimidin-2-yl.
  • R ⁇ represents furo[3,2-fc>]pyridin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, 1 ,3- benzoxazol-2-yl or [1 ,3]oxazolo[4,5-b]pyridin-2-yl.
  • R ⁇ represents furo[3,2- 6]pyridin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, or [1 ,3]oxazolo[4,5-b]pyridin-2-yl.
  • R ⁇ represents furo[3,2-/b]pyridin-2-yl.
  • R ⁇ represents H or halo. In a further aspect, R ⁇ represents H or bromo.
  • R 2 represents -C 6 cycloalkyl (optionally substituted by one or more C 1-2 alkyl substituents) or -CF 3 . In a further aspect, R 2 represents -C 6 cycloalkyl (optionally substituted by one or more Ci. 2 alkyl substituents). In a further aspect, R 2 represents trans-4- methylcyclohexyl or f/-ans-4-(trifluoromethyl)cyclohexyl. In a further aspect, R 2 represents frans-4-methylcyclohexyl.
  • R 3 represents 1-methylethyl, tetrahydrofuran-2-yl or (methyloxy)ethyl. In a further aspect, R 3 represents 1-methylethyl.
  • A represents hydroxy;
  • R x represents phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl;
  • R ⁇ represents bicyclic heteroaryl optionally substituted by one or more substituents selected from -C 1-4 alkyl, halo, hydroxy or -NH 2 , wherein when R x is phenyl or a 6-membered heteroaryl, then R ⁇ is bonded in the para-position;
  • R 2 represents -C ⁇ cycloalkyl optionally substituted by one or more C 1-2 alkyl substituents; and
  • R 3 represents 1-methylethyl, tetrahydrofuran-2-yl or (methyloxy)ethyl.
  • A represents hydroxy;
  • R x represents unsubstituted phenyl;
  • 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, [1 ,3]oxazolo[4,5-b]pyridin-2-yl or 1 ,3-benzoxazol-2-yl;
  • R 2 represents trans- 4-methylcyclohexyl or frans-4-(trifluoromethyl)cyclohexyl;
  • R 3 represents 1-methylethyl, tetrahydrofuran-2-yl or (methyloxy)ethyl.
  • A represents hydroxy;
  • R x represents unsubstituted phenyl;
  • R ⁇ represents furo[3,2-/b]pyridin-2-yl or pyrazolo[1 ,5-a]pyrimidin-2-yl;
  • R 2 represents trans- ⁇ - methylcyclohexyl or fra/7s-4-(tri ⁇ luoromethyl)cyclohexyl;
  • R 3 represents 1-methylethyl, tetrahydrofuran-2-yl or (methyloxy)ethyl.
  • A represents hydroxy;
  • R x represents unsubstituted phenyl;
  • R ⁇ represents furo[3,2-(b]pyridin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, or [1 ,3]oxazolo[4,5-b]pyridin-2-yl;
  • R 2 represents frans-4-methylcyclohexyl; and
  • R 3 represents 1-methylethyl.
  • the term "compounds of the invention” means the compounds according to Formula I and the salts, solvates and esters thereof.
  • a compound of the invention means any one of the compounds of the invention as defined above.
  • acetyl refers to -C(O)CH 3 .
  • alkyl refers to an optionally substituted hydrocarbon group.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl group is linear or branched, 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 hydrocarbon group is unsaturated, it will be understood that there will be a minimum of 2 carbon atoms in the group, for example an alkenyl or alkynyl group.
  • alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group.
  • alkyl moieties are saturated.
  • alkyl moieties are -C ⁇ alkyl.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. In one aspect the alkenyl group 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. In one aspect the alkynyl group has from 2 to 6 carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.
  • cycloalkyl refers to an optionally substituted, cyclic hydrocarbon group.
  • the hydrocarbon group may be saturated or partially unsaturated, monocyclic or bridged bicyclic.
  • examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • the cycloalkyl group has from 5 to 7 carbon atoms.
  • cycloalkyl moieties are cyclohexenyl, cyclopentenyl and cyclohexyl.
  • alkoxy refers to an -O-alkyl group wherein alkyl is saturated but otherwise as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • aryl moieties contain 6-10 carbon atoms.
  • aryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • aryl substituents are selected from the group consisting of -C h alky!, halo, -0R E , -SR E , -C(O)NR 8 R 0 , -C(O)R 0 , -CO 2 H,
  • carbonyl refers to -C(O)-.
  • cyano refers to -CN.
  • halogen 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 an optionally substituted, 5, 6, 8, 9 or 10 membered, aromatic group comprising one to four heteroatoms selected from N, O and S, 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
  • heteroaryl substituents are selected from the group consisting of -C 1-6 alkyl, halo, -OR E , -SR E , -C(O)NR 6 R 0 , -C(O)R 0 , -CO 2 R 0 , -NR B R C , -NR A C(0)R°, -NR A C0 2 R°, -NR A C(O)NR F R G , -S0 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, heterocyclyl, -CF 3 and phenyl.
  • heterocyclic and “heterocyclyl” refer to an optionally substituted, 5 or 6 membered, saturated or partially unsaturated, cyclic group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, -Ci. 6 alkyl, -C(O)R 0 , -C(O)NR B R C , -C(O)OH, -SO 2 R 0 , aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
  • Ring carbon atoms may be optionally substituted by -Ci -6 alkyl, -0R A , -C(O)R 0 , or -SO 2 R 0 .
  • heterocyclic moieties are unsubstituted or monosubstituted tetrahydro-2H-pyran-4-yl, piperidinyl and tetra hyd rof u ra n-3-y I .
  • 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 represents hydrogen or -C 1-6 alkyl.
  • R° is selected from the group consisting of -Ci_ 6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • R E represents hydrogen, -d- ⁇ alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl or heteroaryl.
  • R F and R G are independently selected from the group consisting of hydrogen, -Ci-ealkyl, 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: S ⁇ FurofS ⁇ -jblpyridin ⁇ -yOphenylJ ⁇ -t ⁇ frans- ⁇ methylcyclohexyOcarbony ⁇ i- methylethyl)amino]-3-furancarboxylic acid;
  • 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.
  • the present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, -C ⁇ alkyl or -Ci -4 alkoxy or amino); or for example -
  • R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substitute
  • any alkyl moiety present in such esters preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety present in such esters preferably comprises a phenyl group.
  • the compounds of Formulae (Ia), (1 b) or (1c) are in the form of the parent compound, a salt or a solvate.
  • 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 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.
  • a suitable solvent for example tetrahydrofuran.
  • the temperature is in the range 0 to 5O 0 C, for example 15 to 3O 0 C.
  • A is an alkoxy, benzyloxy or silyloxy group, and R 1 and R 2 are as defined above for
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range -78 to 5O 0 C.
  • A is an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, such as 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 1 ,2-dichloroethane, 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.
  • the temperature is in the range 40 to 90 0 C.
  • A is an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, such as 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 1 ,2-dichloroethane, 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.
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range 0 to 6O 0 C.
  • Compounds of Formula (IV) may be prepared by reaction of a compound of Formula (V) in which A is 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 is an alkoxy, benzyloxy or silyloxy group
  • a suitable vinyl ether or a suitable aldehyde or a suitable ketone
  • a suitable acid such as acetic acid
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • compounds of Formula (IV) may be prepared from compounds of Formula (V) in which A is an alkoxy, benzyloxy or silyloxy, by treatment with a suitable alkylating agent R 3 -X where X is a halo atom such as chloro, bromo or iodo, or X is a sulphonate ester such as methanesulfonate, 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 atom such as chloro, bromo or iodo, or X is a sulphonate ester such as methanesulfonate, in suitable solvent, such as dimethylformamide, in the presence of a suitable base, such as triethylamine.
  • A is an alkoxy, benzyloxy or silyloxy group, and R 1 is as defined above for Formula
  • reaction with a suitable acid, for example trifluoroacetic acid.
  • a suitable acid for example trifluoroacetic acid.
  • the reaction is carried out in a suitable solvent such as dichloromethane at a temperature in the range 0-30 0 C.
  • R 1 is as defined above for Formula (I) and Y is a halo atom such as chloro, bromo or iodo, with a compound of Formula (VIII) in which A is an alkoxy, benzyloxy or silyloxy group.
  • suitable solvent such as dimethylformamide
  • a suitable base such as diethylamine.
  • Z represents a halo atom, such as chloro, bromo or iodo
  • R x , R 2 , R 3 are as defined above for Formula (I)
  • A is hydroxy or an alkoxy, benzyloxy or silyloxy group, by reaction with a suitable heteroaryl boronic acid, R ⁇ -boronic acid, in which 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 1 ,4-dioxane.
  • a palladium catalyst such as palladium (II) acetate
  • a reagent such as 2-dicyclohexylphosphino-2'(N,N-
  • the R ⁇ boronic acid or boronic ester may be reacted in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium(O), a reagent such as sodium carbonate, is a suitable solvent such as dimethoxymethane or ethanol, preferably at a temperature in the range 50-85°C.
  • a palladium catalyst such as tetrakis(triphenylphosphine) palladium(O)
  • a reagent such as sodium carbonate
  • a suitable solvent such as dimethoxymethane or ethanol
  • R ⁇ -Boronic acids are commercially available or may be prepared by analogy to methods provided in Organometallics (1983) 2, 1316, Chem Revs. (1995) 95, 2457, Journal of Org Chem (2004) 69, 1999, SynLett (2004) (5), 892, Bioorg Med Chem (2005) 13, 2305, Tetrahedron Letters (2004) 44, 9359 and Tetrahedron Letters (2005) 45, 6657.
  • Compounds of Formula (IX) are compounds of Formula (II) where R 1 in Formula (II) represents -R x -R ⁇ and R ⁇ represents halo.
  • compounds of Formula (IX) may be prepared according to processes previously described for Formula (II).
  • Compounds of Formula (I) or (II) in which R 1 represents a -R x -(furopyridine), may be prepared by treatment of a compound of Formula (X) in which R 2 , R 3 and A are as defined above for Formula (II), 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 the presence of a suitable base, such as triethylamine, optionally in an additional suitable solvent, such as DMF.
  • a suitable base such as triethylamine
  • an additional suitable solvent such as DMF.
  • the temperature is in the range 50-80 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a -R x -(pyrrolopyridine), may be prepared by treatment of a compound of Formula (X) in which 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 c C.
  • pyrrolopyridine synthesis see Heterocycles (1986) 24, 31 , Tetrahedron (2003) 59, 1571 , Synlet
  • R x , R 2 , and R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group
  • A is an alkoxy, benzyloxy or silyloxy group
  • a suitable base such as potassium carbonate in a suitable solvent such as ethanol
  • a suitable fluoride source for example tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran.
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range 0 to 3O 0 C.
  • Compounds of Formula (Xl) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (IX) in which Z represents a halo atom, such as chloro, bromo or iodo, and R x , R 2 , R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group, by reaction with trimethylsilylacetylene in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, a reagent such as triethylamine, in a suitable solvent such as tetrahydrofuran, suitably at a temperature in the range 50-75 0 C.
  • the reaction may optionally be carried out under nitrogen.
  • A is an alkoxy, benzyloxy or silyloxy group and R x , R 2 and R 3 are as defined above for Formula (I) with 2-aminophenol in a suitable solvent such as 1 ,4-dioxane.
  • the reaction is suitably carried out at elevated temperature by heating in a microwave reactor at a temperature in the range 150 to 210°C.
  • R x , R 2 and R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group by reacting with a reagent such as oxalyl choride or thionyl chloride in a suitable solvent such as dichloromethane.
  • a catalyst such as diethylformamide may optionally be used.
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range 0 to 30 0 C.
  • Compounds of Formula (II) in which R 1 represents a -R x -(oxazolopyridine) may be prepared by reacting a compound of Formula (XIII) with an appropriate pyridine derivative (the pyridine being substituted with adjacent amino and hydroxyl groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200 0 C (see for example J. Med. Chem. (1978) 21 , 1158).
  • the acid chloride (XII) may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) in a microwave reactor at elevated temperature, for example 150-210 0 C, in a suitable solvent such as 1 ,4-dioxane (see for example Tetrahedron Letters (2003) 44, 175).
  • an appropriate pyridine the pyridine being substituted with adjacent amino and hydroxyl groups
  • a suitable solvent such as 1 ,4-dioxane
  • Compounds of Formula (II) in which R 1 represents -R x -(oxazolopyridine) may also be prepared by reacting a compound of Formula (XIII) with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) using a suitable coupling agent such as HATU, and then in a second step cyclised using an appropriate reagent such as phosphorous oxychloride.
  • Compounds of Formula (XIII) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (IX) in which Z represents a halo atom, such as chloro, bromo or iodo, or a trifluoromethanesulphonate group and R x , R 2 , R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group, by reaction with carbon monoxide and water in the presence of a suitable palladium catalyst such as palladium (II) acetate or bis-diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • the temperature is in the range 50 to 80 0 C.
  • R x , R 2 and R 3 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy group and Z represents a halo atom, such as chloro, bromo or iodo, with 2- aminopyridine.
  • the reaction is carried out in a suitable solvent, for example dimethoxyethane.
  • the temperature is in the range to 50 to 80 0 C.
  • R x , R 2 and R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group, with a halogenating agent, for example bromine, in a suitable solvent, such as chloroform.
  • a halogenating agent for example bromine
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range 0 to 3O 0 C.
  • compounds of Formula (XIV) can also be prepared from compounds of Formula (XV) by first reacting with an appropriate silylating agent, such as trimethylsilyl triflate, in the presence of a suitable base, such as 2,6-lutidine, in an appropriate solvent, for example dichloromethane, followed by the addition of a suitable halogenating agent, for example N-bromosuccinamide.
  • an appropriate silylating agent such as trimethylsilyl triflate
  • a suitable base such as 2,6-lutidine
  • a suitable halogenating agent for example N-bromosuccinamide.
  • the temperature is in the range 0 to 3O 0 C.
  • the reaction may optionally be carried out under nitrogen.
  • Compounds of Formula (XV) in which in which R x , R 2 and R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (XII) in which R x , R 2 and R 3 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group by treating with methylzinc chloride in a suitable solvent, for example tetrahydrofuran.
  • the reaction may optionally be carried out under nitrogen.
  • the temperature is in the range -10 to 3O 0 C.
  • compounds of Formula (XV) can be prepared from compounds of Formula (IX) in which Z represents a halo atom, such as chloro, bromo or iodo, and R x , R 2 , R 3 are as defined above for Formula (I), and A is hydroxy or an alkoxy, benzyloxy or silyloxy group, by treatment with a suitable vinyl ether such as butylethenyl ether and a suitable catalyst such as palladium (II) acetate and 1 ,3-bis(diphenylphosphino)propane in the presence of 1-butyl-
  • a suitable base such as diisopropylamine
  • a suitable solvent for example, dimethyl sulphoxide
  • a suitable acid such as hydrochloric acid.
  • the reaction is carried out under nitrogen and suitably the temperature is in the range 100 to 13O 0 C.
  • R 1 represents 4-(phenyl)-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.
  • R x , R 2 and R 3 are as defined above for Formula (I) and A is an alkoxy, benzyloxy or silyloxy group, with hydrazine, such as hydrazone hydrate, in the presence of a suitable acid such acetic acid in a suitable solvent for example ethanol.
  • a suitable acid such as acetic acid in a suitable solvent for example ethanol.
  • the temperature is in the range 50 to 8O 0 C.
  • the reaction may optionally be carried out under nitrogen.
  • Compounds of Formula (XVI) in which R x , R 2 and R 3 are as defined above for Formula (I) and A is an alkoxy, benzyloxy or silyloxy group may be prepared by treating a compound of Formula (XIV) in which R x , R 2 and R 3 are as defined above for Formula (I) and A is an alkoxy, benzyloxy or silyloxy group and Z represents a halo atom, such as chloro, bromo or iodo, with a suitable cyanide such as sodium cyanide or potassium cyanide in a suitable solvent for example ethanol.
  • the temperature is in the range 0 to 3O 0 C.
  • the reaction may optionally be carried out under nitrogen.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(thiazolopyridine)phenyl may be prepared by reacting a compound of Formula (II)' in which R 1 represents 4-phenyl-COCI with an appropriate pyridine (the pyridine being substituted with adjacent amino and chloro groups), in the presence of a suitable base such as pyridine, and then in a second step cyclised using a reagent such as Lawesson's reagent in a suitable solvent such as DMPU, at a suitable temperature such as 90-11O 0 C.
  • a reagent such as Lawesson's reagent in a suitable solvent such as DMPU
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(thiazolopyridine)phenyl may also be prepared by reacting a compound of Formula (II)' in which R 1 represents 4- carboxyphenyl with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200 0 C (see for example J. Med. Chem. (1978) 21 , 1158).
  • the acid chloride of the 4-carboxyphenyl may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in a microwave reactor in a suitable solvent such as 1 ,4-dioxane (see for example Tetrahedron Letters (2003) 44, 175).
  • the 4-carboxyphenyl compound may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), using a suitable coupling agent such as HATU, and then in a second step cyclised using an appropriate reagent such as phosphorous oxychloride.
  • 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.
  • a racemic compound of Formula (I), (II), (II)', (III), (IV), (V), (VI), (IX), (X), (Xl), (XII), (XIII), (XIV) and (XV) may be resolved by chiral preparative HPLC.
  • racemic compounds of Formula (I), (II), (II)', (III), (IV), (V), (Vl), (IX), (X), (Xl), (XII), (XIII), (XIV) and (XV) 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 basic compound may be resolved by treatment with a chiral acid such as (R)-(-)-1 ,1 '-binaphthyl-2,2'-diyl-hydrogen phosphate or (- )-di-0,0'-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), (II)', (III), (IV), (V), (Vl), (IX), (X), (Xl), (XII), (XIII), (XIV) and (XV) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds.
  • the organic phase was then washed with brine, passed through a hydrophobic frit and concentrated.
  • the crude product was dissolved in a minimal amount of 1 ,4-dioxane and loaded onto a 7Og MH 2 SPE cartridge that had been conditioned with 1 ,4-dioxane.
  • the cartridge was washed with 1 ,4-dioxane ( ⁇ 300 mL) and then eluted with acetic acid:1 ,4- dioxane (1:9) to give the title compound.
  • the triflate solution (prepared above) was allowed to warm to room temperature, was washed with 2M HCI and the layers were separated using a hydrophobic frit. The organics were passed through a silica SPE cartridge and the fractions were transferred to a dropping funnel. The solution was then added dropwise to the KHMDS reaction mixture. The reaction was stirred at -78 0 C under nitrogen for 1 h, then at -1O 0 C for 2.5 h. The reaction was quenched with saturated sodium bicarbonate solution and the organics were extracted with EtOAc. The layers were separated and the organic phase was washed with brine. The organics were dried over sodium sulphate, were filtered using a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 5-55% EtOAc in cyclohexane to give the title compound.
  • ntermediate 16 (19 mg) was dissolved in THF (1 ml_) and ethanol (1 ml_). 2N Lithium hydroxide solution (1 mL) was added and the mixture stirred at room temperature for 16 h. The reaction was then neutralised with 2N HCI and extracted with ethyl acetate. The phases were separated and the organic phase passed through a hydrophobic frit and concentrated to give the title compound.
  • compositions for use in therapy comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.
  • the compounds of the present invention can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds 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
  • the chemical entities of the invention are formulated in liquid solutions, preferably, in pharmaceutically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the chemical entities 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 the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC 50 ) potency, (EC 50 ) 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 with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds.
  • 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(l).
  • 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 6 times per day, for example 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 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 non- CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 , 2,3, 3,3-heptafluoropropane.
  • 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.
  • NS5B wildtype HCV polymerase activity genotype 1 b
  • in vitro assay The potential for chemical entities of the invention to inhibit NS5B wildtype HCV polymerase activity, genotype 1 b, may be demonstrated, for example, using the following in vitro assay:
  • 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 m!_), 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), Total 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), Total 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.
  • the exemplified compounds had an IC 50 of ⁇ 10 ⁇ M in the above described assay. In one aspect, compounds have an IC 5O of ⁇ 2 ⁇ M. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV. Accordingly, the compounds of the present invention are of great potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies (eg. 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 alfacon-1 (
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the invention thus provides, in a further aspect, a combination comprising a compound of Formula (I) together with at least one other therapeutically active agent, especially Interferon, ribavirin and/or an additional anti-HCV agent.

Abstract

L'invention concerne des agents antiviraux incluant des composés représentés par la formule (Ia) : dans laquelle A, R1, R2 et R3 sont tels que définis dans la description, des procédés permettant de les préparer et leur utilisation dans le traitement du virus de l'hépatite C (HCV).
PCT/EP2007/055991 2006-06-19 2007-06-18 Dérivés du furanne et leur utilisation comme agents antiviraux WO2007147794A1 (fr)

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GB0612134.7 2006-06-19
GB0612134A GB0612134D0 (en) 2006-06-19 2006-06-19 Compounds
GB0706929.7 2007-04-10
GB0706929A GB0706929D0 (en) 2007-04-10 2007-04-10 Compounds

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008043791A2 (fr) * 2006-10-13 2008-04-17 Smithkline Beecham Corporation Composés
JP2012153645A (ja) * 2011-01-26 2012-08-16 Dainippon Printing Co Ltd ３−（２−アルコキシフェニル）−５−アミノピラゾール中間体の製造方法
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC

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WO2005009539A2 (fr) * 2003-07-23 2005-02-03 Synta Pharmaceuticals, Corp. Composes pour l'inflammation et utilisations liees au systeme immunitaire
WO2005063734A2 (fr) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Thiophenes substitues
WO2005092863A1 (fr) * 2004-03-26 2005-10-06 Smithkline Beecham Corporation Dérivés de 4-carbox pyrazole utiles en tant qu'agents antiviraux

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WO2005009539A2 (fr) * 2003-07-23 2005-02-03 Synta Pharmaceuticals, Corp. Composes pour l'inflammation et utilisations liees au systeme immunitaire
WO2005063734A2 (fr) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Thiophenes substitues
WO2005092863A1 (fr) * 2004-03-26 2005-10-06 Smithkline Beecham Corporation Dérivés de 4-carbox pyrazole utiles en tant qu'agents antiviraux

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PFEFFERKORN J A ET AL: "Inhibitors of HCV NS5B polymerase. Part 1: Evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 15, no. 10, 16 May 2005 (2005-05-16), pages 2481 - 2486, XP004877709, ISSN: 0960-894X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008043791A2 (fr) * 2006-10-13 2008-04-17 Smithkline Beecham Corporation Composés
WO2008043791A3 (fr) * 2006-10-13 2008-06-05 Smithkline Beecham Corp Composés
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
JP2012153645A (ja) * 2011-01-26 2012-08-16 Dainippon Printing Co Ltd ３−（２−アルコキシフェニル）−５−アミノピラゾール中間体の製造方法

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