WO2007039146A1 - Derives de 4-carboxy pyrazole utilises en tant qu'agents antiviraux - Google Patents

Derives de 4-carboxy pyrazole utilises en tant qu'agents antiviraux Download PDF

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WO2007039146A1
WO2007039146A1 PCT/EP2006/009238 EP2006009238W WO2007039146A1 WO 2007039146 A1 WO2007039146 A1 WO 2007039146A1 EP 2006009238 W EP2006009238 W EP 2006009238W WO 2007039146 A1 WO2007039146 A1 WO 2007039146A1
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pyrazole
amino
carboxylic acid
carbonyl
methylcyclohexyl
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PCT/EP2006/009238
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English (en)
Inventor
Gianpaolo Bravi
Anne Goretti Cheasty
John Andrew Corfield
Richard Martin Grimes
David Harrison
Charles David Hartley
Peter David Howes
Katrina Jane Medhurst
Malcolm Lees Meeson
Jacqueline Elizabeth Mordaunt
Pritom Shah
Martin John Slater
Gemma Victoria White
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Smithkline Beecham Corporation
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Priority claimed from GB0519474A external-priority patent/GB0519474D0/en
Priority claimed from GB0605467A external-priority patent/GB0605467D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2007039146A1 publication Critical patent/WO2007039146A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
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    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a 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
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—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 4-carboxy pyrazole 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 ): 71S-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 1 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 JuI.). 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 1 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 1b 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.
  • the present invention involves novel 4-carboxy pyrazole compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides at least one chemical entity chosen from compounds 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 nitrogen atom of the pyrazole;
  • R ⁇ represents heteroaryl, bonded such that when R x is phenyl, R y is in the para-position;
  • R 2 represents phenyl substituted by one or more substituents selected from -C 1-6 alkyl, halo, - OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R D , -NR E CO 2 R D , - NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, and heterocyclyl, or two substituents on neighbouring carbon atoms of the phenyl ring together form a 4-, 5- or 6-membered ring containing one or more heteroatoms selected from O, S and N; or R 2 represents C 5 .
  • R 3 represents heterocyclyl; or phenyl optionally substituted by one or more substituents selected from -C 1-6 alkyl, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -
  • R 3 represents -C 1-6 alkyl optionally substituted by one or more substituents selected from -0R A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -
  • R 4 represents hydrogen
  • R A represents hydrogen, -C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl or heteroaryl;
  • R B and R c independently represent hydrogen, -C 1-6 alkyl, aryl, heterocyclyl or 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;
  • R° is selected from the group consisting of -C 1-6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or -C ⁇ alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, -C 1-6 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;
  • 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 includes 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 which method comprises administering to said human or animal subject an effective amount of at least one chemical entity chosen from compounds of Formula (I) and pharmaceutically acceptable salts, solvates and esters thereof.
  • the chemical entities 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 thienyl; pyridinyl; pyridazinyl; or phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl.
  • R x represents 2,5 thienyl.
  • R x represents phenyl optionally substituted by halo or methyl.
  • R x represents phenyl, 3-chlorophenyl, or 3-methylphenyl, for example phenyl or 3- chlorophenyl.
  • R x represents a heteroaryl group, that group is bonded through one of its ring carbon to the R ⁇ group.
  • R ⁇ represents a heteroaryl group containing 2 fused rings.
  • R ⁇ represents optionally substituted pyrazolopyrimidine, furopyridine, imidazopyridine, benzoxazole, imidazothiazole, benzofuran or pyrazolopyridine, for example optionally substituted pyrazolopyrimidine, furopyridine, imidazopyridine, benzoxazole, or imidazothiazole
  • R ⁇ represents optionally substituted pyrazolo[1 ,5- a]pyrimidin-2-yl, furo[3,2-b]pyridin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, benzoxazol-2-yl, imidazo[2,1-6][1 ,3]thiazol-6-yl, 4-furo[3,2- ⁇ ]pyridin-6-yl, 4-furo[3,2-b]pyridin-5-yl, 1- benzofuran-2-
  • R ⁇ represents optionally substituted pyrazolo[1 ,5-a]pyrimidin-2-yl, furo[3,2- ⁇ ]pyridin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, benzoxazol-2-yl, or imidazo[2,1-b][1 ,3]thiazol-6-yl.
  • R x represents a 6-membered heteroaryl bonded through a ring carbon atom to the nitrogen atom of the pyrazole
  • R ⁇ is bonded so as to be in the para-position.
  • R 2 represents phenyl substituted by one or more substituents selected from - Ci- ⁇ alkyI, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R D , - NR E CO 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, and heterocyclyl; or R 2 represents C 5-7 cycloalkyl optionally substituted by one or more substitutents selected from - C 1-6 alkyl,
  • R 2 represents phenyl substituted by one or more substituents selected from or halo, or R 2 represents C 6 cycloalkyl optionally substituted by one or more C 1-4 alkyl or trifluoromethyl substituents (for example one or more C 1-4 alkyl substituents).
  • R 2 represents frans-4-methylcyclohexyl or trans- 4-trifluoromethylcyclohexyl, for example frans-4-methylcyclohexyl.
  • R 2 represents a phenyl group substituted by two substituents on neighbouring carbon atoms of the phenyl ring and which together form a 5- or 6-membered ring (including the intervening phenyl ring carbon atoms) containing one or more heteroatoms selected from O, S and N.
  • the ring is 5-membered.
  • the ring contains one heteroatom.
  • the heteroatom is O.
  • the ring contains a carbon-carbon double bond.
  • the R2 group may be a benzofuran group.
  • R 3 represents heterocyclyl; or phenyl optionally substituted by one or more substituents selected from -C ⁇ alkyl, halo, -0R A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, - CO 2 R 0 , -NR B R C , -NR E C(O)R°, -NR E CO 2 R°, -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, and heterocyclyl; or R 3 represents -C h alky!
  • R 3 represents 1-methylethyl, 2-methylpropyl, 1-ethylpropyl, 1 ,3-dimethylbutyl, ethyl, propyl, 2-ethylbutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, tetrahydro-2/-/-pyran-4- ylmethyl, tetrahydrofuran-3-yl, 2-methoxyethyl, 2-(methoxy)-1-[(methoxy)methyl]ethyl, 1 ,3- oxazol-2-yl methyl, 2-(phenyloxy)ethyl, 1 ,3-thiazol-4-ylmethyl, (4-methyl-1 ,2,5-oxadiazol-3- yl)methyl, 2-(ethyloxy)ethyl, (2-methyl-1 ,3-thiazol-4-yl)methyl, butyl, (3,5-dimethyl-4- is
  • R 3 represents 1-methylethyl, 2-methylpropyl, 1-ethylpropyl, 1 ,3-dimethylbutyl, ethyl, propyl, 2-ethylbutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydrofuran-3-yl, 2-methoxyethyl, or 2-(methoxy)-1-[(methoxy)methyl]ethyl.
  • R 3 represents 1-methylethyl, ethyl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl or 2-(methoxy)-1- [(methoxy)methyl]ethyl. It is to be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.
  • acetyl refers to -C(O)CH 3 .
  • acetylamino refers to -N(H)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. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. In one aspect, alkyl moieties are Unless otherwise stated, optional substituents include -C h alky!
  • 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 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.
  • -C ⁇ alkyl unsubstituted
  • 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 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 ⁇ alkyl, halo, -0R A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(0)R°, -NR E CO 2 R°, -NR E S0 2 R°, -NR E C(0)NR F R G , -S0 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl, - CF 3 , -OCF 3 and phenyl.
  • they may be selected from -C h alky!, halo, -0R A , -SR A , -C(O)NR 6 R 0 , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R°, -NR 6 CO 2 R 0 , -NR ⁇ C(O)NR F R G , -S0 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl, -CF 3 , -OCF 3 and phenyl.
  • arylalkyl refers to an aryl group attched to the parent molecular moiety through an alkyl group.
  • 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
  • heteroaryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted (where applicable) pyridine, pyrazine, thiazole, thiophene, furan, oxadiazole, oxazole, isoxazole, pyrimidine, pyridazine, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzothiadiazine, benzoxazole, benzisoxazole, benzisothiazole,
  • 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.
  • Each heteroaryl group may be optionally substituted on a carbon atom by one or more substituents.
  • heteroaryl substituents are selected from the group consisting of -C 1-6 alkyl, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R D , -CO 2 R 0 , -NR B R C , -NR E C(O)R D , -NR E CO 2 R D , -NR E SO 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, heterocyclyl, -CF 3 and phenyl.
  • -C 1-6 alkyl halo, -OR A , -SR A , -C(O)NR 6 R 0 , -C(O)R 0 , -CO 2 R 0 , -NR B R C , -NR E C(O)R°, -NR E CO 2 R°, -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, heterocyclyl, -CF 3 and phenyl.
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • heterocyclic and “heterocyclyl” refer to an optionally substituted, 5 or 6 membered, saturated or partially saturated, cyclic group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, -C 1-6 alkyl, -C(O)R 0 , -C(O)NR B R C , -C(O)OR 4 , -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 -C 1-6 alkyl, -0R E , -C(O)R 0 , or -SO 2 R 0 .
  • heterocyclic moieties are unsubstituted or monosubstituted tetrahydro-2H-pyran-4-yl, piperidinyl and tetrahydrofuran- 3-yl.
  • nitro refers to -NO 2 .
  • Ac refers to “acetyl”
  • Et refers to “ethyl”
  • iPr refers to “isopropyl”
  • Me refers to “methyl”
  • OBn refers to "benzyloxy”
  • Ph refers to "phenyl”.
  • chemical entities useful in the present invention may be chosen from compounds of Formula (I) selected 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 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 1-4 alkyl or -C ⁇ alkoxy or amino); or for example - CH 2 OC(O)R' or -CH 2 OCO 2 R' in which R' is alkyl (e.g.
  • R' is f-butyl
  • 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 compound of Formula (Ia) is in the form of 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 a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy group and R 1 , R 2 , R 3 and R 4 are as defined above for Formula (I).
  • R 1 , R 2 , R 3 and R 4 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, tetrahydrofuran or combinations thereof.
  • the temperature is in the range 25 to 100 0 C, more preferably 50 to 100°C.
  • R 1 , R 2 , R 3 and R 4 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, more preferably 15 to 30 0 C.
  • A is silyloxy
  • R 1 , R 2 , R 3 and R 4 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 5O 0 C, more preferably 15 to 30 0 C.
  • Compounds of Formula (I) in which A is hydroxy, or (II) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (III) in which A is hydroxy or an alkoxy, benzyloxy or silyloxy group, and R 1 , R 3 and R 4 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).
  • 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, in the presence of a suitable base, for example pyridine or triethylamine and thereafter removing any protecting group if desired.
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine or triethylamine
  • R 2 represents an aliphatic group
  • a phosphine such as triphenylphosphine may optionally be used.
  • Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • a compound of Formula (II) may be prepared by appropriate manipulation of another compound of Formula (II).
  • a compound of Formula (II) in which any substituent comprises -C ⁇ alkenyl may be prepared from a suitable aldehyde or ketone substituent and a phosphorous ylid generated from a phosphonium salt in the presence of a suitable base, such as potassium tert-butoxide, in a suitable solvent such as THF.
  • a suitable base such as potassium tert-butoxide
  • THF a suitable solvent
  • the trans and cis isomers may be separated by standard techniques known in the art.
  • a compound of Formula (II) in which any substituent comprises -C 2-4 alkyl may be prepared by reduction of an alkenyl substituent, for example using hydrogen, optionally under pressure, in the presence of a suitable catalyst such as palladium on carbon, in a suitable solvent such as ethanol.
  • a compound of Formula (II) in which any substituent comprises -C(O)NR A R B may be prepared by reacting a suitable acid substituent with an amine (HNR A R B ) in the presence of a coupling agent such as HATU, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a compound of Formula (II) in which any substituent comprises -C(O)NR A R B may be prepared by reacting a suitable acid chloride substituent with an amine (HNR A R B ) in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -NR E C(O)R D may be prepared by reacting a suitable amine substituent with a carboxylic acid (R 0 CO 2 H) in the presence of a coupling agent such as HATU, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a compound of Formula (II) in which any substituent comprises -NR E C(O)R D may be prepared by reacting a suitable amine substituent with an acid chloride in the presence of a suitable base such as triethylamine in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -NR E SO 2 R D may be prepared by reacting an amine substituent with a suitable sulfonyl chloride in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -SO 2 NR F R G may be prepared by reacting a sulfonyl chloride substituent with a suitable amine (HNR F R G ) in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -SO 2 R A may be prepared by oxidation of a compound in which a substituent represents -SR A , using for example oxone, sodium periodate, 3-chloro perbenzoic acid, or hydrogen peroxide.
  • a suitable solvent such as dichloromethane
  • A is an alkoxy, benzyloxy or silyloxy, and R 1 and R 4 are as defined above for
  • Formula (I) 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 (III) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared from compounds of Formula (IV) in which A is an alkoxy, benzyloxy or silyloxy, and R 1 and R 4 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, 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, in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • Compounds of Formula (III) in which A is hydroxy may be prepared from compounds of Formula (III) in which A is an alkoxy, benyloxy or silyloxy group, 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).
  • R 1 is as defined above for Formula (I) with compounds of Formula (Vl) in which R 4 and A are as defined above for Formula (II) and R' is -C 1-4 alkyl (such as ethyl) in a suitable solvent such as ethanol or xylene, preferably in the temperature range 50-75 0 C.
  • R 1 is as defined above for Formula (I) and P is a suitable nitrogen protecting group such as benzylidine, with compounds of Formula (Vl) in a suitable solvent such as ethanol or xylene, preferably in the temperature range 50-75 0 C.
  • a suitable acid such as hydrochloric acid
  • a suitable solvent such as ethanol
  • Compounds of Formula (II) may also be prepared by reaction of a compound of Formula (VIII) in which A is an alkoxy, benzyloxy or silyloxy group, and R 1 , R 2 and R 4 are as defined above for Formula (I); with 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, in a suitable solvent such as dimethylformamide, in the presence of a suitable base such as sodium hydride or sodium f-butoxide, optionally in the presence of triethylamine.
  • 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, in a suitable solvent such as dimethylform
  • Compounds of Formula (VIII) may be prepared from compounds of Formula (IV) by reaction with a suitable acylating agent, for example R 2 -C(O)-Y, in which Y is a halo atom, preferably chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable acylating agent for example R 2 -C(O)-Y, in which Y is a halo atom, preferably chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, optionally in the presence of a suitable base, for example pyridine or triethylamine.
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of an amine base.
  • A is a hydroxyl or an alkoxy, benzyloxy or silyloxy group
  • R 2 , R 3 and R 4 are as defined above for Formula (I); by treatment with an aryl or heteroaryl boronic acid (R ⁇ -R x - boronic acid) in the presence of a copper reagent such as copper (II) acetate.
  • a copper reagent such as copper (II) acetate.
  • the reaction is carried out in the presence of a base, such as pyridine, in air, and in a suitable solvent such as dichloromethane or THF, and at a temperature in the range 10-30 0 C.
  • compounds of Formula (II) may be prepared by reaction of compounds of Formula (IX) with an aryl or heteroaryl halide or triflate (R ⁇ -R x -halide or R ⁇ -R x -triflate) in the presence of a copper catalyst such as copper (I) iodide.
  • the reaction is carried out in the presence of a base such as potassium carbonate, and in the presence of a reagent such as trans- ⁇ ,2-diaminocyclohexane or trans-N,N'-dimethyl-1 ,2-cyclohexanediamine, or a combination thereof in a suitable solvent such as dioxane, DMF or pyridine or a combination thereof, and at a temperature in the range 90-180 0 C.
  • a base such as potassium carbonate
  • a reagent such as trans- ⁇ ,2-diaminocyclohexane or trans-N,N'-dimethyl-1 ,2-cyclohexanediamine, or a combination thereof
  • a suitable solvent such as dioxane, DMF or pyridine or a combination thereof
  • This reaction can be suitably be performed in a microwave oven.
  • R x , R 2 , R 3 , R 4 and A are as defined for Formula (II) by reaction with a suitable heteroaryl boronic acid, R ⁇ -boronic acid, 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 cesium fluoride, in a suitable solvent such as dioxane.
  • a palladium catalyst such as palladium (II) acetate
  • a reagent such as 2- dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl
  • an additional reagent such as cesium fluoride
  • Z represents B(OH) 2 , and R x , R 2 , R 3 , R 4 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 cesium 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)
  • Compounds of Formula (II)' in which Z is halo may be prepared by reaction of a compound of Formula (IX) with a boronic acid of Formula Z-R x -boronic acid under the conditions described above for the preparation of compounds of Formula (I) and (II) from (IX) and R ⁇ -R x -boronic acid.
  • R 1 represents a 4-ethynylphenyl derivative
  • R 2 , R 3 , R 4 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 C.
  • R 1 represents a 4-(pyrrolopyridine)phenyl
  • R 1 represents a 4-(pyrrolopyridine)phenyl
  • a compound of Formula (II)" in which R 1 represents 4- ethynylphenyl 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
  • the temperature is in the range 50-80 C.
  • pyrrolopyridine synthesis see Heterocycles (1986) 24, 31 , Tetrahedron (2003) 59, 1571 , Synlett (1992) 515.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(oxazolopyridine)phenyl may be prepared by reacting a compound of Formula (II)" in which R 1 represents 4-carboxyphenyl 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 of the 4-carboxyphenyl may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) in a microwave reactor in a suitable solvent such as dioxan (see for example Tetrahedron Letters (2003) 44, 175).
  • Compounds of Formula (II) in which R 1 represents a 4- (oxazolopyridine)phenyl may also be prepared by reacting the 4-carboxyphenyl derivative 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 (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 90-1 10 0 C.
  • 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-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 dioxan (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.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(2,3-dihydro-1,1-dioxo-1 ,2- benzisothiazol-2(3H)-yl)phenyl derivative may be prepared by treatment of a compound of Formula (II)' in which Z represents 4-halo with a 2,3-dihydro-1 ,2-benzisothiazole 1 ,1-dioxide derivative in the presence of copper (I) iodide with a suitable base such as potassium carbonate, and in the presence of a reagent such as trans- ⁇ ,2-diaminocyclohexane or trans- N.N'-dimethyl-i ⁇ -cyclohexanediamine, or a combination thereof in a suitable solvent such as dioxan, DMF or pyridine or a combination thereof, and at a temperature in the range 90- 160 0 C.
  • R 1 represents a 4-(2,3-dihydro-1,
  • 2-yl)phenyl derivative may be prepared by treatment of a compound of Formula (II)" in which R 1 represents a 4-aminophenyl derivative with a phenyl-1 ,2-di-aldehyde derivative in acetic acid optionally with a suitable solvent such as dichloromethane.
  • compounds of Formula (I) or (II) in which in which R 1 represents a 4-(1-oxo-1 ,3-dihydro-2H- isoindol-2-yl)phenyl derivative may also be prepared by treatment of a compound of Formula (II)" in which R 1 represents a 4-aminophenyl derivative with a phenyl-1 ,2-di-aldehyde derivative in acetic acid optionally with a suitable solvent such as dichloromethane.
  • R 1 represents 4-aminophenyl with a suitable phenyl derivative (this being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine, in a suitable solvent such as acetonitrile.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-((1-oxo-1 ,3-dihydro-2H-isoindol- 2-yl)pyridine)phenyl derivative may be prepared by treatment of a compound of Formula (II)" in which R 1 represents 4-aminophenyl with an appropriate pyridine derivative (the pyridine being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as acetonitrile.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(pyrazolopyrimidine)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4-(5-amino-1 H- pyrazole)phenyl 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-(5-methylpyrazolopyrimidine)- phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4- (5-amino-1 H-pyrazole)phenyl with 4,4-dimethoxy-2-butanone in a suitable solvent such as ethanol, suitably the temperature is in the range 60-70°C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(7-methylpyrazolopyrimidine)- phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4- (5-amino-1 H-pyrazole)phenyl with 4,4-dimethoxy-2-butanone 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-(6- methylpyrazolopyrimidine)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4-(5-amino-1 H-pyrazole)phenyl with 1 ,1 ,3,3-tetraethoxy-2- methylpropane in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-110°C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(6- flouropyrazolopyrimidine)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4-(5-amino-1 H-pyrazole)phenyl with 3-diethylamino-2-fluoro-2-propenal 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-(7- aminopyrazolopyrimidine)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents 4-(5-amino-1 H-pyrazole)phenyl with 3-dimethylamino acrylonitrile in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-11O 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(imidazo[1 ,3]thiazol-6-yl)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents a 4- (bromoacetophenone) with 2-aminothiazole in a suitable solvent such as ethanol or acetone, suitably the temperature is in the range 50-70 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(imidazo[1 ,2-a]pyridine-2- yl)phenyl may be prepared by treating a compound of Formula (II)" in which R 1 represents a 4-(bromoacetophenone) with 2-aminopyridine in a suitable solvent such as ethanol or acetone, suitably the temperature is in the range 50-70 0 C.
  • a 4-(imidazo[1 ,3]thiazol-6-yl)phenyl derivative may be prepared by analogy to methods described in Journal of European Chemistry (1995) 30, 901 or JCS Perkin 1 (1989) 643.
  • a 2-(4-bromophenyl)-2H indazole derivative may be prepared by analogy to methods described in Farmaco Ed Sci (1981) 36, 1037 or J. Chem Soc. Perkin Trans 2 (1975), 1185, for example by treating 2-nitrobenzaldehyde with 4-bromoaniline in a suitable solvent such as methanol, and in a separate step reacting the imine with a phosphite such as triethylphosphite, in a microwave reactor at 210°C for 20 mins.
  • a suitable solvent such as methanol
  • 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 2-(4-bromophenyl)-1H-benzimidazole derivative may be prepared by analogy to methods described in J. Heterocyclic Chem. (1994) 31 , 957.
  • a 2-(4-bromophenyl)-1 H-benzoxazole derivative may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175.
  • a 2-(4-bromophenyl)-1H-benzothiazole derivatives may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175 or Synth. Commun. (1990) 20, 3379.
  • 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 0 C.
  • a 4-(oxazolopyridine)phenyl derivative may be prepared by reacting a 4-carboxyphenyl bromide 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 of the 4-carboxyphenyl bromide may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) in a microwave reactor in a suitable solvent such as dioxane (see for example
  • a 4-(oxazolopyridine)phenyl may also be prepared by reacting a 4-carboxyphenyl bromide derivative 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.
  • a 4-(thiazolopyridine)phenyl bromide may be prepared by reacting an appropriate 4- carboxyphenyl bromide 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 dioxan (see for example Tetrahedron Letters (2003) 44, 175).
  • the 4-carboxyphenyl bromide 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.
  • a 4-(thiazolopyridine)-phenyl bromide may be prepared by reacting an appropriate 4- bromophenyl-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 is cyclised using a reagent such as Lawesson's reagent in a suitable solvent such as DMPU 1 at a suitable temperature such as 90-11O 0 C.
  • a 4-(1 -oxo-1 ,3-dihydro-2H-isoindol-2-yl)phenyl bromide derivative may be prepared by treatment of an appropriate 4-aminophenyl bromide derivative with a phenyl-1 ,2-di-aldehyde derivative in acetic acid optionally with a suitable solvent such as dichloromethane.
  • a 4-(1- oxo-1 ,3-dihydro-2H-isoindol-2-yl)phenyl bromide derivative may also be prepared by treatment of an appropriate 4-aminophenyl bromide with a suitable phenyl derivative (this being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine, in a suitable solvent such as acetonitrile.
  • a 4-(1 -oxo-1 ,3-dihydro-2H-isoindol-2-yl)pyridine bromide may be prepared by treatment of an appropriate 4-aminophenyl bromide with an appropriate pyridine derivative (the pyridine being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as acetonitrile.
  • 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 is an alkoxy, benzyloxy or silyloxy group, and R 2 , R 3 and R 4 are as defined above for Formula (I); and P is a suitable protecting group.
  • Suitable protecting groups include, but are not restricted to, benzyl and tert-butyloxycarbonyl .
  • Benzyl groups can be removed by hydrogenation using hydrogen gas with a catalyst such as palladium on carbon in a suitable solvent such as ethanol, optionally in the presence of a suitable acid, for example hydrochloric acid, and optionally conducting the reaction under pressure
  • tert- Butyloxycarbonyl groups may be removed using an acid such as hydrochloric acid or trifluoroacetic acid.
  • compounds of Formula (X) may be prepared from compounds of Formulae (III), (IV) or (VIII) in which the group R 1 is a protecting group instead of a group as defined for Formula (I), by application of the synthetic routes described above in relation to the synthesis of compounds of Formula (II).
  • 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), (IV), (VIII), (IX) and (X) 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), (IV), (VIII), (IX) and (X).
  • racemic compounds of Formula (I), (II), (III), (IV), (VIII), (IX) and (X) 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), (IV), (VIII), (IX) and (X) may be resolved by chiral preparative HPLC.
  • racemic compounds of Formula (I), (II), (III), (IV), (VIII), (IX) and (X) 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, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propane-diol, (-) ephidrine, quinine, brucine.
  • a chiral base for example (S)-alpha methylbenzylamine, (S)-alpha phenylethylamine, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propane-diol, (-) ephidrine, quinine, brucine.
  • Individual enantiomers of Formula (II), (III), (IV), (VIII), (IX) and/or (X) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds.
  • the DMF was removed in vacuo and the residue partitioned between DCM and water.
  • the DCM layer was separated using a hydrophobic frit and concentrated. This was purified by silica gel chromatography eluting with a gradient of ethyl acetatexyclohexane (5:95 to 100:0) followed by ethyl acetate: methanol (100:0 to 50:50) to give the title compound.
  • the reaction was stirred at room temperature for 18 hours.
  • the catalyst was removed by filtration through Celite under a stream of nitrogen and the filtrate concentrated.
  • the residue was dissolved in DCM and basified with saturated sodium bicarbonate solution.
  • the mixture was extracted with DCM and the organic extract washed with brine, dried (MgSO 4 ) and concentrated to give the title compound.
  • Tetrahydro-3-furanol 14.71 g was dissolved in anhydrous DCM (400 mL) and was treated with pyridine (16.95 mL). The mixture was cooled to -10°C under an atmosphere of nitrogen.
  • Trifluoromethane sulfonic anhydride (51.6 g) was added dropwise ensuring the internal temperature of the reaction did not rise above 0 ° C. The reaction was then stirred at -10 ° C for
  • reaction mixture was quenched with aqueous 2M HCI (200 mL) and the organics were separated, dried (Na 2 SO 4 ) and filtered. This solution was then filtered in portions through pre-packed Celite cartridges (2 X 10 g) to give title compound as a DCM solution.
  • the filtrate was passed through a hydrophobic frit to remove residual water and was concentrated in vacuo and purified directly by ISCO companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound.

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Abstract

L'invention concerne des agents antiviraux constitués de composés de formule (I) dans laquelle A, R1, R2, R3 et R4 sont tels que définis dans la description. La présente invention se rapporte en outre à leurs procédés de préparation, et à leur utilisation pour traiter les infections par le virus de l'hépatite C (HCV).
PCT/EP2006/009238 2005-09-23 2006-09-21 Derives de 4-carboxy pyrazole utilises en tant qu'agents antiviraux WO2007039146A1 (fr)

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Cited By (18)

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WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
WO2010052448A2 (fr) * 2008-11-05 2010-05-14 Ucb Pharma S.A. Dérivés de pyrazine fusionnés en tant qu'inhibiteurs de kinase
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US8080569B2 (en) * 2006-11-16 2011-12-20 Sanofi-Aventis Imidazo[2,1-b]thiazoles and their use as pharmaceuticals
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
JP2013540134A (ja) * 2010-10-20 2013-10-31 ビオタ サイエンティフィック マネージメント ピーティーワイ リミテッド ウイルスポリメラーゼ阻害剤
WO2014053450A1 (fr) 2012-10-02 2014-04-10 Bayer Cropscience Ag Composés hétérocycliques utilisés comme pesticides
WO2015065243A1 (fr) 2013-11-01 2015-05-07 Общество с ограниченной ответственностью "Уральский центр биофармацевтических технологий" 2-méthylsilfanlyl-6-nitr-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide l-alginine dihydrate ayant une activité contre le virus de la fièvre du nil occidental
WO2015179392A1 (fr) * 2014-05-21 2015-11-26 Bristol-Myers Squibb Company Composés 2-(aryl- ou hétéroaryl-)phényl(aza)benzofurane pour le traitement de l'hépatite c
EP2957562A1 (fr) * 2014-06-20 2015-12-23 Masarykova univerzita Pyrazolotriazines en tant qu'inhibiteurs de nucléases
US20160060261A1 (en) * 2011-03-30 2016-03-03 Arrien Pharmaceuticals Llc Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors
CN107056653A (zh) * 2017-06-09 2017-08-18 丽珠医药集团股份有限公司 布南色林中间体对氟苯甲酰乙腈的合成方法
CN109535092A (zh) * 2018-12-24 2019-03-29 温州大学 一种苯并三唑类衍生物的制备方法
CN109734686A (zh) * 2019-01-07 2019-05-10 浙江万里学院 一种2-取代苯并呋喃类化合物的催化合成方法
CN110498759A (zh) * 2019-09-12 2019-11-26 天津瑞岭化工有限公司 异吲哚啉酮类化合物的合成方法
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法
CN114907335A (zh) * 2022-02-25 2022-08-16 陕西维世诺新材料有限公司 2-（苯并噻吩-2-基）苯并[d]惡唑衍生物、制备方法及应用

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WO2004096210A1 (fr) * 2003-05-01 2004-11-11 Glaxo Group Limited Derives acyles d'indolines et de tetrahydroquinoleines constituant des inhibiteurs du vhc
WO2005092863A1 (fr) * 2004-03-26 2005-10-06 Smithkline Beecham Corporation Dérivés de 4-carbox pyrazole utiles en tant qu'agents antiviraux
WO2006050034A1 (fr) * 2004-10-29 2006-05-11 Schering Corporation Pyrazoles a substitution 5-carboxyamide et [1,2,4]triazoles utilises en tant qu'agents antiviraux
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US8080569B2 (en) * 2006-11-16 2011-12-20 Sanofi-Aventis Imidazo[2,1-b]thiazoles and their use as pharmaceuticals
WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
US8791141B2 (en) 2008-06-27 2014-07-29 Novartis Ag Organic compounds
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US9242963B2 (en) 2008-06-27 2016-01-26 Novartis Ag Organic compounds
WO2010052448A2 (fr) * 2008-11-05 2010-05-14 Ucb Pharma S.A. Dérivés de pyrazine fusionnés en tant qu'inhibiteurs de kinase
WO2010052448A3 (fr) * 2008-11-05 2010-09-10 Ucb Pharma S.A. Dérivés de pyrazine fusionnés en tant qu'inhibiteurs de kinase
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
US9611222B2 (en) 2010-09-17 2017-04-04 Purdue Pharma L.P. Pyridine compounds and the uses thereof
US20130303526A1 (en) * 2010-09-17 2013-11-14 Purdue Pharma L.P. Pyridine Compounds and the Uses Thereof
US9056832B2 (en) 2010-09-17 2015-06-16 Purdue Pharma L.P. Pyridine compounds and the users thereof
JP2013540134A (ja) * 2010-10-20 2013-10-31 ビオタ サイエンティフィック マネージメント ピーティーワイ リミテッド ウイルスポリメラーゼ阻害剤
US20160060261A1 (en) * 2011-03-30 2016-03-03 Arrien Pharmaceuticals Llc Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors
US9669028B2 (en) * 2011-03-30 2017-06-06 Arrien Pharmaceuticals Llc Substituted 5-(pyrazin-2-yl)-1H-pyrazolo [3, 4-B] pyridine and pyrazolo [3, 4-B] pyridine derivatives as protein kinase inhibitors
US11548854B2 (en) 2012-10-02 2023-01-10 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2014053450A1 (fr) 2012-10-02 2014-04-10 Bayer Cropscience Ag Composés hétérocycliques utilisés comme pesticides
US9802899B2 (en) 2012-10-02 2017-10-31 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10961201B2 (en) 2012-10-02 2021-03-30 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US11332448B2 (en) 2012-10-02 2022-05-17 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10435374B2 (en) 2012-10-02 2019-10-08 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10689348B2 (en) 2012-10-02 2020-06-23 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2015065243A1 (fr) 2013-11-01 2015-05-07 Общество с ограниченной ответственностью "Уральский центр биофармацевтических технологий" 2-méthylsilfanlyl-6-nitr-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide l-alginine dihydrate ayant une activité contre le virus de la fièvre du nil occidental
US9790227B2 (en) 2013-11-01 2017-10-17 Limited Liability Company “Ural Center Of Biopharmaceutical Technology” 2-methylsulphanyl-6-nitro-7-oxo-1, 2, 4-triazolo [5, 1-C] [1, 2, 4] triazinide L-arginine dihydrate active toward west nile virus
WO2015179392A1 (fr) * 2014-05-21 2015-11-26 Bristol-Myers Squibb Company Composés 2-(aryl- ou hétéroaryl-)phényl(aza)benzofurane pour le traitement de l'hépatite c
US9840511B2 (en) 2014-05-21 2017-12-12 Bristol-Meyers Squibb Company 2-(aryl or heteroaryl-)phenyl (AZA)benzofuran compounds for the treatment of hepatitis C
EP2957562A1 (fr) * 2014-06-20 2015-12-23 Masarykova univerzita Pyrazolotriazines en tant qu'inhibiteurs de nucléases
CN107056653A (zh) * 2017-06-09 2017-08-18 丽珠医药集团股份有限公司 布南色林中间体对氟苯甲酰乙腈的合成方法
CN109535092B (zh) * 2018-12-24 2021-05-11 温州大学 一种苯并三唑类衍生物的制备方法
CN109535092A (zh) * 2018-12-24 2019-03-29 温州大学 一种苯并三唑类衍生物的制备方法
CN109734686A (zh) * 2019-01-07 2019-05-10 浙江万里学院 一种2-取代苯并呋喃类化合物的催化合成方法
CN109734686B (zh) * 2019-01-07 2022-07-01 浙江万里学院 一种2-取代苯并呋喃类化合物的催化合成方法
CN110498759A (zh) * 2019-09-12 2019-11-26 天津瑞岭化工有限公司 异吲哚啉酮类化合物的合成方法
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法
CN114907335A (zh) * 2022-02-25 2022-08-16 陕西维世诺新材料有限公司 2-（苯并噻吩-2-基）苯并[d]惡唑衍生物、制备方法及应用

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