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WO2008017688A1 - Dérivés 2-carboxy-thiophène comme agents anti-viraux - Google Patents

Dérivés 2-carboxy-thiophène comme agents anti-viraux Download PDF

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Publication number
WO2008017688A1
WO2008017688A1 PCT/EP2007/058231 EP2007058231W WO2008017688A1 WO 2008017688 A1 WO2008017688 A1 WO 2008017688A1 EP 2007058231 W EP2007058231 W EP 2007058231W WO 2008017688 A1 WO2008017688 A1 WO 2008017688A1
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WO
WIPO (PCT)
Prior art keywords
amino
trans
carbonyl
ylphenyl
methylcyclohexyl
Prior art date
Application number
PCT/EP2007/058231
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English (en)
Inventor
Charles David Hartley
Jacqueline Elizabeth Mordaunt
Pritom Shah
Martin John Slater
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Smithkline Beecham Corporation
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Publication date
Priority claimed from GB0616060A external-priority patent/GB0616060D0/en
Priority claimed from GB0701197A external-priority patent/GB0701197D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2008017688A1 publication Critical patent/WO2008017688A1/fr

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Classifications

    • 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
    • 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
    • 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 2-carboxy thiophene derivatives useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication.
  • HCV Hepatitis C Virus
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to
  • HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S).
  • HCV post-transfusion non A, non-B hepatitis
  • NANBH non-B hepatitis
  • this virus was assigned as a new genus in the Flaviviridae family.
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and vi rally-en coded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931-960; Raven Press, N.Y.).
  • 3' NTR which roughly consists of three regions: an - 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1 a and 1 b isolates).
  • the essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051 ).
  • inhibition of NS5B RdRp activity is predicted to be useful to treat HCV infection.
  • genotype 1 Although the predominant HCV genotype worldwide is genotype 1 , this itself has two main subtypes, denoted 1a and 1 b. As seen from entries into the Los Alamos HCV database (www.hcv.lanl.gov) (Table 1 ) there are regional differences in the distribution of these subtypes: while genotype 1 a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1 b. Table 1
  • PCT publication number WO2002/100851 generically discloses certain compounds, including certain 2-carboxy thiophene compounds, having HCV inhibitory activity.
  • the data provided relates to an HCV polymerase assay utilising the 1 b genotype.
  • the compounds disclosed have the formula (I) v-Yy s V R'
  • X is chosen from -N(R 3 )M(R 2 ) or -JN(R 2 )(R 3 );
  • M is chosen from -SO 2 -, -SO-, -S-, -C(O)-, -C(S)-, -CH 2 C(O)N(R 4 )-, -CH 2 C(S)N(R 15 )-, -
  • R 4 is Ci -6 alkyl
  • R 8 is chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6 -i 4 aryl, C 3- i 2 heterocycle, C 3- i 2 heteroaralkyl, C 6- i 6 aralkyl;
  • R 15 is chosen from H or d- ⁇ alkyl
  • J is chosen from -C(W)-, -C(R 6 )-, -S-, -S(O)-, or -SO 2 -;
  • W is chosen from O, S or NR 7 ;
  • R 7 is chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6 -i 4 aryl, C 3- i 2 heterocycle, C 3- i 2 heteroaralkyl, C 6- i 6 aralkyl;
  • R 6 is chosen from H, Ci_i 2 alkyl, C 6 -i 4 aryl, or C 6- i 6 aralkyl;
  • Y 1 is chosen from a bond, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
  • Y is chosen from COOR 16 , COCOOR 5 , P(0)0ROR b , S(O)OR 5 , S(O) 2 OR 5 , tetrazole,
  • R 9 , R 5 , R 10 and R 11 are each independently chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2-
  • R a and R b are each independently chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6- i 4 aryl, C 3- i 2 heterocycle, C 3- i 8 heteroaralkyl, C 6- i 8 aralkyl; or R a and R b are taken together with the oxygens to form a 5 to 10 membered heterocycle;
  • R 16 is chosen from H, Ci.-i 2 alkyl, C 2 -i 2 alkenyl, C 2 -i 2 alkynyl, C 6- i 4 aryl, C 3- i 2 heterocycle, C 3- i ⁇ heteroaralkyl, C 6- i 8 aralkyl; provided that R 16 is other than methyl or ethyl;
  • R 1 is chosen from Ci.-i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6- i 4 aryl, C
  • R 3 is chosen from H, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C 6 -i 4 aryl, C 3- i 2 heterocycle, C 3- i ⁇ heteroaralkyl, C 6- i 8 aralkyl; and Z is chosen from H, halogen, or d- ⁇ alkyl.
  • PCT publication number WO2003/062215 generically discloses certain compounds, including certain 2-carboxy thiophene compounds, having kinase inhibiting activity.
  • the compounds disclosed have the fo
  • V is, inter alia, a group of formula (i)
  • R 1 represents T, N-(CO)R 6 R 7 , N(R 6 )COR 7 , or NC(O)OR 6 R 7 ;
  • T represents H, (hetero)alkyl, alkenyl, cycloalkyl, (hetero)aryl, arylalkyl or alkylaryl;
  • R 8 represents T, NR 3 R 4 , N-C(O)R 3 R 4 , N(R 3 )COR 4 , OR 3 , COR 3 , CO 2 R 3 or OCOR 3 ;
  • R 2 , R 5 represent T, alkylaryl, carboxyl, halo or CF 3 ;
  • R 3 , R 4 , R 6 , R 7 represent T, alkylaryl, COOR 5 or COR 5 ;
  • X, Y, Z represent CH or N;
  • Z is chosen from 3-7 membered heterocycle or 3-7 membered cycloalkyl; Y is 6-10 membered aryl; X is 3-10 membered cycloalkyl; and m is an integer from 0-1
  • PCT publication number WO2004/110357 generically discloses a range of compounds, including certain 2-carboxy thiophene compounds, having phosphodiesterase 6 delta (PDE6D) modulating activity.
  • the compounds disclosed have the formula (I)
  • 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 from 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 2-carboxy thiophene compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides a compound of Formula (I) :
  • A represents hydroxy
  • R 1 represents -R x -R ⁇ ;
  • R x represents phenyl (optionally substituted at one of the mef ⁇ -positions to the thiophene by halo, methyl, ethyl or trifluoromethyl) or a 5- or 6-membered heteroaryl (optionally substituted at one of the mef ⁇ -positions to the thiophene by halo, methyl, ethyl, methoxy or trifluoromethyl) bonded through a ring carbon atom to the carbon atom of the thiophene;
  • R ⁇ represents a 8-, 9- or 10-membered heteroaryl, bonded such that when R x is phenyl or a 6-membered heteroaryl, R ⁇ is in the para-position;
  • R 3 represents -(CH 2 ) 2 -O-(CH 2 ) m H, -CH-(CH 2 OMe) 2 , -CH(R 4 )-CH 2 -O-(CH 2 ) m H, - CH 2 -CH(R 4 )- O-(CH 2 ) m H, tetrahydrofuran-3-yl, -CH 2 -tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl, -CH 2 - tetrahydro-2/-/-pyran-4-yl or frans-4-hydroxycyclohex-1-yl;
  • R 4 represents -Ci -3 alkyl
  • n represents an integer selected from 1 or 2;
  • the compounds of the present invention exhibit improved potency against the replication of HCV (1 a and 1 b genotypes), and therefore have the potential to achieve greater efficacy in man. High potency in both genotypes is considered to be advantageous.
  • a compound of Formula (I) or pharmaceutically acceptable salts, solvates and 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 and esters thereof.
  • a compound of Formula (I) or pharmaceutically acceptable salts, solvates and 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 or trifluoromethyl. In a further aspect, 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-t)][1 ,3]thiazol-6-yl, 7-amino-5-methylpyrazolo[1 ,5- a]pyrimidin-2-yl, 5-methylpyrazolo-[1 ,5-a]pyrimidin-2-yl, 7-aminopyrazolo[1 ,5-a]pyrimidin-2-yl, [1 ,3]oxazolo[4,5-b]pyridin-2-yl, furo[2,3-b]pyridin-5-yl, 5-amino-1 ,3-benzoxazol-2-yl, [1 ,3]oxazolo[5,4-b]pyridin-2-yl, or furo[3,2-c]
  • 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-t)][1 ,3]thiazol-6-yl or 7-aminopyrazolo[1 ,5-a]pyrimidin- 2-yl.
  • R ⁇ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo[2,1-b][1 ,3]thiazol-6-yl, 7-aminopyrazolo[1 ,5-a]pyrimidin-2- yl or [1 ,3]oxazolo[4,5-b]pyridin-2-yl.
  • R ⁇ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-2-yl, 7- aminopyrazolo[1 ,5-a]pyrimidin-2-yl or imidazo[1 ,2-a]pyridin-2-yl.
  • R 2 represents C 6 cycloalkyl optionally substituted by one or more Ci -4 alkyl substituents (wherein the alkyl group may itself be optionally substituted by one or more fluoro atoms). In one aspect, the alkyl group is not substituted. In one aspect, R 2 represents C ⁇ cycloalkyl substituted by methyl or trifluoromethyl. In one aspect, R 2 represents C ⁇ cycloalkyl substituted at the 4-position, for example with trans stereochemistry. In a further aspect, R 2 represents frans-4-methylcyclohexyl or frans-4-(trifluoromethyl)cyclohexyl. In a further aspect, R 2 represents frans-4-methylcyclohexyl.
  • R 3 represents -(CH 2 ) 2 -O-(CH 2 ) m H, -CH-(CH 2 OMe) 2 , -CH(Me)CH 2 -O-Me, tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl, -CH 2 -tetrahydro-2/-/-pyran-4-yl or trans-4- hydroxycyclohex-1-yl.
  • R 3 represents methoxyethyl, ethoxyethyl, 1- methyl-2-(methyloxy)ethyl, tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl or trans-4- hydroxycyclohex-1 -yl.
  • R 3 represents -(CH 2 ) 2 -O-(CH 2 ) m H, -CH-(CH 2 OMe) 2 , tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl or -CH 2 -tetrahydro-2/-/-pyran-4-yl.
  • R 3 represents methoxyethyl, ethoxyethyl, tetrahydrofuran-3-yl or tetrahydro-2/-/-pyran-4-yl.
  • R 3 represents methoxyethyl, tetrahydrofuran-3-yl or tetrahydro-2/-/-pyran-4-yl.
  • R 4 represents methyl
  • R x represents phenyl optionally substituted by halo, methyl or trifluoromethyl
  • 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-t)][1 ,3]thiazol-6-yl, 7-amino-5-methylpyrazolo[1 ,5-a]pyrimidin-2-yl, 5- methylpyrazolo-[1 ,5-a]pyrimidin-2-yl, 7-aminopyrazolo[1 ,5-a]pyrimidin-2-yl, [1 ,3]oxazolo[4,5- b]pyridin-2-yl, furo[2,3-b]pyridin-5-yl, 5-amino-1 ,3-benzoxazol-2-yl, [1 ,3]
  • R 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, 7- aminopyrazolo[1 ,5-a]pyrimidin-2-yl or [1 ,3]oxazolo[4,5-b]pyridin-2-yl;
  • R 2 represents trans-4- methylcyclohexyl or frans-4-(trifluoromethyl)cyclohexyl; and
  • R 3 represents methoxyethyl, ethoxyethyl, 1-methyl-2-(methyloxy)ethyl, tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl or frans-4-hydroxycycl
  • the present invention provides at least one chemical entity chosen from compounds of 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 a 5- or 6-membered heteroaryl bonded through a ring carbon atom to the carbon atom of the thiophene;
  • R ⁇ represents a 8-, 9- or 10-membered heteroaryl, bonded such that when R x is phenyl, R ⁇ is in the para-position;
  • R 2 represents C 6 cycloalkyl optionally substituted by one or more unsubstituted Ci -4 alkyl substituents;
  • R 3 represents -(CH 2 ) 2 -O-(CH 2 ) m H, -CH-(CH 2 OMe) 2 , tetrahydrofuran-3-yl, tetrahydro-2H- pyran-4-yl or -CH 2 - tetrahydro-2/-/-pyran-4-yl;
  • n represents an integer selected from 1 or 2;
  • the present invention provides at least one chemical entity chosen from compounds of Formula (Ib) :
  • 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 thiophene;
  • R ⁇ represents a 8, 9 or 10-membered heteroaryl, bonded such that when R x is phenyl or a 6- membered heteroaryl, R ⁇ is in the para-position;
  • R 3 represents -(CH 2 ) 2 -O-(CH 2 ) m H, -CH-(CH 2 OMe) 2 , -CH(R 4 )-CH 2 -O-(CH 2 ) m H, - CH 2 -CH(R 4 )- O-(CH 2 ) m H , tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-4-yl or -CH 2 -tetrahydro-2/-/-pyran-4-yl;
  • R 4 represents Ci -3 alkyl
  • n represents an integer selected from 1 or 2;
  • At least one chemical entity means at least one chemical substance chosen from the group of compounds consisting of compounds of Formula I and pharmaceutically acceptable derivatives thereof.
  • 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.
  • At least one chemical entity means at least one chemical substance chosen from the group of compounds consisting of compounds of Formula I and salts, solvates and esters thereof.
  • 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 -Ci -4 alkyl.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds.
  • 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.
  • 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 -Ci -6 alkyl, halo, -OR E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR A C(0)R°, -NR A C0 2 R°, -NR A C(0)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl, -CF 3 , -OCF 3 and phenyl.
  • 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 -Ci -6 alkyl, halo, -OR E , -SR E , -C(O)NR B R C , -C(O)R 0 , -CO 2 R 0 , -NR B R C , -NR A C(O)R°, -NR A CO 2 R D , -NR A C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , oxo, nitro, cyano, heterocyclyl, -CF 3 and phenyl.
  • 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, -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- ⁇ 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 tetrahydrofuran- 3-yl.
  • 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 -Ci -6 alkyl.
  • R B and R c independently represent hydrogen, -d- ⁇ alkyl, aryl, heterocyclyl or heteroaryl; or RR BB aanndd RR cc ttooggeetthheerr wwiitthh tthhee nniittirogen atom to which they are attached form a 5 or 6 membered saturated cyclic group.
  • R D is selected from the group consisting of -Ci -6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • R E represents hydrogen, -Ci -6 alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl or heteroaryl.
  • R F and R G are independently selected from the group consisting of hydrogen, -d- ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group.
  • the present invention provides a compound chosen from the group consisting of:
  • compositions are also included in the present invention.
  • present invention also covers the pharmaceutically acceptable salts of the compounds 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, 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 (I) 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 , and R 3 are as defined above for Formula (I).
  • R 1 , R 2 , and R 3 are as defined above for Formula (I)
  • an appropriate base for example aqueous sodium hydroxide or lithium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or combinations thereof.
  • the temperature is in the range 25 to 100 0 C, for example 25 to 5O 0 C.
  • A is te/f-butoxy
  • R 1 , R 2 and R 3 are as defined above for Formula (I)
  • an appropriate acid for example trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 0 to 5O 0 C, for example 15 to 3O 0 C.
  • A is hydroxy or an alkoxy, benzyloxy or silyloxy group, and R 2 and R 3 are as defined above for Formula (I) and X is a halogen such as bromide or iodide; with a suitable boronic acid R 1 -B(OH) 2 or boronate ester R 1 -B(0R')(0R"), in which R' and R" are independently alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by alkyl, such as a pinacol ester, in the presence of a palladium catalyst such as tetrakistriphenyl phosphine palladium or bis-[(diphenylphosphino)- ferrocene]-palladium-(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, DME, 1 ,4-dioxane, a
  • A is hydroxy or an alkoxy, benzyloxy or silyloxy group
  • R 2 and R 3 are as defined above for Formula (I) and
  • X is a suitable boronic acid -B(OH) 2 or boronate ester -B(OR')(OR"), in which R' and R" are independently alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by alkyl, such as a pinacol ester, with R 1 -Hal wherein Hal is a halogen such as bromide or iodide, in the presence of a palladium catalyst such as (tetrakistriphenyl phosphine) palladium or bis- [(diphenylphosphino)-ferrocene]-palladium-(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, DME, 1 ,4-dio
  • 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 (I2V a > nd R 3 are as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a halogen source such as iodine in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78°C to -20 0 C, optionally under an inert atmosphere.
  • a suitable base such as lithium diisopropylamide
  • a halogen source such as iodine
  • a suitable solvent such as tetrahydrofuran
  • A is an alkoxy, benzyloxy or silyloxy, and R (I2V a > nd R 3 are as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a boronate source such as B(OR)3 wherein R is an alkyl group, for example methyl, in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78°C to -20 0 C.
  • a suitable base such as lithium diisopropylamide and a boronate source such as B(OR)3 wherein R is an alkyl group, for example methyl
  • 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 are as defined above may be prepared by reaction of a compound of Formula (V)
  • a an alkoxy, benzyloxy or silyloxy group by treatment with a suitable vinyl ether, or a suitable aldehyde or a suitable ketone in the presence of a suitable acid, such as acetic acid, and a suitable reducing agent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane.
  • a suitable acid such as acetic acid
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • compounds of Formula (V) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared from compounds of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy are as defined above for Formula (I), by treatment with a suitable alkylating agent R 3 -X' where X' is a halo group such as chloride, bromide or iodide, or X' is a sulphonate ester such as methanesulfonate and R 3 is as defined above for Formula (I), in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • 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 and R 3 is as defined above for Formula (I)
  • suitable solvent such as
  • A is an alkoxy, benzyloxy or silyloxy group and X is a halo group such as bromo
  • a palladium catalyst such as tris(dibenzylidenacetone)dipalladium in the presence of a reagent such as 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP) and a base such as cesium carbonate
  • BINAP 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl
  • BINAP 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl
  • a base such as cesium carbonate
  • A is an alkoxy, benzyloxy or silyloxy group, and R 2 is as defined above for Formula
  • Compounds of Formula (VIII) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (Vl) in which A an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • a an alkoxy, benzyloxy or silyloxy group, and R 1 and R 3 are as defined above for Formula (I) with a suitable acylating agent, for example R 2 -C(0)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine or triethylamine and thereafter removing any protecting group if desired.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • X is a halogen such as bromide or iodide and R 3 is as defined above for Formula (I)
  • R 1 is as defined above for Formula (I)
  • a palladium catalyst such as tetrakistriphenyl phosphine palladium or bis-[(diphenylphosphino)-ferrocene]-palladium-(ll) chloride
  • a suitable base such as sodium carbonate
  • a suitable solvent such as DMF, methanol or toluene, or combinations thereof
  • A is an alkoxy, benzyloxy or silyloxy group and X is a halogen such as bromide or iodide, 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.
  • compounds of Formula (X) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared from compounds of Formula (Xl) in which A is an alkoxy, benzyloxy or silyloxy, 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 and R 2 is as defined above for Formula (I), in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • Compounds of Formula (X) in which A is an alkoxy, benzyloxy or silyloxy group, R 3 is as defined above for Formula (I) and X is a halogen such as bromide or iodide, may also be prepared by reaction of a compound of Formula (V), by treatment with a suitable base such as lithium diisopropylamide and a halogen source such as iodine or bromine, in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78°C to -20 0 C.
  • P is a suitable protecting group such as COCF 3 or CO 2 1 Bu.
  • a suitable protecting group such as COCF 3 or CO 2 1 Bu.
  • a suitable base such as aqueous potassium carbonate optionally in the presence of an alcohol such as methanol
  • a suitable acid such as hydrochloric acid in a suitable solvent such as 1 ,4-dioxane.
  • Compounds of Formula (XII) in which A is an alkoxy, benzyloxy or silyloxy group as defined above for Formula (I), X is a halo atom such as iodide and P is a suitable protecting group such as COCF 3 or CO 2 1 Bu, may be prepared by reaction of a compound of Formula (XIII) wherein P is a suitable protecting group such as COCF 3 or CO 2 1 Bu, with a suitable base such as lithium diisopropylamide and a halogen source such as iodine, in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78°C to -20 0 C.
  • Compounds of Formula (XIII) in which A is an alkoxy, benzyloxy or silyloxy group as defined above for Formula (I) may be prepared by treating compounds of Formula (VI) with trifluoroacetic anhydride or di-tert-butyl di carbonate in a suitable solvent such as ether or acetonitrile, optionally in the presence of a catalyst such as DMAP.
  • A is an alkoxy, benzyloxy or silyloxy, and R 2 is as defined above for Formula (I)
  • R 3 is 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 and R 3 is as defined above for Formula (I), in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • Compounds of Formula (XIV) in which A is an alkoxy, benzyloxy or silyloxy group may also be prepared from compounds of Formula (Xl) with a suitable acylating agent, for example R 2 - C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable acylating agent for example R 2 - C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of the base.
  • R ⁇ -boronic acid in which R ⁇ is as defined in Formula (I), in the presence of a palladium catalyst such as palladium (II) acetate, Pd(PPh 3 ) 4 , 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, Pd(PPh 3 ) 4
  • a reagent such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl
  • an additional reagent such as caesium fluoride
  • the heteroaryl boronic acids may be reacted 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- dimethylamino)-biphenyl
  • an additional reagent such as caesium fluoride
  • Z represents B(OH) 2 , and R x , R 2 , R 3 and A are as defined for Formula (II), by reaction with a suitable heteroaryl halide R ⁇ -hal, in which suitably the halide is bromo or iodo, in the presence of a palladium catalyst such as palladium (II) acetate, Pd(PPh 3 ) 4 , 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, Pd(PPh 3 ) 4
  • a reagent such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl
  • the heteroaryl boronic acids may be reacted 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-dimethylamino)- biphenyl
  • an additional reagent such as caesium fluoride
  • Compounds of Formula (II)' in which Z is halo may be prepared by reaction of a compound of Formula (III) 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.
  • Boronic acids Z-R x -boronic acid, R ⁇ -R x -boronic acid and R ⁇ -boronic acid are commercially available or may be prepared by analogy to methods provided in Organometallics (1983) 2, 1316, Chem Revs.
  • R 1 represents a 4-ethynylphenyl derivative
  • R 2 , R 3 , and A are as defined above for Formula (II)
  • a suitable pyridine the pyridine being substituted with adjacent hydroxy and iodo groups
  • a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide
  • a suitable solvent such as triethylamine or DMF.
  • the temperature is in the range 50-80 0 C.
  • Compounds of Formula (I) or (II) in which R 1 represents a 4-(pyrrolopyridine)phenyl may be prepared by treatment of 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 0 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-(pyrazolopyrimidine)phenyl may be prepared by treating a compound of Formula (II)" in which 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.
  • a 2-(4-bromophenyl)imidazo[1 ,2-a]pyridine derivative may be prepared by analogy to methods described in Tetrahedron Letters (2001 ) 42, 3077.
  • a 4-(furopyridine)phenyl bromide may be prepared by treatment of a 4-ethynylphenyl bromide with a suitable pyridine (the pyridine being substituted with adjacent hydroxy and iodo groups), with a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, in a suitable solvent such as triethylamine or DMF.
  • a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide
  • a suitable solvent such as triethylamine or DMF.
  • the temperature is in the range 50-80 0 C.
  • a 4-(pyrazolopyrimidine)phenyl bromide may be prepared by treating a 3-(4-bromophenyl)- 1 H-pyrazole-5-amine with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-110 0 C.
  • 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 te/f-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.
  • 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 (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.
  • Ref 2 Burkholder, Conrad; Dolbier, William R.; Medebielle, Maurice; Ait-Mohand, Samia, Tetrahedron Lett, 42, 17, 2001 , 3077 - 3080.
  • 6-(4-lodophenyl)imidazo[2,1-b][1 ,3]thiazole (2 g) was dissolved in dry 1 ,4-dioxane (40 mL). To this stirred solution was added potassium acetate (1.8 g), bis(pinacolato)diboron (2.34 g) and 1 ,1 '-bis (diphenylphosphino)ferrocene dichloro palladium (II) (350 mg). The reaction mixture was heated to 100 0 C, and stirred under nitrogen for 18 h.
  • Tetrahydro-4H-pyran-4-one (5.87 mL) was added to a solution of methyl-3-amino-2 thiophene carboxylate (5 g) in dry DCM (100 mL) at room temperature under nitrogen.
  • Glacial acetic acid (5.46 mL) was added slowly.
  • Sodium triacetoxyborohydride (10.11 g) was then added in portions over 30 min. The resulting solution was left to stir at room temperature for 20 h. The mixture was treated with 8% sodium bicarbonate solution slowly
  • Triphenylphosphine (5.52 g) was added in portions to a solution of intermediate 12 (2.99 g) in dry DCM (48 mL) at room temperature under nitrogen.
  • n-Butyl lithium (10 ml_, 1.6 mol in hexanes) was added dropwise to diisiopropylamine (2.27 ml.) at O 0 C under nitrogen, followed by the addition of 10 ml. dry THF. The reaction mixture was stirred at O 0 C for 10 mins and then cooled to -78 0 C. A solution of Intermediate 23 (2.84 g) in dry THF (30 ml.) was added dropwise under nitrogen to the solution of the LDA maintaining an internal temperature -78°C. The reaction was stirred at -78°C for 1 h.
  • the crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 0-100% EtOAc in cyclohexane.
  • Ref 3 Burkholder, Conrad; Dolbier, William R.; Medebielle, Maurice; Ait-Mohand, Samia, Tetrahedron Lett, 42, 17, 2001 , 3077 - 3080.
  • the crude material was purified by reverse phase ISCO Companion chromatography, using a C18 cartridge, eluting with a gradient 40% MeCN (0.05% formic acid)/water (0.1% formic acid) to 95% MeCN (0.05% formic acid) to give the title compound.
  • the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of Formula (I) or a pharmaceutically acceptable salt 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 compounds 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 compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of 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, and preferably 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, preferably 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 In Vitro Detection of inhibitors of HCV RNA-dependent RNA Polymerase Activity
  • 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 (1 1 ), 1997, 8416. 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 4 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1 M MnCI 2 (0.25 ml_), glycerol (2.5ml_), 10% NP-40 (0.025 ml.) and Water (7.225 ml_), Total 10 ml_.
  • 2x concentrated enzyme buffer contained 1 M-Tris-HCI, pH7.5 (0.4 ml_), 5M NaCI (0.2 ml_), 1 M-MgCI 2 (0.4 ml_), glycerol (1 ml_), 10% NP-40 (10 ⁇ l_), 1 M DTT (20 ⁇ l_) and water (7.97 ml_), Tota ⁇ O 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_), Tote/ 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 0 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 0 C after which 120 ⁇ l_ 0.1 M EDTA in PBS was added.
  • the plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.
  • genotype 1 a and genotype 1 b may be demonstrated, for example, using the following cell based assay:
  • 100 ⁇ l_ of medium containing 10% FCS were added to each well of clear, flat-bottomed 96 well microplates, excepting wells in the top row.
  • Test compound was diluted in assay medium to twice the final required starting concentration from a 40 mM stock solution in DMSO.
  • 200 ⁇ l_ of the starting dilution were introduced into two wells each in the top row and doubling dilutions made down the plate by the sequential transfer of 100 ⁇ l_ aliquots with thorough mixing in the wells; the final 100 ⁇ l_ were discarded.
  • the two bottom rows were not used for compound dilutions.
  • Huh-7 HCV replicon cell monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells were resuspended in assay medium at either 2 x 10 5 cells/mL (sub-line 5-15; genotype 1 b; Lohmann, V., Korner, F., Koch, J-O., Herian, U., Thielmann, L. and Bartenschlager, R., Science, 1999, 285, 110- 1 13) or at 3 x 10 5 cells/mL (genotype 1 a; Gu, B., Gates, AT., Isken, O., Behrens, S. E. and Sarisky, R.T., J.
  • the plates were incubated at 37°C for 2 hours and washed 3 times with PBS/0.05% Tween 20, then 50 ⁇ L of horseradish peroxidase conjugated, anti-mouse, rabbit polyclonal serum (Dako #P0260), diluted 1/1000, were added to all wells. The plates were incubated for a further hour, the antibody removed and the cell sheets washed 5 times with PBS/Tween and blotted dry. The assay was developed by the addition of 50 ⁇ L of ortho- phenylenediamine/peroxidase substrate in urea/citrate buffer (SigmaFast, Sigma #P-9187) to each well, and colour allowed to develop for up to 15 minutes. The reaction was stopped by the addition of 25 ⁇ l_ per well of 2 M sulphuric acid and the plates were read at 490 nm on a Fluostar Optima spectrophotometer.
  • the substrate solution was removed and the plates were washed in tap water, blotted dry and the cells stained with 5 % carbol fuchsin in water for 30 minutes. The stain was discarded and the cell sheets washed, dried and examined microscopically to assess cytotoxicity. Data analysis
  • the absorbance values from all compound-free wells that had received both primary and secondary antibodies were averaged to obtain a positive control value.
  • the mean absorbance value from the compound-free wells that had not received the primary antibody was used to provide the negative (background) control value.
  • the readings from the duplicate wells at each compound concentration were averaged and, after the subtraction of the mean background from all values, were expressed as a percentage of the positive control signal.
  • the quantifiable and specific reduction of expressed protein detected by the ELISA in the presence of a drug can be used as a measure of replicon inhibition.
  • GraFit software (Erithacus Software Ltd.) was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC 50 ) for the compound.
  • a 4OmM stock solution in DMSO of each test compound was further diluted into 50 ⁇ L of DMSO in the first row of a 96 well, V-bottom microplate, to give 100 times the top concentration of the required dilution series. Aliquots of 25 ⁇ L of DMSO were added to each well of the remaining rows, and doubling dilutions of compound were prepared by the serial transfer of 25 ⁇ L volumes from the first row onwards.
  • a Plate-mate robot was used to transfer 1 ⁇ L volumes from each dilution well into duplicate wells of a clear bottom, black walled, 96 well assay plate (COSTAR #3603). Control wells received 1 ⁇ L of DMSO alone.
  • Suspensions were prepared from cultures of Huh-7 cells stably transfected with sub-genomic HCV NS3-NS5B replicons of either genotype 1 b (the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021 ) or genotype 1a (subline 1.19 constructed in-house) linked to a firefly luciferase reporter gene.
  • genotype 1 b the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021
  • genotype 1a subline 1.19 constructed in-house linked to a firefly
  • Monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells re- suspended in assay medium comprising DMEM (Invitrogen #41965-039) supplemented with 5% v/v foetal calf serum, 1% v/v non-essential amino acids solution, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin and 2mM L-glutamine.
  • DMEM Invitrogen #41965-039
  • Potency The luminescence values from all compound-free wells containing cells were averaged to obtain a positive control value. The mean luminescence value from the compound-free wells that had received no cells was used to provide the negative (background) control value. The readings from the duplicate wells at each compound concentration were averaged and, after the subtraction of the mean background from all values, were expressed as a percentage of the positive control signal. The quantifiable and specific reduction of luciferase signal in the presence of a drug is a direct measure of replicon inhibition. GraFit software was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC 50 ) for the compound.
  • Genotype 1a Genotype 1 b
  • Compound A corresponds to the compound disclosed as Example 572 in WO2002/100851 .
  • Compound B corresponds to the compound disclosed as Example 578 in WO2002/100851 .
  • Compounds A to B may be made according to the processes described in WO2002/100851 or as described hereinabove.
  • the compounds of the present invention which have been tested demonstrate a surprisingly superior potency as HCV polymerase inhibitors, as shown by the IC 5 O values in the cell- based assays across both of the 1a and 1 b genotypes of HCV, compared to Compounds A - B. 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 [e.g. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), interferon 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), interferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1
  • HCV NS3 protease inhibitors for example HCV NS3 protease inhibitors, e.g.
  • 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.

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Abstract

L'invention concerne des agents anti-viraux de composés de Formule (I) où A, R1, R2 et R3 sont tels que définis dans la spécification, des procédés pour leur préparation et leur utilisation dans un traitement du VHC.
PCT/EP2007/058231 2006-08-11 2007-08-08 Dérivés 2-carboxy-thiophène comme agents anti-viraux WO2008017688A1 (fr)

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GB0616060.0 2006-08-11
GB0616060A GB0616060D0 (en) 2006-08-11 2006-08-11 Compounds
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GB0701197A GB0701197D0 (en) 2007-01-22 2007-01-22 Compounds

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
WO2009000818A1 (fr) * 2007-06-26 2008-12-31 Smithkline Beecham Corporation Acides 3-carbonylaminothiophène-2-carboxyliques en tant qu'inhibiteurs du virus de l'hépatite c
WO2010101967A2 (fr) 2009-03-04 2010-09-10 Idenix Pharmaceuticals, Inc. Inhibiteurs de phosphothiophène et phosphothiazole vhc polymérase
EP2448410A1 (fr) * 2009-06-30 2012-05-09 Siga Technologies, Inc. Traitement et prévention d'infections par le virus de la dengue
WO2013010947A2 (fr) 2011-07-15 2013-01-24 Basf Se Méthodes pesticides utilisant des composés 3-pyridyl thiazole substitués et dérivés pour combattre les parasites animaux de type ii
US8771665B2 (en) 2010-12-17 2014-07-08 Cocrystal Discovery, Inc. Inhibitors of hepatitis C virus polymerase
US8993604B2 (en) 2009-06-30 2015-03-31 Siga Technologies, Inc. Treatment and prevention of dengue virus infections
WO2016154241A1 (fr) 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibiteurs de polymérase du virus de l'hépatite c
US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
CN108586486A (zh) * 2018-06-19 2018-09-28 四川大学 一种芳基取代噻吩并嘧啶类化合物的制备方法
WO2019217643A1 (fr) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Polythérapie pour le traitement du virus de l'hépatite c

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WO2002100851A2 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et procedes destines au traitement des infections par flavivirus
WO2004052885A1 (fr) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Composes et procedes de traitement ou de prevention d'infections a flavivirus
WO2005063734A2 (fr) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Thiophenes substitues
WO2007071434A1 (fr) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Composes antiviraux contenant du 2-carboxy-thiophene

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Publication number Priority date Publication date Assignee Title
WO2002100851A2 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et procedes destines au traitement des infections par flavivirus
WO2004052885A1 (fr) * 2002-12-10 2004-06-24 Virochem Pharma Inc. Composes et procedes de traitement ou de prevention d'infections a flavivirus
WO2005063734A2 (fr) * 2003-12-19 2005-07-14 Aicuris Gmbh & Co. Kg Thiophenes substitues
WO2007071434A1 (fr) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Composes antiviraux contenant du 2-carboxy-thiophene

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009000818A1 (fr) * 2007-06-26 2008-12-31 Smithkline Beecham Corporation Acides 3-carbonylaminothiophène-2-carboxyliques en tant qu'inhibiteurs du virus de l'hépatite c
WO2010101967A2 (fr) 2009-03-04 2010-09-10 Idenix Pharmaceuticals, Inc. Inhibiteurs de phosphothiophène et phosphothiazole vhc polymérase
US8993604B2 (en) 2009-06-30 2015-03-31 Siga Technologies, Inc. Treatment and prevention of dengue virus infections
EP2448410A1 (fr) * 2009-06-30 2012-05-09 Siga Technologies, Inc. Traitement et prévention d'infections par le virus de la dengue
EP2448410A4 (fr) * 2009-06-30 2013-12-18 Siga Technologies Inc Traitement et prévention d'infections par le virus de la dengue
US8771665B2 (en) 2010-12-17 2014-07-08 Cocrystal Discovery, Inc. Inhibitors of hepatitis C virus polymerase
WO2013010947A2 (fr) 2011-07-15 2013-01-24 Basf Se Méthodes pesticides utilisant des composés 3-pyridyl thiazole substitués et dérivés pour combattre les parasites animaux de type ii
US9707215B2 (en) 2012-06-20 2017-07-18 Cocrystal, Discovery, Inc. Inhibitors of hepatitis C virus polymerase
US10426762B2 (en) 2012-06-20 2019-10-01 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
WO2016154241A1 (fr) 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibiteurs de polymérase du virus de l'hépatite c
US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US10947210B2 (en) 2015-03-23 2021-03-16 Cocrystal Pharma, Inc. Inhibitors of Hepatitis C virus polymerase
WO2019217643A1 (fr) 2018-05-09 2019-11-14 Cocrystal Pharma, Inc. Polythérapie pour le traitement du virus de l'hépatite c
US11752166B2 (en) 2018-05-09 2023-09-12 Cocrystal Pharma, Inc. Combination therapy for treatment of HCV
CN108586486A (zh) * 2018-06-19 2018-09-28 四川大学 一种芳基取代噻吩并嘧啶类化合物的制备方法

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