WO2004096210A1 - Acylated indoline and tetrahydroquinoline derivatives as hcv inhibitors - Google Patents

Acylated indoline and tetrahydroquinoline derivatives as hcv inhibitors Download PDF

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Publication number
WO2004096210A1
WO2004096210A1 PCT/EP2004/004663 EP2004004663W WO2004096210A1 WO 2004096210 A1 WO2004096210 A1 WO 2004096210A1 EP 2004004663 W EP2004004663 W EP 2004004663W WO 2004096210 A1 WO2004096210 A1 WO 2004096210A1
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carbonyl
phenyl
methyloxy
dimethylethyl
indole
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PCT/EP2004/004663
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French (fr)
Inventor
Gianpaolo Bravi
Richard Martin Grimes
Rossella Guidetti
David Haigh
Charles David Hartley
Jacqueline Elizabeth Mordaunt
Pritom Shah
Martin John Slater
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Glaxo Group Limited
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Priority claimed from GB0310066A external-priority patent/GB0310066D0/en
Priority claimed from GB0310070A external-priority patent/GB0310070D0/en
Priority claimed from GB0404215A external-priority patent/GB0404215D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2004096210A1 publication Critical patent/WO2004096210A1/en

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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/06—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 only aliphatic carbon atoms
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D413/06—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 only aliphatic carbon atoms
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/06—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 only aliphatic carbon atoms
    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel acyl indoline and novel acyl tetrahydroquinoline derivatives useful as anti-viral agents. Specifically, the present invention involves novel HCV inhibitors.
  • 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).
  • hepatitis C virus HCV
  • NNBH non-B hepatitis
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 Jul.). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931- 960; Raven Press, N.Y.).
  • 3' NTR which roughly consists of three regions: an - 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1a 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 cure HCV infection.
  • US5843972 discloses heterocyclic ⁇ -adrenergic agonists including 2H-indole-2,2- dicarboxylic acid, 1 -benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]- 1 ,3-dihydro-, dimethyl ester; 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3- dihydro-, dimethyl ester; and 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2- oxopropyl)-, dimethyl ester. There is no mention of activity against HCV.
  • WO2001/27077 discloses Cdc25 inhibiting compounds, including certain indoline derivatives, for use in treating Cdc25-mediated conditions such as excessive cellular proliferation, cancer, restenosis, reocclusion of a coronary artery or infalmmation. There is no mention of activity against HCV.
  • US6297270 discloses a process for the preparation of indoline derivatives which derivatives are useful as, amongst other things, angiotensin (II) antagonists. There is no mention of activity against HCV.
  • the present invention involves novel acyl indoline and novel acyl tetrahydroquinoline compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • R 1 represents hydroxy or NR B R C ;
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C 1-6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, d ⁇ alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 7 and R 8 independently represent hydrogen, C -6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • n 0 or 1 ;
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C ⁇ alkyl, aryl 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 D is selected from the group consisting of C ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or C 1-6 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;
  • R 1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • One embodiment of the invention provides use of compounds of Formula (I) represented by Formula (la)
  • R 1 represents hydroxy or NR B R C ;
  • R represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C h alky!, halo, OR A , C(0)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl arylalkyl, or heteroarylalkyl;
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C ⁇ . 6 alkyl, aryl 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 D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R represents hydrogen or C 1-6 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;
  • R 1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than terf-butyl; in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • the present invention also provides novel compounds of Formula (I) represented by Formula (lb)
  • R 1 represents hydroxy or NR B R C ;
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C 1-6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • n 0 or 1 ;
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C -6 alkyl, aryl 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 D is selected from the group consisting of C 1-6 alkyl, aryl, 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 ⁇ 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;
  • R 1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3-dihydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-o
  • the present invention also provides novel compounds of Formula (I) represented by Formula (laa): wherein:
  • R 1 represents hydroxy or NR B R C ;
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C ⁇ -6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl arylalkyl, or heteroarylalkyl;
  • R A represents hydrogen, d- ⁇ alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C 1-6 alkyl, aryl 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 D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R represents hydrogen or C 1-6 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;
  • R 1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3-dihydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-o
  • the present invention also provides novel compounds of Formula (I) represented by Formula (lc):
  • R 1 represents hydroxy or NR B R C ;
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R represents one or two substituents independently selected from hydrogen, C 1-6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C ⁇ -6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C 1-6 alkyl, aryl 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 D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or C 1-6 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;
  • R 1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl.
  • a compound of Formula (laa), (lb) or (Ic) or a physiologically acceptable salt, solvate or ester thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly 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 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 comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a physiologically acceptable salt, solvate or ester thereof.
  • 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 1 is hydroxy
  • R 2 represents C 1-6 alkyl, arylalkyl or heteroarylalkyl; more preferably R 2 represents isobutyl, 2-methyl-2-propen-1-yl, benzyl, 3-pyridinylmethyl, 1 ,3-thiazol-4- ylmethyl, or 1 ,3-oxazol-2-ylmethyl; most preferably R 2 represents isobutyl, benzyl or 1 ,3- thiazol-4-ylmethyl.
  • R 3 represents phenyl optionally substituted by halo, C 1-6 alkyl or C ⁇ -3 alkoxy; more preferably tert-butylphenyl optionally 3-substituted by halo, C 1-3 alkyl or C ⁇ . 3 alkoxy; especially preferred is 4-tert-butylphenyl optionally 3-substituted by halo, C 1-3 alkyl or d. 3 alkoxy, especially bromo, chloro, methyl or methoxy; most preferably R 3 is 3-methoxy-4- tert-butylphenyl.
  • R 4 is positioned on the C4 or C5 positions of the indoline ring or the C6 position of the tetrahydroquinoline ring.
  • R4 is a single substituent.
  • R 4 represents hydrogen, -NH 2 , -NHC(O)CH 3 , -NHC(O)OCH 3 , -C(O)NH 2 , -C(O)NHCH 3 , - C(O)N(CH 3 ) 2 , C(O)NH'Pr, C(O)NH-1 ,2-pyrazol-3-yl, C(O)NH-1 ,3-thiazol-2-yl, C(O)NH- 1 ,2,4-triazol-3-yl, bromo, hydroxy, -OCH 2 CN, -OCH 2 Ph, -OCH 2 -5-methyl-3-isoxazolyl, - OCH 2 -3-pyridinyl, -O-(2-methyl
  • R 5 , R 6 , R 7 and R 8 each represent hydrogen.
  • alkyl refers to an optionally substituted hydrocarbon group.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. Preferably, the group is saturated. Preferred alkyl moieties are C 1-4 alkyl.
  • optional substituents include C 1-6 alkyl, halo, OR A , SR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR R G , SO 2 NR F R G , SO 2 R D , nitro, cyano, oxo, and heterocyclyl.
  • 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. Preferred "aryl” moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • Preferred "aryl" substituents are selected from the group consisting of C 1-6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , 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 D , nitro, cyano, heterocyclyl, and CF 3 .
  • heteroaryl refers to an optionally substituted, 5 or 6 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.
  • Preferred “heteroaryl” moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted pyridyl and thiazolyl.
  • Preferred "heteroaryl" substituents are selected from the group consisting of C 1-6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , 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 D , nitro, cyano, heterocyclyl, CF 3 .
  • heterocyclic and heterocyclyl refer to an optionally substituted, 5 or 6 membered, saturated cyclic hydrocarbon group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, C 1-6 alkyl, C(O)R D , SO 2 R D , aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
  • R 1 is hydroxy
  • R 2 is CO 2 H, CO 2 R x , CHO, COR x , CH 2 OH, CH 2 OCH 2 CO 2 R x or CH 2 OCH 2 CH 2 OR x wherein R x is hydrogen or C 1-4 alkyl; and R 3 is optionally substituted phenyl; and R 4 is CH 2 CH(R Y )N(R Y )CH 2 CH(OH)R v wherein R ⁇ is hydrogen or C 1-6 alkyl and R v is optionally substituted phenyl, phenoxyC 1-4 alkyl, pyridinyl, pyrimidinyl, thiazolyl or oxazolyl; then at least one of R 5 and R 6 is other than hydrogen.
  • Preferred compounds of Formula (I) useful in the present invention are selected from the group consisting of:
  • physiologically acceptable salt complexes also covers the physiologically acceptable salts of the compounds of Formula (I).
  • suitable physiologically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • the present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C 1-4 alkyl or or amino).
  • 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.
  • Compounds of Formula (I) in which R 1 is NR B R C may be prepared from a compound of Formula (I) where R 1 is hydroxy using a coupling agent such as HATU (O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and an amine NHR B R C .
  • a coupling agent such as HATU (O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and an amine NHR B R C .
  • Compounds of Formula (I) in which R 1 is hydroxy may be prepared from a compound of Formula (II) in which R 1 is an alkoxy, benzyloxy or silyloxy group, and n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I).
  • R 1 is methoxy and n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • an appropriate base for example an alkali such as aqueous sodium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or combinations thereof.
  • the temperature is in the range 25 to 100°C, more preferably 50 to 100°C.
  • R 1 is methoxy and n
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • a suitable solvent such as pyridine, lutidine or collidine, preferably in the temperature range 100-170°C.
  • R is tert-butoxy
  • n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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°C, more preferably 15 to 30°C.
  • R 1 is silyloxy
  • n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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.
  • R 1 is hydroxy or a protected form thereof, and n, R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I); with a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine and thereafter removing any protecting group.
  • suitable protecting groups can be found, but are not restricted to, those found in T W Greene and G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • R 1 is an alkoxy, benzyloxy or silyloxy group
  • n, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • a suitable base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6- tetramethylpiperidide (LTMP), sodium hydride, and an alkylating agent R 2 Y where Y is a halo atom such as chloro, bromo or iodo, or Y is sulphonate leaving group such as mesylate or tosylate, and R 2 is as defined above for Formula (I), in a suitable solvent such as tetrahydrofuran.
  • a suitable solvent such as tetrahydrofuran.
  • R 1 is an alkoxy, benzyloxy or silyloxy group
  • n, R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • P is a suitable protecting group such as tert- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ).
  • R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I) by a Beckman rearrangement, that is by forming an oxime of (VI) for example with hydroxylamine and then treatment with an acid such as polyphosphoric acid, see for example Chem Pharm Bull (1988) 36, 2386.
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I), for example by treatment with acids such as hydrochloric acid in a suitable solvent such as methanol or ethanol, or by treatment with lithium hydroxide and hydrogen peroxide in a suitable solvent such as aqueous methanol followed by treatment with an acid such as hydrochloric acid, and followed by esterification of the resulting acid with diazomethane or by using an acid such as hydrochloric acid in the presence of an alcohol such as methanol.
  • acids such as hydrochloric acid in a suitable solvent such as methanol or ethanol
  • lithium hydroxide and hydrogen peroxide in a suitable solvent such as aqueous methanol
  • R 1 is an alkoxy, benzyloxy or silyloxy group, and n, R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I), with a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine and thereafter removing any protecting group.
  • 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.
  • Compounds of Formula (V) may be prepared from compounds of Formula (IX) in which R 1 is an alkoxy, benzyloxy or silyloxy group, and n, R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I) and P is a suitable protecting group such as tert- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), by treatment with a suitable base such as lithium bis(thmethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6-tetramethylpiperidide (LTMP), or sodium hydride, and an alkylating agent R 2 Y where Y is a halo atom such as chloro, bromo or iodo, and R 2 is as defined above for Formula (I), in a suitable solvent such as tetrahydrofuran.
  • R 1 is an alkoxy, benzyloxy or silyloxy group
  • R 3 , R 4 , R 5 and R 7 are as defined above for Formula (I), for example using palladium on carbon and hydrogen in a suitable solvent such as ethanol, or Rhodium and hydrogen in a suitable solvent such as ethyl acetate, see for example J. Amer Chem. Soc (2001 ) 123, 6801.
  • R 1 , R 4 , R 5 and R 7 are as defined above for Formula (I), for example by the use of sodium borohydride and nickel chloride in methanol, or by the use of platinum oxide and hydrogen in a suitable solvent such as ethanol.
  • Compounds of Formula (IX) may be prepared by protection of a compound of Formula (VIII).
  • suitable protecting groups are BOC or CBZ.
  • 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.
  • R 4 , R 5 and R 7 are as defined above for Formula (I) with a cyanide source such as sodium cyanide or trimethylsilyl cyanide and a suitable acylating agent, for example R 3 - C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I), and optionally including a Lewis acid such as aluminium trichloride or diethylaluminium chloride.
  • a cyanide source such as sodium cyanide or trimethylsilyl cyanide
  • a suitable acylating agent for example R 3 - C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I), and optionally including a Lewis acid such as aluminium trichloride or diethylaluminium chloride.
  • R 4 , R 5 and R 7 are as defined above for Formula (I), with a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine and thereafter removing any protecting group.
  • Compounds of Formula (XI) may be prepared from compounds of Formula (VII) or (X) by use of hydrochloric acid in a suitable solvent such as methanol or ethanol, at elevated temperatures (see for example Bioorg. Med. Chem. Letters (1995) 5, 1527).
  • R 4 , R 5 and R 7 are as defined above for Formula (I), for example by using Rhodium and hydrogen in a suitable solvent such as ethyl acetate.
  • R 4 , R 5 and R 7 are as defined above for Formula (I) and Y is a halo atom, preferably chloro or bromo or iodo, and a cyanide source such as copper cyanide.
  • R 1 is an alkoxy or silyloxy group
  • R 4 and R 6 are as defined above for Formula (I)
  • suitable reducing agents with suitable reducing agents.
  • the indole N-H may be protected with a suitable nitrogen protecting group such as Boc (tert-butoxycarbonyl), the double bond reduced with suitable reducing agents, and the protecting group then removed by standard techniques.
  • Such reducing agents include the use of triethylsilane in trifluoroacetic acid, hydrogen with a catalyst such as palladium on carbon or platinum oxide, in a suitable solvent such as acetic acid or ethanol, or by using sodium borohyd de or sodium cyanoborohydride in a suitable solvent such as acetic acid or methanol, or by using magnesium in methanol, or by using tin and aqueous hydrochloric acid or by using nickel-aluminium alloy.
  • R 1 is an alkoxy or silyloxy group
  • R 3 , R 4 and R 6 are as defined above for Formula (I)
  • suitable reducing agents include the use of triethylsilane in trifluoroacetic acid, hydrogen with a catalyst such as palladium on carbon or platinum oxide in a suitable solvent such as acetic acid or ethanol, or by using sodium borohydride or sodium cyanoborohydride in a suitable solvent such as acetic acid or methanol, or by using magnesium in methanol, or by using tin and aqueous hydrochloric acid.
  • Compounds of Formula (XVII) are commercially available, or may be prepared by acylation of compounds of Formula (XVI) in which R 1 is an alkoxy or silyloxy group, and R 3 , R 4 and R 6 are as defined above with a suitable acylating agent, for example R 3 -C(O)- Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable acylating agent for example R 3 -C(O)- Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine.
  • Compounds of Formula (IV) in which n is 0, R 5 is hydrogen, and R 1 is an alkoxy or silyloxy group, and R 3 , R 4 and R 6 are as defined above for Formula (I), may also be prepared by reaction of a compound of Formula (VIII) in which n is 0, R 5 is hydrogen, and R 1 an alkoxy or silyloxy group, and R 2 , R 4 , and R 6 are as defined above for Formula (I); with a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine.
  • Compounds of Formula (IV) in which n is 0 and neither R 5 or R 6 are hydrogen may be prepared by decarboxylation of compounds of Formula (XVIII) (XVIII) in which R is an alkoxy, benzyloxy or silyloxy group, and R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I), and R 9 is hydrogen, C 1-6 alkyl or aryl, for example see Tetrahedron Letters (1996) 39, 6965.
  • Decarboxylation methods include but are not restricted to the use of aqueous sodium hydroxide in a suitable solvent such as dioxan or by using aqueous hydrochloric acid and preferably at elevated temperatures.
  • Compounds of Formula (XVIII) may be prepared by reaction of compounds of Formula (XIX) and For
  • R 1 is an alkoxy, benzyloxy or silyloxy group
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I)
  • R 9 is C 1-6 alkyloxy or aryloxy
  • Y is a halo atom, for example bromo, chloro or iodo.
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is a carboxylic acid may be prepared from a compound of Formula (II) in which R 4 is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide and water in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene or combinations thereof
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is an ester (CO 2 R D ), may be prepared from a compound of Formula (II) in which R 4 is is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide an alcohol R D OH in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis- diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a suitable palladium catalyst such as palladium (II) acetate and bis- diphenylphosphinoferrocene or combinations thereof
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is trifluoromethanesulphonate may be prepared from a compound of Formula (II) in which R 4 is OH, by treatment with trifluoromethanesulphonic anhydride in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is an aryl or heteroaryl group may be prepared by reaction between a compound of Formula (II) in which R 4 is trifluoromethanesulphonate or a halide such bromide, and an appropriate aryl or heteroaryl boronic acid derivative (R 4 - B(OH) 2 ), in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base such as potassium phosphate in a suitable solvent such as dimethoxymethane.
  • the aryl or heteroaryl group may be in the form an organozinc reagent (R 4 -Zn-hal) or an organotin reagent (R 4 -Sn(n-alkyl) 3 ).
  • a suitable base such as sodium hydride or potassium carbonate
  • a suitable solvent such as DMF.
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and the compound of Formula (I) contains an amide group may be prepared from the corresponding carboxylic acid using an amine or amine equivalent R B R C NH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate
  • Compounds of Formula (I) in which R 1 is NR B R C may be prepared from compounds of Formula (I) in which R 1 is hydroxy, using an amine or amine equivalent R B R C NH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is NH 2 may be prepared from compounds of Formula (I) in which R 4 is a halogen such as bromo by treatment with lithium bis(trimethylsilyl)amide and catalyst reagents such as tris(dibenzylidenacetone)dipalladium(0) and 2-(dicyclohexylphosphino)biphenyl or combinations therof, in a suitable solvent such as tetrahydrofuran.
  • Compounds of Formula (I) in which R 1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is SO 2 R D may be prepared from compounds of Formula (I) in which R 4 is a halogen such as bromo by teatment with a sodium salt of an akylsulfinic acid (eg sodium methylsulfinic acid), in the presence of a copper cataylst (such as coper triflate complexed with toluene) in a suitable solvent such as dimethylsulfoxide, preferably in the temperature range 80-120 °C.
  • R 4 is a halogen such as bromo by teatment with a sodium salt of an akylsulfinic acid (eg sodium methylsulfinic acid), in the presence of a copper cataylst (such as coper triflate complexed with toluene) in a suitable solvent such as dimethylsulfoxide
  • Racemic lndoline-2-carboxylic acid, methyl ester (500 mg) was dissolved in dichloromethane (10 mL) and treated with 3-methoxy-4-tert-butylbenzoyl chloride 1 (704 mg). Triethylamine (785 uL) was added and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with dilute hydrochloric acid solution (2N, 50 mL), saturated sodium hydrogen carbonate solution, brine, dried (Na 2 SO 4 ) and concentrated to give a brown gum. This was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (15:85 v/v) to give the title compound.
  • Trifluromethane sulphonic anhydride (1.2 mL, 4.7 mmol) was added dropwise to a stirred solution of intermediate 8 (2.1 g, 4.7 mmol) and triethylamine (2.0 mL, 14.2 mmol) in dichloromethane (20 mL) at -78°C under nitrogen.
  • the reaction was stirred at this temperature for 3.5 hours and was then quenched by the successive addition of water and 2N hydrochloric acid and was then extracted with dichloromethane. The extracts were combined, dried and evaporated to give crude product as a yellow oil.
  • Carbon monoxide gas was gently bubbled through a dry DMF (2 mL) solution of intermediate 13 (0.2 g, 0.33 mmol), triethylamine (66 mg, 0.66 mmol), benzyl alcohol (0.68 mL, 6.6 mmol), palladium (II) acetate (4.5 mg, 0.02 mmol) and bis- diphenylphosphinoferrocene (22 mg, 0.03 mmol) for 5 minutes. The reaction was then stirred at 60°C under carbon monoxide (balloon pressure) for 3 hours and left to stand overnight. This was partitioned between ethyl acetate and sat.
  • the title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material and purified by reverse phase HPLC on a C 18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy.
  • the title compound was prepared in a similar manner to Example 33 using Intermediate 64. Purification was by SPE (silica) eluted with ethyl acetate/cyclohexane (1 :4) to give the title compound.
  • the title compound was prepared in a similar manner to Example 33 from Intermediate 67. Purification was by SPE (silica) with gradient elution using ethyl acetate/cyclohexane (1 :4 v/v), DCM/AcOH (99:1 v/v), H 2 O/AcOH (99:1 v/v), DCM/MeOH (99:1 v/v) to give the title compound.
  • N-Bromosuccinimide (2.45 g, 13.77 mmol) in DMF (10 mL) was added dropwise to a solution of methyl 1 ,2,3,4-tetrahydroquinoline-2-carboxylate (2.63 g, 13.77 mmol) at ambient temperature under nitrogen.
  • the mixture was left to stir at room temperature for 1 hour.
  • the solvent was evaporated and the residue partitioned between water (100 mL) and ethyl acetate/toluene (1 :1 ; 3x60 mL).
  • the organics were dried (Na 2 SO ) and evaporated.
  • Tris(dibenzylideneacetone)dipalladium(0) (0.4 mg) and 2-(dicyclohexylphosphino)biphenyl (0.9 mg) were added to a solution of Intermediate 75 (100 mg, 0.18 mmol) and lithium bis(trimethylsilyl)amide (1M in THF, 0.21 mL) in THF (3 mL) at room temperature under nitrogen. The mixture was heated to 70°C for 4 hours. On cooling, 2N HCI (2 mL) was added and the reaction stirred for a further 10 minutes. The mixture was basified with 2N NaOH, extracted with EtOAc (3 x10 mL), dried (Na 2 SO 4 ) and evaporated.
  • Example 1 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -2-(phenylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid
  • Example 8 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -4-[(2-methylpropyl)oxy]-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
  • Example 11 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -4-phenyl-2-(phenylmethyl)- 2,3-dihydro-1 H-indole-2 -carboxylic acid
  • Example 20 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -2-(2-methylpropyl)-4- phenyl-2,3-dihydro-1 H-indole-2-carboxylic acid
  • Example 21 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -2-(2-methylpropyl)-4- phenyl-2,3-dihydro-1 H-indole-2-carboxylic acid
  • Example 32 1 - ⁇ [4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -2-(1 ,3-oxazol-2-ylmethyl)- 2,3-dihydro-1 H-indole-2-carboxylic acid racemic
  • Example 37 4- ⁇ [2-(Dimethylamino)-2-oxoethyl]oxy ⁇ -1 - ⁇ [4-(1 ,1 -dimethylethyl)-3-
  • Example 45 4-[(Cyanomethyl)oxy]-1 - ⁇ [4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl ⁇ -2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
  • compositions for use in therapy comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically 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 physiologically 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.
  • Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • compositions are 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.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • Reaction Conditions were 0.5 ⁇ M [ 33 P]-GTP (0.2 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI 2 , 5mM MnCI 2, 20 mM Tris-HCI, pH7.5, 1.6 ⁇ g/mL polyC/0.256 ⁇ M biotinylated oligoG13, 10% glycerol, 0.01% NP-40, 0.2 u/ ⁇ L RNasin and 50 mM NaCI.
  • HCV RNA Polymerase Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11 ), 1997, 8416 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 10 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1 M MnCI 2 (0.25 mL), glycerol (4mL), 10% NP-40 (0.025 mL) and Water (7.225 mL), Total 10 mL.
  • 2x concentrated enzyme buffer contained 1 M-Tris-HCI, pH7.5 (0.4 mL), 5M NaCI (0.2 mL), 1 M-MgCI 2 (0.4 mL), glycerol (1 mL), 10% NP-40 (10 ⁇ L), 1 M DTT (20 ⁇ L) and water (7.97 mL), Total 10 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), 0.4 u/ ⁇ L RNasin (0.04 ⁇ 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 2.811 mL 2x-concentrated enzyme buffer.
  • the Assay was set up using compound (1 ⁇ L), Substrate Mix (10 ⁇ L), and Enzyme Mix (added last to start reaction) (10 ⁇ L), Total 21 ⁇ L.
  • the reaction was performed in a U-bottomed, white, 96-well plate.
  • the reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1h at 22°C. After this time, the reaction was stopped by addition of 40 ⁇ L 1.875 mg/ml streptavidin SPA beads in 0.1 M EDTA.
  • the beads were incubated with the reaction mixture for 1 h at 22°C after which 120 ⁇ L 0.1 M EDTA in PBS was added.
  • the plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.
  • the exemplified compounds had an IC 50 of ⁇ 35 ⁇ M in the above described assay.
  • Preferred compounds had an IC 50 of ⁇ 5 ⁇ M, more preferably ⁇ 1 ⁇ M. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies ((eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche))
  • immune therapies eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys
  • 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) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent.

Abstract

Use of a compound of Formula (I) : wherein: R1 represents hydroxy or NR BRC; R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; R3 represents aryl or heteroaryl; R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRC, C(O)RD, CO2H , CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3; R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; n represents 0 or 1; RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl; RB and RC independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and RC together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group; RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; RE represents hydrogen or C1-6alkyl; RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group; and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; in the manufacture of a medicament for the treatment of viral infection is provided. Also provided are certain novel compounds of Formula (I) represented by Formula (Ib). Further provided are processes for the preparation of compounds of Formula (I), pharmaceutical compositions comprising them, and methods of using them in HCV treatment.

Description

ACYLATED INDOLINE AND TETRAHYDROQUINOLINE DERIVATIVES AS HCV INHIBITORS
FIELD OF THE INVENTION
The present invention relates to novel acyl indoline and novel acyl tetrahydroquinoline derivatives useful as anti-viral agents. Specifically, the present invention involves novel HCV inhibitors.
BACKGROUND OF THE INVENTION
Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. 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.
Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, 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). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of those treated, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.
First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359- 362), hepatitis C virus (HCV) is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-3; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061 ), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang 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.
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 2nd Edition, p931- 960; Raven Press, N.Y.). Following the termination codon at the end of the long ORF, there is a 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 1a 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 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to cure HCV infection.
Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit HCV.
US5843972 discloses heterocyclic β-adrenergic agonists including 2H-indole-2,2- dicarboxylic acid, 1 -benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]- 1 ,3-dihydro-, dimethyl ester; 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3- dihydro-, dimethyl ester; and 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2- oxopropyl)-, dimethyl ester. There is no mention of activity against HCV.
WO2001/27077 discloses Cdc25 inhibiting compounds, including certain indoline derivatives, for use in treating Cdc25-mediated conditions such as excessive cellular proliferation, cancer, restenosis, reocclusion of a coronary artery or infalmmation. There is no mention of activity against HCV.
US6297270 discloses a process for the preparation of indoline derivatives which derivatives are useful as, amongst other things, angiotensin (II) antagonists. There is no mention of activity against HCV.
SUMMARY OF THE INVENTION The present invention involves novel acyl indoline and novel acyl tetrahydroquinoline compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides the use of compounds of Formula (I) :
Figure imgf000005_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, d^alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R7 and R8 independently represent hydrogen, C -6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C^alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C^alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or C1-6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
One embodiment of the invention provides use of compounds of Formula (I) represented by Formula (la)
Figure imgf000006_0001
wherein:
R1 represents hydroxy or NRBRC;
R represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, Chalky!, halo, ORA, C(0)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl arylalkyl, or heteroarylalkyl;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, Cι.6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
R represents hydrogen or C1-6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than terf-butyl; in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
The present invention also provides novel compounds of Formula (I) represented by Formula (lb)
Figure imgf000007_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl; R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C -6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or C^alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C^alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3-dihydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-oxopropyl)-, dimethyl ester.
The present invention also provides novel compounds of Formula (I) represented by Formula (laa):
Figure imgf000009_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, Cι-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl arylalkyl, or heteroarylalkyl;
RA represents hydrogen, d-βalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
R represents hydrogen or C1-6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3-dihydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-oxopropyl)-, dimethyl ester.
The present invention also provides novel compounds of Formula (I) represented by Formula (lc):
Figure imgf000010_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, Cι-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or C1-6alkyl; RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl.
There is provided as a further aspect of the present invention a compound of Formula (laa), (lb) or (Ic) or a physiologically acceptable salt, solvate or ester thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly HCV infection.
It will be appreciated that reference 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.
In a further or alternative aspect there is provided 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 a compound of Formula (I) or a physiologically acceptable salt, solvate or ester thereof.
It will be appreciated that 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.
Preferably, R1 is hydroxy.
Preferably, R2 represents C1-6alkyl, arylalkyl or heteroarylalkyl; more preferably R2 represents isobutyl, 2-methyl-2-propen-1-yl, benzyl, 3-pyridinylmethyl, 1 ,3-thiazol-4- ylmethyl, or 1 ,3-oxazol-2-ylmethyl; most preferably R2 represents isobutyl, benzyl or 1 ,3- thiazol-4-ylmethyl.
Preferably, R3 represents phenyl optionally substituted by halo, C1-6alkyl or Cι-3alkoxy; more preferably tert-butylphenyl optionally 3-substituted by halo, C1-3alkyl or Cι.3alkoxy; especially preferred is 4-tert-butylphenyl optionally 3-substituted by halo, C1-3alkyl or d. 3alkoxy, especially bromo, chloro, methyl or methoxy; most preferably R3 is 3-methoxy-4- tert-butylphenyl. Preferably, R4 is positioned on the C4 or C5 positions of the indoline ring or the C6 position of the tetrahydroquinoline ring. Preferably, R4 is a single substituent. Preferably, R4 represents hydrogen, -NH2, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -C(O)NHCH3, - C(O)N(CH3)2, C(O)NH'Pr, C(O)NH-1 ,2-pyrazol-3-yl, C(O)NH-1 ,3-thiazol-2-yl, C(O)NH- 1 ,2,4-triazol-3-yl, bromo, hydroxy, -OCH2CN, -OCH2Ph, -OCH2-5-methyl-3-isoxazolyl, - OCH2-3-pyridinyl, -O-(2-methylpropyl), -OCH2C(O)NH2, -OCH2C(O)NHCH3, OCH2C(O)N(CH3)2, -OCH2C(O)OH, -C(O)OH, CH2CH2C(O)OH, CH=CHC(O)OH, phenyl, thiazol-2-yl, pyrimidin-5-yl, pyridin-3-yl, -SO2CH3, -(CH2)2SO2CH3, or -(CH2)2COCH3; most preferably, R4 represents phenyl, -C(O)OH, -OCH2C(O)OH, -OCH2C(O)NH2 and - OCH2C(O)N(CH3)2.
Preferably, R5, R6, R7 and R8 each represent hydrogen.
It is to be understood that the present invention covers all combinations of suitable, convenient and preferred groups described herein.
As used herein unless otherwise specified, "alkyl" refers to an optionally substituted hydrocarbon group. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. Preferably, the group is saturated. Preferred alkyl moieties are C1-4alkyl. Unless otherwise stated, optional substituents include C1-6alkyl, halo, ORA, SRA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NR RG, SO2NRFRG, SO2RD, nitro, cyano, oxo, and heterocyclyl.
As used herein, "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. Preferred "aryl" moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl. Preferred "aryl" substituents are selected from the group consisting of C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, and CF3.
As used herein, "heteroaryl" refers to an optionally substituted, 5 or 6 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. Preferred "heteroaryl" moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted pyridyl and thiazolyl. Preferred "heteroaryl" substituents are selected from the group consisting of C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, CF3. As used herein, "heterocyclic" and "heterocyclyl" refer to an optionally substituted, 5 or 6 membered, saturated cyclic hydrocarbon group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, C1-6alkyl, C(O)RD, SO2RD, aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
In one embodiment, there is provided compounds of Formula (laa) as defined above, provided that when R1 is hydroxy; and R2 is CO2H, CO2Rx, CHO, CORx, CH2OH, CH2OCH2CO2Rx or CH2OCH2CH2ORx wherein Rx is hydrogen or C1-4alkyl; and R3 is optionally substituted phenyl; and R4 is CH2CH(RY)N(RY)CH2CH(OH)Rv wherein Rγ is hydrogen or C1-6alkyl and Rv is optionally substituted phenyl, phenoxyC1-4alkyl, pyridinyl, pyrimidinyl, thiazolyl or oxazolyl; then at least one of R5 and R6 is other than hydrogen.
In one embodiment, there is provided compounds of Formula (laa) as defined above, provided that when R2 is C1-6alkyl or arylalkyl; then R4 is other than -(CH2)ι-3- SO2N(H)Heteroaryl.
Preferred compounds of Formula (I) useful in the present invention are selected from the group consisting of:
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3-dihydro-1 H- indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-
1 H-indole-2-carboxylic acid;
1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3-dihydro-1 H- indole-2,4-dicarboxylic acid; 4-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-
[(phenylmethyl)oxy]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-[(3- pyridinylmethyl)oxy]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(5-methyl-3- isoxazolyl)methyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(2-methylpropyl)oxy]-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 4-[(E)-2-Carboxyethenyl]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-(2-Carboxyethyl)-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 /-/-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-phenyl-2-(phenylmethyl)-2,3- dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-(5- pyrimidinyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-( 1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-( 1 ,3-thiazol-2- yl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
5-[(Carboxymethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(3-pyridinyl)-
2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(1 ,3-thiazol-2- yl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(Carboxymethyl)oxy]-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(£)-2-Carboxyethenyl]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 /-/-indole-2-carboxylic acid;
4-(2-Carboxyethyl)-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-phenyl-2,3- dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-phenyl-2,3- dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro- 1H-indole-2,4-dicarboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[2-(methylsulfonyl)ethyl]-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-(3-oxobutyl)-
2,3-dihydro-1 H-indole-2-carboxylic acid; 5-Bromo-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid;
5-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3- dihydro-1 H-indole-2-carboxylic acid;
5-Bromo-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4- ylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1-yl)-2,3- dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4-ylmethyl)-2,3- dihydro-1 r -indole-2-carboxylic acid; 1-{[4-(1,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4-ylmethyl)-2,3- dihydro-1 /- -indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(3-pyridinylmethyl)-2,3-dihydro-
1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-oxazol-2-ylmethyl)-2,3- dihydro-1 r-/-indole-2-carboxylic acid;
4-[(Carboxymethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 4-[(2-Amino-2-oxoethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(2-Amino-2-oxoethyl)oxy]-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methylamino)-2- oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
4-{[2-(Dimethylamino)-2-oxoethyl]oxy}-1-{[4-(1 ,1-dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
4-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(methylamino)carbonyl]-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1 -{[4-( 1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[( 1 - methylethyl)amino]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid; 4-[(Dimethylamino)carbonyl]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 /-/-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 ,3-thiazol-
2-ylamino)carbonyl]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 /-/- pyrazol-3-ylamino)carbonyl]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1H-1 ,2,4- triazol-3-ylamino)carbonyl]-2,3-dihydro-1/-/-indole-2-carboxylic acid;
4-[(Cyanomethyl)oxy]-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methylsulfonyl)-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
2-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-4-carboxylic acid;
{[2-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1H-indol-4-yl]oxy}acetic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid;
6-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1-yl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid;
1 -{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-1 , 2,3,4- tetrahydro-2-quinolinecarboxylic acid;
6-Amino-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid;
6-(Acetylamino)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid; and 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-6-{[( methyloxy)carbonyl]amino}-
2-(phenylmethyl)-1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid; and salts, solvates and esters, and individual enantiomers thereof.
Also included in the present invention are pharmaceutically acceptable salt complexes. The present invention also covers the physiologically acceptable salts of the compounds of Formula (I). Suitable physiologically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
The present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
The present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C1-4alkyl or
Figure imgf000016_0001
or amino). Unless otherwise specified, 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.
It will further be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
Compounds of Formula (I) in which R1 is NRBRC may be prepared from a compound of Formula (I) where R1 is hydroxy using a coupling agent such as HATU (O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and an amine NHRBRC.
Compounds of Formula (I) in which R1 is hydroxy may be prepared from a compound of Formula (II)
Figure imgf000017_0001
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R2, R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I). For example when R1 is methoxy and n, R2, R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I), by treatment with an appropriate base, for example an alkali such as aqueous sodium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or combinations thereof. Preferably, the temperature is in the range 25 to 100°C, more preferably 50 to 100°C. Alternatively, when R1 is methoxy and n, R2, R3, R4, R5, R6, R7 and R8are as defined above for Formula (I), by treatment with lithium iodide in a suitable solvent such as pyridine, lutidine or collidine, preferably in the temperature range 100-170°C.
For example when R is tert-butoxy, and n, R2, R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I), by treatment with an appropriate acid, for example trifluoroacetic acid. Suitably, the reaction is carried out in a solvent, for example dichloromethane. Preferably, the temperature is in the range 0 to 50°C, more preferably 15 to 30°C.
For example when R1 is silyloxy, and n, R2, R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I), by treatment with a suitable fluoride source for example tetrabutylammonium fluoride. The reaction is carried out in a suitable solvent, for example tetrahydrofuran.
Compounds of Formula (I) in which R1 is hydroxy or a protected form thereof, and compounds of Formula (II) ompound of Formula (III)
Figure imgf000017_0002
in which R1 is hydroxy or a protected form thereof, and n, R2, R4, R5, R6, R7and R8 are as defined above for Formula (I); with a suitable acylating agent, for example R3-C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I). Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine and thereafter removing any protecting group. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and G M Wuts 'Protective Groups in Organic Synthesis', 3rd Ed (1999), J Wiley and Sons.
Compounds of Formula (II) in which R is an alkoxy, benzyloxy or silyloxy group may be prepared from compounds of Formula (IV)
Figure imgf000018_0001
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R3, R4, R5, R6, R7and R8 are as defined above for Formula (I), by treatment with a suitable base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6- tetramethylpiperidide (LTMP), sodium hydride, and an alkylating agent R2Y where Y is a halo atom such as chloro, bromo or iodo, or Y is sulphonate leaving group such as mesylate or tosylate, and R2 is as defined above for Formula (I), in a suitable solvent such as tetrahydrofuran.
Compounds of Formula (III) in which R1 is an alkoxy, benzyloxy or silyloxy group, may be prepared by deprotection of a compound of Formula (V)
Figure imgf000018_0002
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R2, R4, R5, R6, R7and R8 are as defined above for Formula (I), and P is a suitable protecting group such as tert- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ).
Compounds of Formula (III) in which n is 1 may also be prepared from a compound of Formula (VI)
Figure imgf000018_0003
in which R2, R4, R5, R6, R7and R8 are as defined above for Formula (I) by a Beckman rearrangement, that is by forming an oxime of (VI) for example with hydroxylamine and then treatment with an acid such as polyphosphoric acid, see for example Chem Pharm Bull (1988) 36, 2386.
Compounds of Formula (IV) in which R1 is an alkoxy group and n is 1 may be prepared from compounds of Formula (VII)
Figure imgf000019_0001
in which R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I), for example by treatment with acids such as hydrochloric acid in a suitable solvent such as methanol or ethanol, or by treatment with lithium hydroxide and hydrogen peroxide in a suitable solvent such as aqueous methanol followed by treatment with an acid such as hydrochloric acid, and followed by esterification of the resulting acid with diazomethane or by using an acid such as hydrochloric acid in the presence of an alcohol such as methanol.
Compounds of Formula (IV) in which n is 0 or 1 may be prepared from compounds of Formula (VIII)
Figure imgf000019_0002
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R4, R5, R6, R7and R8 are as defined above for Formula (I), with a suitable acylating agent, for example R3-C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I). Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine and thereafter removing any protecting group. 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', 3rd Ed (1999), J Wiley and Sons.
Compounds of Formula (V) may be prepared from compounds of Formula (IX)
Figure imgf000020_0001
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R4, R5, R6, R7and R8 are as defined above for Formula (I) and P is a suitable protecting group such as tert- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), by treatment with a suitable base such as lithium bis(thmethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6-tetramethylpiperidide (LTMP), or sodium hydride, and an alkylating agent R2Y where Y is a halo atom such as chloro, bromo or iodo, and R2 is as defined above for Formula (I), in a suitable solvent such as tetrahydrofuran.
Compounds of Formula (VII) in which R6 and R8 are both hydrogen may be prepared by reducing compounds of Formula (X)
Figure imgf000020_0002
in which R3, R4, R5 and R7 are as defined above for Formula (I), for example using palladium on carbon and hydrogen in a suitable solvent such as ethanol, or Rhodium and hydrogen in a suitable solvent such as ethyl acetate, see for example J. Amer Chem. Soc (2001 ) 123, 6801.
Compounds of Formula (VIII) in which n is 1 and R and R are both hydrogen may be prepared by reducing compounds of Formula (XI)
Figure imgf000020_0003
in which R1, R4, R5 and R7 are as defined above for Formula (I), for example by the use of sodium borohydride and nickel chloride in methanol, or by the use of platinum oxide and hydrogen in a suitable solvent such as ethanol.
Compounds of Formula (IX) may be prepared by protection of a compound of Formula (VIII). Examples of suitable protecting groups are BOC or CBZ. 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', 3rd Ed (1999), J Wiley and Sons.
Compounds of Formula (X) may be prepared by a Reissert process, that is reaction of compounds of Formula (XII)
Figure imgf000021_0001
in which R4, R5 and R7 are as defined above for Formula (I) with a cyanide source such as sodium cyanide or trimethylsilyl cyanide and a suitable acylating agent, for example R3- C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I), and optionally including a Lewis acid such as aluminium trichloride or diethylaluminium chloride. A review of the Reissert reaction is given in Adv Heterocyclic Chem. (1968) 9, 1 and examples given in Bioorg. Med. Chem Letters (1995) 5, 1527 and J. Amer. Chem Soc. (2001 ) 123, 6801.
Compounds of Formula (X) may also be prepared by reaction of a compound of Formula
Figure imgf000021_0002
in which R4, R5 and R7 are as defined above for Formula (I), with a suitable acylating agent, for example R3-C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I). Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine and thereafter removing any protecting group.
Compounds of Formula (XI) may be prepared from compounds of Formula (VII) or (X) by use of hydrochloric acid in a suitable solvent such as methanol or ethanol, at elevated temperatures (see for example Bioorg. Med. Chem. Letters (1995) 5, 1527).
Compounds of Formula (XIII) may be prepared by reduction of a compound of Formula
Figure imgf000021_0003
in which R4, R5 and R7 are as defined above for Formula (I), for example by using Rhodium and hydrogen in a suitable solvent such as ethyl acetate.
Compounds of Formula (XIV) may be prepared from a compound of Formula (XV)
Figure imgf000022_0001
in which R4, R5 and R7 are as defined above for Formula (I) and Y is a halo atom, preferably chloro or bromo or iodo, and a cyanide source such as copper cyanide.
Further examples of the synthesis of tetrahydroquinolines are given in Tetrahedron (1996) 52, 15031.
Compounds of Formula (VIII) in which n is 0 and R5 is hydrogen or both R5 and R6 are hydrogen are commercially available, or may be prepared by reduction of compounds of Formula (XVI)
Figure imgf000022_0002
in which R1 is an alkoxy or silyloxy group, and R4 and R6 are as defined above for Formula (I), with suitable reducing agents. Alternatively the indole N-H may be protected with a suitable nitrogen protecting group such as Boc (tert-butoxycarbonyl), the double bond reduced with suitable reducing agents, and the protecting group then removed by standard techniques. Such reducing agents (for the N-H indole or the N-protected indole) include the use of triethylsilane in trifluoroacetic acid, hydrogen with a catalyst such as palladium on carbon or platinum oxide, in a suitable solvent such as acetic acid or ethanol, or by using sodium borohyd de or sodium cyanoborohydride in a suitable solvent such as acetic acid or methanol, or by using magnesium in methanol, or by using tin and aqueous hydrochloric acid or by using nickel-aluminium alloy. Examples are given in (but are not restricted to) the following references: Heterocycles (1982) 19, 229, Synthetic Communications (1983), 13, 489, Organic Letters (2000), 2, 1069, J. Med Chem. (1983) 26, 1267, J.Med. Chem. (1987) 30, 1555, Tetrahedron Letters (1986) 27, 2409, J. Het. Chem. (1986), 27, 2409, J. Het Chem. (1966) 3, 124, J. Org. Chem. (1979) 44, 4809, Synthesis (1977), 859, Angew. Chem. Int. Ed. Eng. (1968) 7, 208, J. Amer. Chem. Soc. (1970) 92, 2476, Tetrahedron (1996) 52, 15031. Compounds of Formula (IV) in which n is 0 and R5 is hydrogen or both R5 and R6 are hydrogen are commercially available, or may be prepared by reduction of compounds of Formula (XVII)
Figure imgf000023_0001
in which R1 is an alkoxy or silyloxy group, and R3, R4 and R6 are as defined above for Formula (I), with suitable reducing agents. Such reducing agents include the use of triethylsilane in trifluoroacetic acid, hydrogen with a catalyst such as palladium on carbon or platinum oxide in a suitable solvent such as acetic acid or ethanol, or by using sodium borohydride or sodium cyanoborohydride in a suitable solvent such as acetic acid or methanol, or by using magnesium in methanol, or by using tin and aqueous hydrochloric acid. Examples are given in (but are not restricted to) the following references: Heterocycles (1982) 19, 229, Synthetic Communications (1983), 13, 489, Organic Letters (2000), 2, 1069, J. Med Chem. (1983) 26, 1267, J.Med. Chem. (1987) 30, 1555, Tetrahedron Letters (1986) 27, 2409, J. Het. Chem. (1986), 27, 2409, J. Het Chem. (1966) 3, 124, J. Org. Chem. (1979) 44, 4809, Synthesis (1977), 859, Angew. Chem. Int. Ed. Eng. (1968) 7, 208, J. Amer. Chem. Soc. (1970) 92, 2476.
Compounds of Formula (XVII) are commercially available, or may be prepared by acylation of compounds of Formula (XVI) in which R1 is an alkoxy or silyloxy group, and R3, R4 and R6 are as defined above with a suitable acylating agent, for example R3-C(O)- Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I). Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
Compounds of Formula (IV) in which n is 0, R5 is hydrogen, and R1 is an alkoxy or silyloxy group, and R3, R4 and R6 are as defined above for Formula (I), may also be prepared by reaction of a compound of Formula (VIII) in which n is 0, R5 is hydrogen, and R1 an alkoxy or silyloxy group, and R2, R4, and R6 are as defined above for Formula (I); with a suitable acylating agent, for example R3-C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R3 is as defined above for Formula (I). Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
Compounds of Formula (IV) in which n is 0 and neither R5 or R6 are hydrogen may be prepared by decarboxylation of compounds of Formula (XVIII) (XVIII)
Figure imgf000024_0001
in which R is an alkoxy, benzyloxy or silyloxy group, and R3, R4, R5 and R6 are as defined above for Formula (I), and R9 is hydrogen, C1-6alkyl or aryl, for example see Tetrahedron Letters (1996) 39, 6965. Decarboxylation methods include but are not restricted to the use of aqueous sodium hydroxide in a suitable solvent such as dioxan or by using aqueous hydrochloric acid and preferably at elevated temperatures. Examples are given in (but are not restricted to) the following references: J. Med Chem. (1992) 35, 4498, J. Med Chem. (1994) 37, 4371 , J. Med Chem. (1997) 40, 3359, J. Org Chem. (1986) 51 , 2377, J. Chem. Soc. Perkin Trans 1 , (1995) 10, 1251 , J. Org Chem (1990) 55, 270.
Compounds of Formula (XVIII) may be prepared by reaction of compounds of Formula (XIX) and For
Figure imgf000024_0002
in which R1 is an alkoxy, benzyloxy or silyloxy group, and R3, R4, R5 and R6 are as defined above for Formula (I), and R9 is C1-6alkyloxy or aryloxy, and Y is a halo atom, for example bromo, chloro or iodo.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is a carboxylic acid, may be prepared from a compound of Formula (II) in which R4 is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide and water in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
Figure imgf000024_0003
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is an ester (CO2RD), may be prepared from a compound of Formula (II) in which R4 is is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide an alcohol RDOH in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis- diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is a substituted vinyl group may be prepared by reaction between a compound of Formula (II) in which R4 is trifluoromethanesulphonate or a halide such bromide, and an appropriate vinyl compound (XXI) (examples include vinyl ester L= CO2RH, vinyl sulphone L= SO2RH, vinyl ketone L = CORH wherein RH is a vinyl group) in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene complexed with dichloromethane in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
•^^L (XXI) Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is a 2-substituted ethyl group may be prepared by hydrogenation of an appropriately substituted vinyl derivative using a catalyst such as palladium on carbon, in a suitable solvent such as ethanol.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is trifluoromethanesulphonate, may be prepared from a compound of Formula (II) in which R4 is OH, by treatment with trifluoromethanesulphonic anhydride in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is an aryl or heteroaryl group may be prepared by reaction between a compound of Formula (II) in which R4 is trifluoromethanesulphonate or a halide such bromide, and an appropriate aryl or heteroaryl boronic acid derivative (R4- B(OH)2), in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base such as potassium phosphate in a suitable solvent such as dimethoxymethane. Alternatively the aryl or heteroaryl group may be in the form an organozinc reagent (R4-Zn-hal) or an organotin reagent (R4-Sn(n-alkyl)3).
Compounds of Formula (I) in which R is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is OH, may be prepared from a compound of Formula (II) in which R4 is benzyloxy, by hydrogenation with a suitable catalyst such as palladium on carbon in a suitable solvent such as ethanol.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is an optionally substituted ether (ORA) may be prepared by treatment of a compound in which R4 is OH with an alkylating agent (hal- (CH2)n-RA, hal-(CH2)n-het, n= 1-5) in the presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and the compound of Formula (I) contains an amide group, may be prepared from the corresponding carboxylic acid using an amine or amine equivalent RBRCNH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
Compounds of Formula (I) in which R1 is NRBRC may be prepared from compounds of Formula (I) in which R1 is hydroxy, using an amine or amine equivalent RBRCNH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is NH2 may be prepared from compounds of Formula (I) in which R4 is a halogen such as bromo by treatment with lithium bis(trimethylsilyl)amide and catalyst reagents such as tris(dibenzylidenacetone)dipalladium(0) and 2-(dicyclohexylphosphino)biphenyl or combinations therof, in a suitable solvent such as tetrahydrofuran.
Compounds of Formula (I) in which R1 is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R4 is SO2RD may be prepared from compounds of Formula (I) in which R4 is a halogen such as bromo by teatment with a sodium salt of an akylsulfinic acid (eg sodium methylsulfinic acid), in the presence of a copper cataylst (such as coper triflate complexed with toluene) in a suitable solvent such as dimethylsulfoxide, preferably in the temperature range 80-120 °C.
Compounds of Formula (VI), (VIII), (IX), (XI), (XII), (XV), (XVI), (XVII), (XIX) and (XX) are commercially available or well known in the art.
With appropriate manipulation and protection of any chemical functionality, synthesis of compounds of Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section. 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', 3rd Ed (1999), J Wiley and Sons. ABBREVIATIONS
Strata cartridge Dual action SPE cartridge available from Phenomenex
SPE solid phase extraction column
HPLC high pressure liquid chromatography
DCM dichloromethane
DMF dimethylformamide
THF tetrahydrofuran
EtOAc ethyl acetate
AcOH acetic acid
HATU O-(7-azabenzothazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate
DME dimethoxymethane
OASIS cartridge Sample extraction cartridge available from Waters h hour
EXAMPLES
All mass spectroscopy was performed using electrospray as the method of ionisation.
Intermediate 1
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2,3-dihydro-1 H- indole-2-carboxylate
Figure imgf000027_0001
Racemic lndoline-2-carboxylic acid, methyl ester (500 mg) was dissolved in dichloromethane (10 mL) and treated with 3-methoxy-4-tert-butylbenzoyl chloride1 (704 mg). Triethylamine (785 uL) was added and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with dilute hydrochloric acid solution (2N, 50 mL), saturated sodium hydrogen carbonate solution, brine, dried (Na2SO4) and concentrated to give a brown gum. This was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (15:85 v/v) to give the title compound.
MS calcd for (C22H25NO4 + H)+: 368 MS found (electrospray): (M+H)+ = 368.
Ref.(1 ) Synthesised from 3-methoxy-4-tert-butylbenzoic acid (J. Org. Chem. 1961 , 26, 1732-1737).
Intermediate 2 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)- 2,3-dihydro-1
Racemic
Figure imgf000028_0001
Intermediate 1 (359 mg) was dissolved in tetrahydrofuran (THF) (3 mL) and the solution cooled to -78°C under nitrogen. Lithium bis(trimethylsilyl)amide (1 M in THF, 1.17 mL) was added keeping the internal reaction temperature below -70°C. After 20 min. benzyl bromide (235 uL) was added and the reaction mixture allowed to warm to room temperature over 5 hours. The reaction was quenched with saturated ammonium chloride solution and the mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a colourless gum. The crude product was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (30:70 v/v) to give the title compound. MS calcd for (C29H31NO4 + H)+: 458 MS found (electrospray): (M+H)+ = 458
Intermediate 3
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-
2,3-dihydro-1 H-indole-2-carboxylate
Racemic
Figure imgf000028_0002
The title compound was prepared in a similar manner to Intermediate 2, using Intermediate 1 as starting material. MS calcd for (C26H33NO4 + H)+: 424 MS found (electrospray): (M+H)+ = 424
Intermediate 4
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4- [(phenylmethyl)oxy]-1H-indole-2-carboxylate
Figure imgf000029_0001
Racemic
To a stirred solution of methyl 1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4- hydroxy-1/- -indole-2-carboxylate2 (4.5 g, 0.016 mol) in anhydrous dichloromethane (150 mL) under nitrogen was added 4-dimethylaminopyridine (4.6 g, 0.038 mol) followed by 3- methoxy-4-tert-butylbenzoyl chloride (4.5 g , 0.019 mol). The resultant mixture was stirred at ambient temperature for 18 hours and then washed with water. The organic phase was separated, washed with water, dried over sodium sulphate and evaporated to an oily solid. This was then purified by chromatography over silica using ethyl acetate/cyclohexane (1 :9 v/v) as eluent. The fractions containing the desired product were combined and evaporated to give the title compound. MS calcd for (C29H29NO5+H)+: 472. Found (M+H)+ = 472. 2. Tetrahedron Letters 29(7) 799-802, 1988.
Intermediate s
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-hydroxy-2,3- dihydro-1 H-indole-2-carboxylate
Figure imgf000029_0002
Racemic
Intermediate 4 (6.5 g, 0.014 mol.) was dissolved in glacial acetic acid (100 mL) and to this was added 10% palladium on carbon (1 g, wet). The reaction mixture was then placed under hydrogen (50 psi ) and hydrogenated for 16 hours at room temperature. The suspension was then filtered and after several washings with acetic acid, evaporated to dryness to give the title compound.
MS calcd for (C22H25NO5+H)+: 383 Found (M+H)+ = 383.
Intermediate 6 Methyl 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4- [(phenylmethyl)oxy]-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000030_0001
Racemic
To a stirred solution of Intermediate 5; (0.4 g, 0.0016 mol) in anhydrous dimethylformamide (5 mL) and tetrahydrofuran (10 mL) under nitrogen was added potassium carbonate (0.41 g, 0.0029 mol) followed by benzyl bromide (0.26 g, 0.0021 mol). The resultant mixture was stirred at 50°C for 18 hours and then evaporated, partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over sodium sulphate and evaporated to an oily solid. This was then purified by chromatography over silica using ethyl acetate/cyclohexane (15:85 v/v) as eluent. The fractions containing the desired product were combined and evaporated to give the title compound. MS calcd for (C2gH29NO5+H)+: 474. Found (M+H)+ = 474.
Intermediate 7
Methyl 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2- propen-1-yl)-4-[(phenylmethyl)oxy]-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000030_0002
To intermediate 6 (6 g, 12.7 mmol) in dry THF (60 mL) at -78°C, under nitrogen, was added 1 M lithium bis(trimethylsilyl)amide in THF (13.3 mL, 13.3 mmol). The reaction stirred at -78°C for 20 minutes then 3-bromo-2-methylpropene (2.57 g, 19.0 mmol) was added. The reaction was stirred at -78°C for 5 minutes then room temperature for 2 hours. The reaction quenched with saturated ammonium chloride, extracted with ethyl acetate, organics washed with brine, dried over Na2SO4 and concentrated to give a yellow oil. Purification was by Biotage column (silica) eluting with ethyl acetate/cyclohexane (1 :9 v/v) to give the title compound. MS calcd for (C33H37NO5 + H)+ = 528. Found : (M+H)+ = 528 Intermediate 8
MethyH -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-hydroxy-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000031_0001
Intermediate 7 (5.34 g, 10.1 mmol) in ethanol (210 mL) was subjected to atmospheric pressure hydrogenation with 10% palladium on carbon (1g, wet) for 16 hours. The reaction filtered through a pad of Celite, washed with ethanol and combined organics concentrated to give the title compound. MS calcd for (C26H33NO5 + H)+ = 440. Found : (M+H)+ = 440
Intermediate 9
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)- 4-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000031_0002
Trifluromethane sulphonic anhydride (1.2 mL, 4.7 mmol) was added dropwise to a stirred solution of intermediate 8 (2.1 g, 4.7 mmol) and triethylamine (2.0 mL, 14.2 mmol) in dichloromethane (20 mL) at -78°C under nitrogen. The reaction was stirred at this temperature for 3.5 hours and was then quenched by the successive addition of water and 2N hydrochloric acid and was then extracted with dichloromethane. The extracts were combined, dried and evaporated to give crude product as a yellow oil. This material was purified by chromatography on silica gel eluting with ethyl acetate/cyclohexane (1 :19 v/v). Appropriate fractions were combined and then evaporated to give the title compound. MS calcd for (C27H32F3NO7S + H)+: 572. Found: (M+H)+ = 572.
Intermediate 10
1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-[(methyloxy)carbonyl]-2- (2-methylpropyl)-2,3-dihydro-1H-indole-4-carboxylic acid racemic
Figure imgf000032_0001
To a dry DMF (10 mL) solution of intermediate 9 (1 g, 1.75 mmol) was added triethylamine (0.35 g, 3.5 mmol), water (0.63 g, 35.9 mmol), palladium (II) acetate (23 mg, 0.1 mmol) and bis-diphenylphosphinoferrocene (116 mg, 0.2 mmol). Carbon monoxide was bubbled through the solution for 10 minutes then stirred at 60°C, under carbon monoxide (balloon pressure) for 3 hours. The reaction was left to stand overnight at room temperature under carbon monoxide. The reaction was partitioned between ethyl acetate and 2N hydrochloric acid, organics washed with brine, dried over Na2SO4 and concentrated to give a brown oil. This was purified by SPE (silica) eluting with methanol/acetic acid/dichloromethane (1 :1 :198 v/v) to give the title compound. MS calcd for (C27H33NO6 + H)+ = 468. Found : (M+H)+ = 468
Intermediate 11 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4- [(phenylmethyl)oxy]-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000032_0002
To intermediate 6 (2.78g) in dry THF (29mL, 6.06mmol)) at -78°C, under nitrogen, was added 1 M lithium bis(trimethylsilyl)amide in THF (6.36mL, 6.36mmol) and stirred for 1 hour. Benzyl bromide (0.79 mL, 6.67 mmol) was added and allowed to warm to room temperature, with stirring overnight. The reaction quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give a brown oil. Purified using a Biotage column (silica) eluted with ethyl acetate/ cyclohexane (1 :9 v/v) to give the title compound. MS calcd for (C36H37NO5 + H)+ = 564. Found : (M+H)+ =564
Intermediate 12
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-hydroxy-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000033_0001
Intermediate 11 in ethanol (115 mL) was subjected to atmospheric pressure catalytic hydrogenation with 10% palladium on carbon (0.28 g, wet) for 16 hours. The reaction was filtered through a pad of Celite, washed with ethanol and combined organics concentrated to give the title compound.
MS calcd for (C29H31NO5 + H)+ = 474. Found : (M+H)+ =474
Intermediate 13 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4- {[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000033_0002
To intermediate 12 (1 g, 2.11 mmol) in dry DMF (30 mL) at 0°C, under nitrogen, was added triethylamine (0.53 g, 5.3 mmol) and N-phenyl trifluoromethanesulphonimide (0.166 g, 0.465 mmol). The reaction was stirred at 0°C for 30 minutes, then room temperature for 2 hours. A small amount of water was added, solvent removed and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics washed with brine, dried over sodium sulphate and concentrated to give a pale yellow oil. This was purified by a Biotage column (silica) eluting with ethyl acetate/cyclohexane (1 :9) then a second column eluting with DCM/cyclohexane (1 :1 ) then DCM to give the title compound. MS calcd for (C30H30F3NO7S + H)+ = 606. Found (M+H)+ = 606
Intermediate 14
2-Methyl 4-(phenylmethyl) 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}- 2-(phenylmethyl)-2,3-dihydro-1H-indole-2,4-dicarboxylate
Figure imgf000034_0001
Carbon monoxide gas was gently bubbled through a dry DMF (2 mL) solution of intermediate 13 (0.2 g, 0.33 mmol), triethylamine (66 mg, 0.66 mmol), benzyl alcohol (0.68 mL, 6.6 mmol), palladium (II) acetate (4.5 mg, 0.02 mmol) and bis- diphenylphosphinoferrocene (22 mg, 0.03 mmol) for 5 minutes. The reaction was then stirred at 60°C under carbon monoxide (balloon pressure) for 3 hours and left to stand overnight. This was partitioned between ethyl acetate and sat. NaHCO3 solution, organics washed with brine, dried over Na2SO4 and concentrated to give a brown oil. This was purified by silica Biotage column (silica) eluting with ethyl acetate/cyclohexane (15:85) to give product containing benzyl alcohol. The crude product dissolved in ethyl acetate and washed twice with 2N sodium hydroxide, brine, dried over Na2SO4 and concentrated to give the title compound. MS calcd for (C37H37NO6 + H)+= 592. Found (M+H)+ =592
Intermediate 15
1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-[(methyloxy)carbonyl]-2- (phenylmethyl)-2,3-dihydro-1 H-indole-4-carboxylic acid
Figure imgf000034_0002
Intermediate 14 (50 mg, 0.085 mmol) in ethanol (5mL) was subjected to atmospheric pressure catalytic hydrogenation with 10% palladium on carbon (5 mg, wet) for 3 hours.
The reaction was filtered through a pad of Celite, washed with ethanol and combined organics concentrated to give the title compound.
MS calcd for (C30H31NO6 + H)+=502. Found (M+H)+=502
Intermediate 16
Methyl 4-(aminocarbonyl)-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-
2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000035_0001
To intermediate 15 (37 mg, 0.074 mmol) was added dry DMF (1 mL), N,N- diisopropylethylamine (0.256 mL, 1.47 mmol), HATU (31.1 mg, 0.081 mmol) and ammonium chloride (79 mg, 1.47 mmol). The reaction was stirred at room temperature, under nitrogen for 16 hours. The solvent removed, partitioned between ethyl acetate and 2N hydrochloric acid, organics washed with water, sat. NaHCO3 and brine, dried over Na2SO4 and concentrated to give the title compound. MS calcd for (C30H32N2O5 + H)+=501 Found (M+H)+=501
Intermediate 17
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methyloxy)-2- oxoethyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000035_0002
To intermediate 12 (50 mg, 0.105 mmol) was added acetonitrile (1 mL), triethylamine (17.7 uL, 0.12 mmol) and bromoacetamide (16 mg, 0.116 mmol). The reaction stirred at 50°C for 4 hours then heated under reflux for 16 hours. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C31H34N2O6 + H)+ = 531. Found : (M+H)+ = 531
Intermediate 18
Methyl 4-[(cyanomethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2- carboxylate
Figure imgf000036_0001
To intermediate 8 (0.2 g, 0.45 mmol) in DMF (1 mL ) was added portionwise sodium hydride (0.018 g, 0.45 mmol) at 0°C . After 15 minutes the reaction mixture was treated with chloroacetonitrile (0.04g, 0.052 mmol) dropwise and allowed to stir at room temperature for 16 hrs. The solution was then partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and evaporated. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C28H34N2O5 + H)+: 479. Found : (M+H)+ =479.
Intermediate 19 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methyloxy)-2- oxoethyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000036_0002
The title compound was prepared in a similar manner to Intermediate 17, using Intermediate 12 as starting material. MS calcd for (C32H35NO7 + H)+ = 546. Found : (M+H)+ = 546
Intermediate 20
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(2- methylpropyl)oxy]-2-(phenylmethyl)-2,3-dihydro-1W-indole-2-carboxylate
Figure imgf000037_0001
The title compound was prepared in a similar manner to Intermediate 17, using Intermediate 12 as starting material. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C33H39NO5 + H)+ = 530 Found : (M+H)+ = 530
Intermediate 21
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-
[(3-pyridinylmethyl)oxy]-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000037_0002
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 12 as starting material. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C35H36N2O5 + H)+ = 565. Found : (M+H)+ = 565
Intermediate 22 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(5-methyl-3- isoxazolyl)methyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000038_0001
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 12 as starting material. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C34H36N2O6 + H)+ = 569. Found : (M+H)+ = 569
Intermediate 23
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-phenyl-2-
(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000038_0002
To intermediate 13 (50 mg, 0.083 mmol) was added dry DME (1 mL), phenyl boronic acid (12.1 mg, 0.099 mmol), potassium phosphate (35 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (9.5 mg, 0.008 mmol). The reaction stirred at 80°C, under nitrogen for 16 hours. The reaction cooled, partitioned between ethyl acetate and sat. NaHCO3, organics washed with 2N hydrochloric acid and brine, dried over Na2SO4 and concentrated. Purified by a Biotage column (silica) eluting with (1 :9 DCM/cyclohexane (1 :9 v/v) then ethyl acetate/cyclohexane (1 :19 v/v) to give the title compound.
MS calcd for (C35H35NO4 + H)+ = 534 Found : (M+H)+ = 534
Intermediate 24
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-
(5-pyrimidinyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000039_0001
To intermediate 13 (47 mg, 0.077 mmol) was added dry DME (0.75 mL), pyrimidine-5- boronic acid (14.4 mg, 0.116 mmol), potassium phosphate (35 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (0) (9.5 mg, 0.008 mmol) and water (0.25 mL). The reaction was stirred at 80°C, under nitrogen for 3 hours. The reaction cooled, partitioned between ethyl acetate and sat. NaHCO3, organics washed with brine, dried over Na2SO4 and concentrated. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to furnish the title compound. MS calcd for (C33H33N3O4 + H)+ = 536 Found : (M+H)+ = 536
Intermediate 25
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-
(1 ,3-thiazol-2-yl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000039_0002
To intermediate 13 (60 mg, 0.01 mmol) was added dry THF (1 mL), tetrakis(triphenylphosphine)palladium (0) (11.5 mg, 0.001 mmol) and 0.5M 2-thiazole zinc bromide in THF (0.22 mL, 0.011 mmol). The reaction was stirred at 80°C under nitrogen for 16 hours. The reaction was quenched with 2N hydrochloric acid, extracted with ethyl acetate, organics washed with brine, dried over Na2SO4 and concentrated. The solvent was removed and purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spec. Further purification by SPE (silica) eluting with ethyl acetate/cyclohexane (1 :9) gave the title compound. MS calcd for (C32H32N2O4S + H)+ = 541 Found : (M+H)+ = 541
Intermediate 26
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(E)-2-
(methylsulfonyl)ethenyl]-2-(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000040_0001
To intermediate 9 (0.1 g, 0.17 mmol) in dry DMF (1 mL,) at ambient temperature, under nitrogen, was added triethylamine (4.6 ul, 0.32 mmol,) followed by 1 ,1- bis(diphenylphosphino)ferrocenedichloro palladium (II) complex with dichloromethane (0.013 g , 0.016 mmol) and methyl vinyl sulphone (0.02 g, 0.262 mmol ). This was heated at 120°C for 16 hours in a reacti-vial. The reaction was cooled and partitioned between 2 N HCI / ethyl acetate. The organics washed with water, dried over Na2SO4, filtered and evaporated to give an oil. This was purified by SPE (silica) column eluting with ethyl acetate/cyclohexane (1 :4 v/v) to give the title compound. MS calcd for (C29H37NO6S + H)+: 527. Found : (M+H)+ = 527
Intermediate 27
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[2-
(methylsulfonyl)ethyl]-2-(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000040_0002
Intermediate 26 (0.05 g, 0.0944 mmol) in ethanol (10 mL) was subjected to atmospheric pressure catalytic hydrogenation with 10% palladium on carbon (0.01 g, wet) for 16 hours. The reaction was filtered through a pad of Celite, washed with ethanol and combined organics concentrated to give the title compound. MS calcd for (C29H39NO6S + H)+: 529. Found : (M+H)+ = 529.
Intermediate 28
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)- 4-[(1E)-3-oxo-1-buten-1-yl]-2,3-dihydro-1H-indole-2-carboxylate
racemic
Figure imgf000041_0001
The title compound was prepared in a similar manner to Intermediate 26, using Intermediate 13 as starting material. MS calcd for (C30H37NO5+H)+: 492. Found (M+H)+ = 492.
Intermediate 29
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-
4-(3-oxobutyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000041_0002
The title compound was prepared in a similar manner to Intermediate 27, using
Intermediate 12 as starting material. After chromatography over silica using ethyl acetate/cyclohexane (1 :9, v/v) as eluent, the fractions containing the desired product were combined and evaporated to give the title compound. MS calcd for (C30H37NO5+H)+: 494.
Found (M+H)+ 494.
Intermediate 30
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(1 E)-3- (methyloxy)-3-oxo-1 -propen-1 -yl]-2-(phenylmethyl)-2,3-dihydro-1 H-indole-2- carboxylate
Figure imgf000042_0001
The title compound was prepared in a similar manner to Intermediate 26, using Intermediate 13 as starting material, and purified by chromatography over silica gel eluting with ethyl acetate/cyclohexane (1:9 v/v) to give the title compound. MS calcd for (C33H35NO6 + H)+ = 542 Found : (M+H)+ = 542
Intermediate 31
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[3-(methyloxy)-3- oxopropyl]-2-(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylate
Figure imgf000042_0002
Intermediate 30 (32 mg, 0.059 mmol) in ethanol (5 mL) was subjected to atmospheric pressure hydrogenation with 10% palladium on carbon (3 mg, wet) for 4 hours. The reaction was filtered through a pad of Celite, washed with ethanol and the combined organics concentrated to give the title compound. MS calcd for (C33H37NO6 + H)+ = 544 Found : (M+H)+ = 544
Intermediate 32
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methyloxy)-2- oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000043_0001
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 8 as starting material. MS calcd for (C29H37NO7 + H)+ = 512. Found : (M+H)+ = 512
Intermediate 33
Methyl 4-[(2-amino-2-oxoethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3- (methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1W-indole-2- carboxylate
Figure imgf000043_0002
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 8 as starting material. MS calcd for (C28H36N2O6 + H)+ = 497. Found : (M+H)+ = 497
Intermediate 34
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methylamino)-
Figure imgf000043_0003
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 8 as starting material. MS calcd for (C29H38N2O6 + H)+ = 511. Found : (M+H)+ = 511
Intermediate 35
Methyl 4-{[2-(dimethylamino)-2-oxoethyl]oxy}-1 -{[4-(1 ,1 -dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2- carboxylate
Figure imgf000044_0001
The title compound was prepared in a similar manner to Intermediate 18, using Intermediate 8 as starting material. MS calcd for (C30H4oN2O6 + H)+ = 525. Found : (M+H)+ = 525
Intermediate 36 Methyl 1-{[4-(1,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(1E)-3-
(methyloxy)-3-oxo-1 -propen-1 -yl]-2-(2-methylpropyl)-2,3-dihydro-1 H-indole-2- carboxylate
Figure imgf000044_0002
The title compound was prepared in a similar manner to Intermediate 26, using Intermediate 9 as starting material. Purification was by chromatography over silica gel eluting with ethyl acetate/cyclohexane (15:85 v/v) to give the title compound. MS calcd for (C30H37NO6 + H)+ = 508 Found : (M+H)+ = 508
Intermediate 37
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[3-(methyloxy)-3- oxopropyl]-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000045_0001
The title compound was prepared in a similar manner to Intermediate 27, using Intermediate 36 as starting material. MS calcd for (C30H39NO6 + H)+ = 510 Found : (M+H)+ = 510
Intermediate 38
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-
4-phenyl-2,3-dihydro-1W-indole-2-carboxylate
Figure imgf000045_0002
The title compound was prepared in a similar manner to Intermediate 23, using Intermediate 9 as starting material. Purification was by chromatography over silica gel, eluting with ethyl acetate:cyclohexane (1 :19 v/v) to give the title compound. MS calcd for (C32H37NO4 + H)+ = 500 Found : (M+H)+ = 500
Intermediate 39
2-Methyl 4-(phenylmethyl) 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-
2-(2-methylpropyl)-2,3-dihydro-1H-indole-2,4-dicarboxylate
The title compound was prepared in a similar manner to Intermediate 14, using Intermediate 9 as starting material. MS calcd for (C34H39NO6 + H)+ = 558. Found : (M+H)+ = 558
Intermediate 40
Methyl 4-(aminocarbonyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-
2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000046_0001
The title compound was prepared in a similar manner to Intermediate 16, using Intermediate 10 as starting material. Purification was by STRATA cartridge, loaded in DCM, washed successively with DCM and methanol. Combined organics were concentrated to give the title compound. MS calcd for (C27H34N2O5 + H)+= 467 Found (M+H)+= 467
Intermediate 41
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4- [(methylamino)carbonyl]-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000046_0002
The title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material. Purification was by STRATA cartridge, loaded in DCM, washed successively with DCM and methanol. Combined organics were concentrated to give the title compound. MS calcd for (C28H36N2O5 + H)+= 481 Found (M+H)+= 481
Intermediate 42
Methyl 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(1- methylethyl)amino]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1W-indole-2- carboxylate
Figure imgf000047_0001
The title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material. Purification was by STRATA cartridge, loaded in DCM, washed successively with DCM and methanol. Combined organics were concentrated to give the title compound. MS calcd for (C30H4oN2O5 + H)+= 510 Found (M+H)+= 510
Intermediate 43 Methyl4-[(dimethylamino)carbonyl]-1 -{[4-(1 ,1 -dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1 H-indole-2- carboxylate
Figure imgf000047_0002
The title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material. Purification was by STRATA cartridge, loaded in DCM, washed successively with DCM and methanol. Combined organics were concentrated to give the title compound. MS calcd for (C29H38N2O5 + H)+= 495 Found (M+H)+= 495
Intermediate 44
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-
4-[(1,3-thiazol-2-ylamino)carbonyl]-2,3-dihydro-1W-indole-2-carboxylate
Figure imgf000048_0001
The title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material and purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy. MS calcd for (C30H35N3O5S + H)+= 550 Found (M+H)+= 550
Intermediate 45
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)- 4-[(1H-pyrazol-3-ylamino)carb ole-2-carboxylate
Figure imgf000048_0002
The title compound was prepared in a similar manner to Intermediate 40, using Intermediate 10 as starting material and purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy.
MS calcd for (C30H36N4O5 + H)+= 533 Found (M+H)+= 533
Intermediate 46
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-
4-[(1H-1 ,2,4-triazol-3-ylamino)carbonyl]-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000049_0001
To Intermediate 10 (30 mg, 0.064 mmol) was added dry DMF (1 mL), carbonyldiimidazole (10.4 mg, 0.069 mmol) and 3-aminotriazole (16.1 mg, 0.19 mmol). The reaction was stirred at room temperature, under nitrogen for 16 hours. Solvent removed and purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy. MS calcd for (C29H35N5O5 + H)+= 534 Found (M+H)+= 534
Intermediate 47
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methyloxy)-2,3- dihydro-1 H-indole-2-carboxylate
Figure imgf000049_0002
The title compound was prepared in a similar manner to Intermediate 1 , using 5- methoxyindoline-2(R,S)-carboxylic acid methyl ester.3 MS calcd for (C23H27NO5 + H)+ = 398. Found : (M+H)+ = 398 Ref 3 as described in WO 99/33801
Intermediate 48
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methyloxy)-2-
(phenylmethyl)-2,3-dihydro-1W-indole-2-carboxylate
Figure imgf000049_0003
The title compound was prepared in a similar manner to Intermediate 2, using Intermediate 47 as starting material. MS calcd for (C30H33NO5 + H)+ = 488. Found : (M+H)+ = 488
Intermediate 49
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-hydroxy-2-
(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000050_0001
To Intermediate 48 (1 g, 2.05 mmol) was added dry DCM (20 mL) and 1 M boron tribromide dimethyl sulphide complex in dichloromethane (6.15 mL, 6.15 mmol). The reaction was stirred for 3 days at 40°C under nitrogen, partitioned between 2N hydrochloric acid and dichloromethane, the organics washed with brine, dried over Na2SO4 and concentrated to give a brown oil. This was purified by Biotage column (silica) eluted with ethyl acetate/cyclohexane (1 :1 v/v containing 1% acetic acid) to give the title compound.
MS calcd for (C28H29NO5 + H)+ = 460. Found : (M+H)+ = 460
Intermediate 50
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-hydroxy-2- (phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000050_0002
To Intermediate 49 (0.71 g, 1 ,5 mmol) was added dry methanol (35 mL) and thionyl chloride (0.178 g, 1.5 mmol). The reaction was heated under reflux for 16 hours, and the solvent evaporated to give a brown gum. This was purified by Biotage column (silica) eluted with ethyl acetate/cyclohexane (1 :4) to give the title compound. MS calcd for (C29H31NO5 + H)+ = 474. Found : (M+H)+ = 474 Intermediate 51
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-
{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000051_0001
To Intermediate 50 (0.45 g, 0.95 mmol) in dry DMF (13.5 mL) at 0°C, under nitrogen, was added triethylamine (0.33 mL, 2.38 mmol) and N-phenyltrifluoromethanesulfonimide (0.75 g, 2.09 mmol). The reaction was stirred at 0°C for 30 minutes then room temperature for 2 hours. A small amount of water was added and then the solvent evaporated The residue was partitioned between ethyl acetate and water, organics washed with brine, dried over Na2SO4 and concentrated to give a yellow oil. This was purified by Biotage column (silica) eluting with ethyl acetate/cyclohexane (1 :9) to give the title compound. MS calcd for (C3oH30F3NO7S + H)+ = 606. Found : (M+H)+ = 606
Intermediate 52
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-{[2-(methyloxy)-2- oxoethyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
racemic
Figure imgf000051_0002
To Intermediate 50 (62 mg, 0.131 mmol) in dry DMF (1 mL) at 0°C, under nitrogen, was added sodium hydride 60% in oil (5.5 mg, 0.137 mmol). The reaction was stirred for 15 minutes then methyl bromoacetate (15 uL, 0157 mmol) added and stirred at 0°C for 1 hour. The solvent was removed, the residue partitioned between ethyl acetate and water, organics washed with brine, dried over Na2SO4 and concentrated to give a pale yellow gum. Purification was by SPE (silica) eluting with ethyl acetate/cyclohexane (1:3 v/v) to give the title compound. MS calcd for (C32H35NO7 + H)+ = 546. Found : (M+H)+ = 546
Intermediate 53 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5- (3-pyridinyl)-2,3-dihydro-1H-indole-2-carboxylate racemic
Figure imgf000052_0001
The title compound was prepared in a similar manner to Intermediate 24, using Intermediate 51 as starting material. MS calcd for (C34H34N2O4 + H)+ = 535. Found : (M+H)+ = 535
Intermediate 54 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5- (1 ,3-thiazol-2-yl)-2,3-dihydro-1 H-indole-2-carboxylate
racemic
Figure imgf000052_0002
The title compound was prepared in a similar manner to Intermediate 25, using Intermediate 51 as starting material. MS calcd for (C32H32N2O4S + H)+ = 541. Found : (M+H)+ = 541
Intermediate 55
Methyl 5-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2,3- dihydro-1 H-indole-2-carboxylate
Figure imgf000052_0003
The title compound was prepared in a similar manner to Intermediate 1 , using methyl 5- bromo-2,3-dihydro-1/-/-indole-2-carboxylate (EP 801060 A1 ) as starting material. MS calcd for (C22H24BrNO4 + H)+: 446/448 Found : (M+H)+ =446/448 (isotopic splitting) Intermediate 56
Methyl 5-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1AV-indole-2-carboxylate
Figure imgf000053_0001
racemic The title compound was prepared in a similar manner to Intermediate 2, using Intermediate 55 as starting material. MS calcd for (C29H30BrNO4 + H)+:536/538 Found: (M+H)+ = 536/538 (isotopic splitting)
Intermediate 57
Methyl 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methylsulfonyl)-2- (phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
racemic
Figure imgf000053_0002
Intermediate 56 (100 mg) was dissolved in dimethylsulfoxide (0.4 mL) and treated with sodium methylsulfinic acid (23 mg), N-methylethylendiamine (20% mol) and copper triflate complexed with toluene, Cu(OTf)2tol (10% mol). The reaction mixture was stirred in a reacti-vial at 100°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 mL) and filtered through silica to remove inorganic material.
The filtrate was washed with brine (5 mL) and water (5 mL) dried (Na2SO4) and concentrated to give a brown solid. This was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (20:80 v/v) to give the title compound.
MS calcd for (C30H33NO6S + H)+: 536.
Found: (M+H)+ = 536.
Intermediate 58
Methyl 5-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000054_0001
racemic The title compound was prepared in a similar manner to Intermediate 2, using Intermediate 55 as starting material. MS calcd for (C26H32BrNO4 + H)+:502/504. Found: (M+H)+ = 502/504 (isotopic splitting)
Intermediate 59
Methyl 5-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3- thiazol-4-ylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000054_0002
racemic
The title compound was prepared in a similar manner to Intermediate 2, using
Intermediate 55 as starting material.
MS calcd for (C26H27BrN2O4S + H)+:543/545
Found: (M+H)+ = 543/545 (isotopic splitting)
Intermediate 60
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2- propen-1 -yl)-2,3-dihydro-1 H-indole-2-carboxylate
racemic
Figure imgf000054_0003
The title compound was prepared in a similar manner to Intermediate 2, using Intermediate 55 as starting material. MS calcd for (C26H31NO4 + H)+: 422. Found : (M+H)+ = 422
Intermediate 61 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4- ylmethyl)-2,3-dihydro-1AV-indole-2-carboxylate
Figure imgf000055_0001
This was similarly prepared following the procedure described for intermediate 2 using 4- methylchlorothiazole instead of benzyl bromide, to give the title compound. MS calcd for (C26H28N2O4S+ H)+: 465. Found : (M+H)+ =465
Intermediate 62 Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(3- pyridinylmethyl)-2,3-dihydro-1H-indole-2-carboxylate
racemic
Figure imgf000055_0002
The title compound was prepared in a similar manner to Intermediate 2, using 3-methyl chloropyridine instead of benzyl bromide. MS calcd for (C28H30N2O4+ H)+: 459. Found : (M+H)+ = 459
Intermediate 63
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-oxazol-2- ylmethyl)-2,3-dihydro-1 H-indole-2-carboxylate racemic
Figure imgf000056_0001
The title compound was prepared in a similar manner to Intermediate 2, using 2- chloromethyloxazole instead of benzyl bromide. MS calcd for (C26H28N2O5+ H)+: 449. Found : (M+H)+ = 449
Intermediate 64
4-Ethyl 2-methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1H-indole-2,4-dicarboxylate
Figure imgf000056_0002
A reacti-vial was charged with Intermediate 10 (150 mg, 0.32 mmol), dry acetonitrile (1.5 mL), 1 ,8-diazabicycloundec-7-ene (48 uL, 0.32 mmol) and ethyl iodide (33 uL, 0.42 mmol). The reaction was stirred at 70°C for 20 hours. The solvent removed and material partitioned between 2N hydrochloric acid and ethyl acetate, organics washed with brine, dried over Na2SO4, and concentrated to give the title compound. MS calcd for (C29H37NO6 + H)+ = 496. Found : (M+H)+ = 496
Intermediate 65 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(ethyloxy)carbonyl]-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000056_0003
The title compound was prepared in a similar manner to Example 33 using Intermediate 64. Purification was by SPE (silica) eluted with ethyl acetate/cyclohexane (1 :4) to give the title compound.
MS calcd for (C28H35NO6 + H)+ = 482. Found : (M+H)+ = 482
Intermediate 66
Ethyl 2-(aminocarbonyl)-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(2-methylpropyl)-2,3-dihydro-1H-indole-4-carboxylate
Figure imgf000057_0001
The title compound was prepared in a similar manner to Intermediate 16, replacing intermediate 15 with Intermediate 65. Purification was by SPE (NH2) loaded in 1 ,4-dioxan, the column washed with 1 ,4-dioxan and eluted with acetic acid: 1 ,4-dioxan (1 :9 v/v) to give the title compound. MS calcd for (C28H36N2O5 + H)+ = 481. Found : (M+H)+ = 481
Intermediate 67
Methyl 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(ethyloxy)-2- oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylate
Figure imgf000057_0002
The title compound was prepared in a similar manner to Intermediate 18 using Intermediate 8. Purification was by SPE (silca) eluting with ethyl acetate/cyclohexane (1 :9) to give the title compound. MS calcd for (C30H39NO7 + H)+ = 526. Found : (M+H)+ = 526 Intermediate 68 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-
(ethyloxy)-2-oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
racemic
Figure imgf000058_0001
The title compound was prepared in a similar manner to Example 33 from Intermediate 67. Purification was by SPE (silica) with gradient elution using ethyl acetate/cyclohexane (1 :4 v/v), DCM/AcOH (99:1 v/v), H2O/AcOH (99:1 v/v), DCM/MeOH (99:1 v/v) to give the title compound.
MS calcd for (C29H37NO7 + H)+ = 512. Found : (M+H)+ = 512
Intermediate 69
Ethyl {[2-(aminocarbonyl)-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-
2-(2-methylpropyl)-2,3-dihydro-1H-indol-4-yl]oxy}acetate
Figure imgf000058_0002
The title compound was prepared in a similar manner to Intermediate 16, replacing intermediate 15 with intermediate 68. Purification was by STRATA cartridge loaded in
DCM, washed with DCM and methanol. Combined organics were concentrated to give the title compound. MS calcd for (C30H40N2O6 + H)+ = 511
Found : (M+H)+ = 511
Intermediate 70
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-1 ,2,3,4-tetrahydro-2- quinolinecarboxylate
Figure imgf000059_0001
1 H-1 ,2,3,4-tetrahydroquinoline-2-carboxylic acid, methyl ester (484 mg) was dissolved in dichloromethane (10 mL) and treated with 3-methoxy-4-tert-butylbenzoyl chloride (530 mg). Triethylamine (885 uL) was added and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with dilute hydrochloric acid solution (2N, 50 mL), saturated sodium hydrogen carbonate solution, brine, dried (Na2SO4) and concentrated to give a brown gum. The crude product was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (gradient elution, from 5% to 50% ethyl acetate) to give the title compound. MS calcd for (C23H2 NO4 + H)+: 382 MS found (electrospray): (M+H)+ = 382
Intermediate 71
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)- 1 ,2,3,4-tetrahydro-2-quinolinecarboxylate
racemic
Figure imgf000059_0002
Intermediate 70 (325 mg) was dissolved in tetrahydrofuran (THF) (3 mL) and the solution cooled to -78°C under nitrogen. Lithium bis(trimethylsilyl)amide (1 M in THF, 1.02 mL) was added keeping the internal reaction temperature below -70°C. After 20 minutes benzyl bromide (202 uL) was added and the reaction mixture allowed to warm to room temperature over 5h and then left to stand at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution and the mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give an oil. The crude product was purified by silica gel chromatography eluting with ethyl acetate/cyclohexane (gradient elution, from 5% to 30% ethyl acetate) to give the title compound. MS calcd for (C30H33NO4 + H)+: 472 MS found (electrospray): (M+H)+ = 472
Intermediate 72
Methyl 1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2- propen-1 -yl)-1 ,2,3,4-tetrahydro-2-quinolinecarboxylate racemic
Figure imgf000060_0001
Similarly prepared to Intermediate 71 to give the title compound MS calcd for (C27H33NO4 + H)+: 436 MS found (electrospray): (M+H)+ = 436
Intermediate 73
Methyl 6-bromo-1 ,2,3,4-tetrahydro-2-quinolinecarboxylate
Figure imgf000060_0002
N-Bromosuccinimide (2.45 g, 13.77 mmol) in DMF (10 mL) was added dropwise to a solution of methyl 1 ,2,3,4-tetrahydroquinoline-2-carboxylate (2.63 g, 13.77 mmol) at ambient temperature under nitrogen. The mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue partitioned between water (100 mL) and ethyl acetate/toluene (1 :1 ; 3x60 mL). The organics were dried (Na2SO ) and evaporated. The resulting residue was purified by silica column chromatography, eluting with cyclohexane to cydohexane/DCM [(4:1 ), (3:1 ), (1 :1), (1 :3) then DCM] to give the title compound.
MS calcd for (CnH12BrNO2 + H)+: 271/273 MS found (electrospray): (M+H)+ = 271/273
Intermediate 74
Methyl 6-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-1 ,2,3,4- tetrahydro-2-quinolinecarboxylate
Figure imgf000060_0003
This was similarly prepared following the procedure described for Intermediate 70, replacing 7/-/-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylic acid, methyl ester with Intermediate 73, to afford the title compound. MS calcd for (C23H26BrNO4+ H)+: 461/463 MS found (electrospray): (M+H)+ = 461/463
Intermediate 75
Methyl 6-bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate racemic
Figure imgf000061_0001
This was similarly prepared following the procedure described for Intermediate 71 , replacing Intermediate 70 with Intermediate 74, to afford the title compound. MS calcd for (C30H32BrNO4 + H)+: 551/553 MS found (electrospray): (M+H)+ = 551/553
Intermediate 76
Methyl 6-amino-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
racemic
Figure imgf000061_0002
Tris(dibenzylideneacetone)dipalladium(0) (0.4 mg) and 2-(dicyclohexylphosphino)biphenyl (0.9 mg) were added to a solution of Intermediate 75 (100 mg, 0.18 mmol) and lithium bis(trimethylsilyl)amide (1M in THF, 0.21 mL) in THF (3 mL) at room temperature under nitrogen. The mixture was heated to 70°C for 4 hours. On cooling, 2N HCI (2 mL) was added and the reaction stirred for a further 10 minutes. The mixture was basified with 2N NaOH, extracted with EtOAc (3 x10 mL), dried (Na2SO4) and evaporated. Purification was by SPE (silica) cartridge, elutiing with DCM/cyclohexane (1 :3 vv/ then 1:1 , then 3:1), then DCM, then DCM /EtOAc (1:1) and finally EtOAc gave the title compound. MS calcd for (C30H34N2O4 + H)+: 487 MS found (electrospray): (M+H)+ = 487.
EXAMPLES
Example 1 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid
Figure imgf000061_0003
Intermediate 2 (164 mg) was dissolved in tetrahydrofuran (4 mL) and methanol (1 mL). The solution was treated with aqueous sodium hydroxide solution (2M, 1 mL) and the mixture stirred at room temperature for 24h and then heated at 75°C for 24h. The tetrahydrofuran and methanol were removed in vacuo and the residue treated with aqueous hydrochloric acid (2N, 10 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with brine, dried (Na2SO4) and concentrated to give the title compound.
MS calcd for (C28H29NO4 + H)+: 444 MS found (electrospray): (M+H)+ = 444
The following compounds were prepared using a similar procedure to that described for Example 1
Example 2 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro- 1 H-indole-2-carboxylic acid
Figure imgf000062_0001
Prepared from Intermediate 3. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C25H31NO4 + H)+: 410 MS found (electrospray): (M+H)+ = 410
Example 3
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3- dihydro-1 H-indole-2,4-dicarboxylic acid
Figure imgf000062_0002
From Intermediate 14. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C29H29NO6 + H)+ = 488. Found : (M+H)+ = 488
Example 4
4-(Aminocarbonyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
racemic
Figure imgf000063_0001
From Intermediate 16 and purified by SPE (NH2). The column was conditioned with 1 ,4- dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9). Then further purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, then SPE (silca) with gradient elution (cyclohexane then DCM then 1 to 5 % methanol in DCM) to give the title compound. MS calcd for (C29H30N2O5 + H)+ = 487 Found : (M+H)+ = 487
Example 5
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4- [(phenylmethyl)oxy]-2,3-dihydro-1H-indole-2-carboxylic acid
racemic
Figure imgf000063_0002
From Intermediate 11 to give the title compound. MS calcd for (C35H35NO5 + H)+ = 550. Found : (M+H)+ = 550
Example 6
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-[(3- pyridinylmethyl)oxy]-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000064_0001
From Intermediate 21 to give the title compound. MS calcd for (C34H34N2O5 + H)+ = 551. Found : (M+H)+ = 551
Example 7
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(5-methyl-3- isoxazolyl)methyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000064_0002
From Intermediate 22 to give the title compound. MS calcd for (C33H34N2O6 + H)+ = 555. Found : (M+H)+ = 555
Example 8 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(2-methylpropyl)oxy]-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000064_0003
From Intermediate 20. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C32H37NO5 + H)+ = 516. Found : (M+H)+ = 516
Example 9
4-[(E)-2-Carboxyethenyl]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000065_0001
From Intermediate 30 to give the title compound. MS calcd for (C31H31NO6 + H)+ = 514. Found : (M+H)+ = 514
Example 10
4-(2-Carboxyethyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000065_0002
From Intermediate 31 to give the title compound. MS calcd for (C31H33NO6 + H)+ = 516 Found : (M+H)+ = 516
Example 11 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-phenyl-2-(phenylmethyl)- 2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000065_0003
From Intermediate 38 to give the title compound. MS calcd for (C34H33NO4 + H)+ = 520 Found : (M+H)+ = 520
Example 12
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-(5- pyrimidinyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000066_0001
From Intermediate 24 to give title compound. MS calcd for (C32H31N3O4 + H)+ = 522 Found : (M+H)+ = 522
Example 13
1 -{[4-(1,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-(1 ,3- thiazol-2-yl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000066_0002
From Intermediate 25 to give the title compound.
MS calcd for (C31H30N2O4S + H)+ = 527
Found : (M+H)+ = 527
Example 14
5-[(Carboxymethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
racemic
Figure imgf000066_0003
From Intermediate 52 to give the title compound. MS calcd for (C30H31NO7 + H)+ = 518. Found : (M+H)+ = 518
Example 15
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(3- pyridinyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
racemic
Figure imgf000067_0001
From Intermediate 53 to give the title compound. MS calcd for (C33H32N2O4 + H)+ = 521. Found : (M+H)+ = 521
Example 16
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(1 ,3- thiazol-2-yl)-2,3-dihydro-1 H-indole-2-carboxylic acid
racemic
Figure imgf000067_0002
From Intermediate 54 to give the title compound. MS calcd for (C31H30N2O4S + H)+ = 527. Found : (M+H)+ = 527
Example 17
4-[(Carboxymethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(2-methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000067_0003
From Intermediate 32 to give the title compound. MS calcd for (C27H33NO7 + H)+ = 484. Found : (M+Hf = 484 1H NMR (400MHz, CDCI3) δ 7.29(s, 1 H), 7.2-7.0 (br, 2H), 6.82 (t, 1 H), 6.38 (d, 1 H), 5.77 (d, 1 H), 4.73-4.64 (ABq, 2H), 3.93-3.71 (br, 4H), 3.28 (d, 1 H), 2.42 (dd, 1 H), 2.22 (dd, 1 H), 1.79 (m, 1 H), 1.39 (s, 9H), 1.00 (d, 3H), 0.96 (d, 3H). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 18
4-[(£)-2-Carboxyethenyl]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2- (2-methylpropyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000068_0001
From Intermediate 30 to give the title compound. MS calcd for (C28H33NO6 + H)+ = 480. Found : (M+H)+ = 480
1H NMR (400MHz, CDCI3) δ 7.78 (d, 1 H), 7.30 (d, 1 H), 7.20 (d, 1 H), 7.2-7.07 (br, 2H), 6.94 (t, 1 H), 6.40 (d, 1 H), 6.18 (d, 1H), 4.03 (d, br, 1H), 3.82 (s, br, 3H), 3.42 (d, 1 H), 2.47- 2.27 (m, br, 2H), 1.82 (m, 1 H), 1.40 (s, 9H), 1.02 (d, 3H), 0.97 (d, 3H). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 19
4-(2-Carboxyethyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000068_0002
From Intermediate 31 to give the title compound.
MS calcd for (C28H35NO6 + H)+ = 482.
Found : (M+H)+ = 482
1H NMR (400MHz, d6-DMSO) δ 12.3 (br, 2H), 7.27 (d, br, 1 H), 6.90 (s, br, 2H), 6.79-6.68 (br, 2H), 5.70(d, 1 H), 3.75 (s, 3H), 3.36 (d, 1 H), 3.18 (d, 1 H), 2.71 (t, br, 2H), 2.54-2.43 (under solvent peak, 3H), 1.82 (dd, 1 H), 1.55 (m, 1 H), 1.35 (s, 9H), 0.87 (d, 3H), 0.83 (d, 3H)
Example 20 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4- phenyl-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000069_0001
From Intermediate 38 and purified by reverse phase HPLC on a C18 column using a two- solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile- water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C31H35NO4 + H)+ = 486 Found : (M+H)+ = 486 1H NMR (400MHz, CDCI3) δ 7.47 (br, 4H), 7.38 (br, 1 H), 7.33-7.14 (br, under solvent, 3H), 6.99 (d, 1 H), 6.94 (t, 1 H), 6.16 (d, 1 H), 4.11 (1 H), 3.87 (s, br, 3H), 3.32 (d, 1 H), 2.49 (m, 1 H), 2.18 (dd, 1 H), 1.87 (m, 1 H), 1.40 (s, 9H), 1.02 (d, 3H), 0.98 (d, 3H). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 21 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4- phenyl-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000069_0002
Isolated from purification of Example 20 to give the title compound. MS calcd for (C25H31NO5 + H)+ = 426 Found : (M+H)+ = 426
Example 22
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3- dihydro-1 H-indole-2,4-dicarboxylic acid
Figure imgf000070_0001
From Intermediate 10 and purified by reverse phase HPLC on a C18 column using a two- solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile- water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C26H31NO6 + H)+ = 454 Found : (M+H)+ = 454
Example 23 1-{[4-(1,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[2-(methylsulfonyl)ethyl]- 2-(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000070_0002
From Intermediate 27 to give the title compound. MS calcd for (C28H37NO6S + H)+: 515. Found : (M+H)+ = 515.
1 H NMR (CDCI3): δ 7.28 (1 H, bs), 7.15 (2H, bs), 6.86 (2H, m), 6.08 (1 H, d), 4.04 (1 H, d), 3.85 (3H, bs), 3.35 (1 H, m), 3.27 (2H,dd ), 3.16 (2H ,t ), 2.9 (3H, s ), 2.5 (1 H, dd ), 2.25 (1 H, dd), 1.85 (1 H, m), 1.39 (9H, s), 1.02 (6H, dd). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 24
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-(3- oxobutyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000070_0003
From Intermediate 29 to give the title compound. MS calcd for (C29H35NO5+H)+:480. Found (M+H)+ 480.
1 H NMR (CDCI3): δ 7.3 (1 H, bs), 7.15 (2H, bd), 6.8 (2H, m), 6.00 (1 H, d), 4.01 (1 H, d), 3.85 (3H, bs), 3.22 (1H,d), 2.85 (4H, m), 2.5 (1 H, dd), 2.25 (1H, m), 2.18 (3H, s ),1.90 (1 H, m), 1.39 (9H, s), 1.02 (6H, dd). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 25
5-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)- 2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000071_0001
From Intermediate 56 to give the title compound MS calcd for (C28H28BrNO4 + H)+: 522/524 Found: (M+H)+ = 522/524 (isotopic splitting)
Example 26
5-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 W-indole-2 -carboxylic acid
racemic
Figure imgf000071_0002
From Intermediate 58 to give the title compound MS calcd for (C25H30BrNO4 + H)+: 488/490 Found: (M+H)+ = 488/490
Example 27 5-Bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4- ylmethyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000072_0001
From Intermediate 59 to give the title compound. MS calcd for (C25H25BrN2O4S + H)+:529/531 Found: (M+H)+ 529/531 (isotopic splitting)
Example 28
1 -{[4-(1 A -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1 -yl)-
2,3-dihydro-1 H-indole-2 -carboxylic acid
racemic
Figure imgf000072_0002
From Intermediate 60 to give the title compound. MS calcd for (C25H29NO4 + H)+: 408. Found : (M+H)+ =408
Example 29
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4-ylmethyl)-
2,3-dihydro-1 W-indole-2 -carboxylic acid
racemic
Figure imgf000072_0003
From Intermediate 61 to give the title compound.
MS calcd for (C25H26N2O4S+ H)+: 451.
Found : (M+H)+ = 451
1H NMR (CD3OD): δ 8.6 (s,1 H);. 7.3 (d,1 H); 7.2 (s,1 H); 7.1 (s,1 H); 7.0 (d,1 H); 6.9 (d,1 H);
6.6 (t,1 H); 6.5 (t, 1 H); 5.6 (d,1 H); 4.2 (d,1 H); 3.75 (s,3H); 3.7 (d,1 H); 3.6 (d,1 H); 3.5
(d,1 H); 1.39 (1s, 9H). Carboxylic acid proton assumed to be exchanged with moisture in the solvent. Example 30
Enantiomer A of 1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1,3- thiazol-4-ylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000073_0001
The enantiomers of Intermediate 61 were separated by chiral HPLC using a Chiralpak AD column, eluting with EtOH/heptane (15:85 v/v), 15 mUmin, λ 215nm, ~8 mg/2 ml injection. The fastest eluting enantiomer (enantiomer 1 Rt 6.35 min) was collected. MS calcd for (C26H28N2O4S+ H)+: 465 Found : (M+H)+ = 465 Enantiomer 1 was deprotected using a similar procedure to that described for Example 1 , to afford the title compound. MS calcd for (C25H26N2O4S+ H)+: 451. Found : (M+H)+ = 451 1H NMR was identical to that of Example 29.
Example 31
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(3-pyridinylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid
Figure imgf000073_0002
From Intermediate 62 to give the title compound. MS calcd for (C27H28N2O4+ H)+: 445. Found : (M+H)+ =445
Example 32 1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-oxazol-2-ylmethyl)- 2,3-dihydro-1 H-indole-2-carboxylic acid racemic
Figure imgf000074_0001
From Intermediate 63 to give the title compound. MS calcd for (C25H26N2O5+ H)+: 435. Found : (M+H)+ = 435
Example 33
4-[(Carboxymethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
To Intermediate 19 (20 mg, 0.037 mmol) was added pyridine (1 ml) and lithium iodide (12.3 mg, 0.11 mmol). The reaction was stirred at 120°C for 16 hours, then cooled and partitioned between ethyl acetate and 2N hydrochloric acid, organics washed with brine, dried over Na2SO4 and concentrated. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C30H31NO7 + H)+ = 518. Found : (M+H)+ = 518 1H NMR (400MHz, d4MeOH) δ 7.37 (d, 1 H), 7.18 (d, 2H), 7.10-7.01 (m, 3H), 6.96 (d, 1 H), 6.90 (s, 1 H), 6.55 (t, 1 H), 6.26 (d, 1 H), 5.22 (d, 1 H), 4.56 (s, 2H), 4.02 (d, 1 H), 3.72 (s, 3H), 3.48 (q, 2H), 3.26 (under solvent, 1 H), 1.38 (s, 9H). Acid proton assumed to be exchanged with solvent.
The following compounds were prepared using a similar procedure to that described for Example 33:
Example 34 4-[(2-Amino-2-oxoethyl)oxy]-1-{[4-(1,1-dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000075_0001
From Intermediate 17. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C30H32N2O6 + H)+ = 517. Found : (M+H)+ = 517
Example 35
4-[(2-Amino-2-oxoethyl)oxy]-1-{[4-(1,1-dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000075_0002
From Intermediate 33. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C27H34N2O6 + H)+ = 483. Found : (M+H)+ = 483
1H NMR (400MHz, d4 MeOH) δ 7.37 (d, 1 H), 7.0 (br, 2H), 6.82 (t, 1 H), 6.4 (d, 1 H), 5.58 (d, 1 H), 4.41 (s, 2H), 3.77 (s, 3H), 3.48 (d, 1 H), 3.32 (d, 1 H) 2.66 (dd, 1 H), 1.95 (dd, 1 H), 1.67 (m, 1H), 1.40 (s, 9H), 0.93 (d, 3H), 0.89 (d, 3H). Acid proton assumed to be exchanged with solvent.
Example 36
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methylamino)-2- oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
Figure imgf000076_0001
From Intermediate 34. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C28H36N2O6 + H)+ = 497. Found : (M+H)+ = 497
Example 37 4-{[2-(Dimethylamino)-2-oxoethyl]oxy}-1 -{[4-(1 ,1 -dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
Figure imgf000076_0002
From Intermediate 35. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C29H38N2O6 + H)+ = 511. Found : (M+H)+ = 51 1 1H NMR (400MHz, d4MeOH) δ 7.37 (d, 1 H), 7.02-6.96 (br, 2H), 6.79 (t, 1 H), 6.48 (d, 1 H), 5.55 (d, 1 H), 4.82 (s, 2H), 3.78 (s, 3H), 3.43 (d, 1 H), 3.28 (d, slightly under solvent peak, 1 H), 3.07 (s, 3H), 2.95 (s, 3H), 2.65 (dd, 1 H), 1.94 (dd, 1 H), 1.66 (m, 1 H), 1.40 (s, 9H), 0.92 (d, 3H), 0.88 (d, 3H). Acid proton assumed to be exchanged with solvent.
Example 38
4-(Aminocarbonyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid racemic
Figure imgf000077_0001
From Intermediate 40 and purified by SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) to give the title compound. MS calcd for (C26H32N2O5 + H)+ = 452 Found : (M+H)+ = 452
Example 39
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(methylamino)carbonyl]- 2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
racemic
Figure imgf000077_0002
From Intermediate 41 and purified SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) to give the title compound. MS calcd for (C26H32N2O5 + H)+ = 452 Found : (M+H)+ = 452
Example 40
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(1 - methylethyl)amino]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
racemic
Figure imgf000077_0003
From Intermediate 40 and purified by SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) to give the title compound.
MS calcd for (C29H38N2O5 + H)+ = 495 Found : (M+H)+ = 495
Example 41
4-[(Dimethylamino)carbonyl]-1 -{[4-(1 ,1 -dimethylethyl)-3- (methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid
racemic
Figure imgf000078_0001
From Intermediate 43 and purified by SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) and then by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C29H38N2O5 + H)+ = 495 Found : (M+H)+ = 495
Example 42
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 ,3- thiazol-2-ylamino)carbonyl]-2,3-dihydro-1W-indole-2-carboxylic acid
racemic
Figure imgf000078_0002
From Intermediate 44 and purified by SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) to give the title compound.
MS calcd for (C29H33N3O5S + H)+ = 536 Found : (M+H)+ = 536
Example 43
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 H- pyrazol-3-ylamino)carbonyl]-2,3-dihydro-1W-indole-2-carboxylic acid racemic
Figure imgf000079_0001
From Intermediate 45 and purified by SPE (NH2) column, conditioned with 1 ,4-dioxan, loaded in dioxan, washed with dioxan then eluted with acetic acid/dioxan (1 :9) to give the title compound. MS calcd for (C29H34N4O5 + H)+ = 519 Found : (M+H)+ = 519
Example 44
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 H- 1 ,2,4-triazol-3-ylamino)carbo indole-2 -carboxylic acid
racemic
Figure imgf000079_0002
From Intermediate 46. Purification was by reverse phase HPLC on a Cι8 column using a two-solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C28H33N5O5 + H)+ = 520 Found : (M+H)+ = 520
Example 45 4-[(Cyanomethyl)oxy]-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2 -carboxylic acid
Figure imgf000079_0003
From Intermediate 18. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1 %) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C27H32N2O5 + H)+: 465. Found : (M+H)+ = 465.
1 H NMR (CDCI3): δ 7.3 (1 H, bs), 7.1 (2H, bs), 6.9 (1 H, t), 6.57 (1 H, d), 5.85 (1 H, d), 4.71 (2H, q), 4.00 (1 H,d), 3.85 (3H, bs),3.22 (1 H,d), 2.43 (1 H, dd), 2.25 (1 H, dd), 1.85 (1 H, m), 1.4 (9H, s), 1.02 (6H, dd). Carboxylic acid proton is assumed to be exchanged with moisture in the solvent.
Example 46
1-{[4-(1,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methylsulfonyl)-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid
racemic
Figure imgf000080_0001
From Intermediate 57 to give the title compound.
MS calcd for (C29H31NO6S + H)+:522.
Found: (M+H)+ = 522
Example 47
2-(Aminocarbonyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-4-carboxylic acid
Figure imgf000080_0002
To Intermediate 66 (35 mg, 0.072 mmol) in THF (1 mL) and water (1 mL) was added 2N NaOH (0.04 mL, 0.072 mmol). The reaction was stirred at room temperature for 16 hours, partitioned between ethyl acetate and 2N hydrochloric acid, organics washed with brine, dried over Na2SO4 and concentrated. Purification was by reverse phase HPLC on a C1β column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C26H32N2O5 + H)+ = 453. Found : (M+H)+ = 453
Example 48
{[2-(Aminocarbonyl)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indol-4-yl]oxy}acetic acid
racemic
Figure imgf000081_0001
This was prepared similarly to the procedure described for Example 47, replacing Intermediate 66 with Intermediate 69. Purification was by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents. Analysis of the fractions by electrospray mass spectroscopy to afford the title compound. MS calcd for (C28H36N2O6 + H)+ = 483 Found : (M+H)+ = 483
Example 49
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid
racemic
Figure imgf000081_0002
Intermediate 71 (152 mg) was dissolved in tetrahydrofuran (2 mL) and methanol (3 mL). The solution was treated with aqueous sodium hydroxide solution (2M, 1 mL) and the mixture heated at 80°C for 24 hours. Sodium hydroxide solution (10M, 0.5 mL) was added and the mixture heated at 80°C for 24 hours. The THF and methanol were removed in vacuo and the residue treated with aqueous hydrochloric acid (2N, 20 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with water, brine, dried (Na2SO4) and concentrated to give the title compound. MS calcd for (C29H31NO4 + H)+: 458 MS found (electrospray): (M+H)+ = 458
Example 50 6-Bromo-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)- 1,2,3,4-tetrahydro-2-quinolinecarboxylic acid racemic
Figure imgf000082_0001
This was similarly prepared following the procedure described for Example 49, replacing Intermediate 71 with Intermediate 75 to afford the title compound. MS calcd for (C29H30BrNO4 + H)+: 537/539 MS found (electrospray): (M+H)+ = 537/539
Example 51
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1 -yl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid
racemic
Figure imgf000082_0002
This was similarly prepared following the procedure described for Example 49, from
Intermediate 72 to afford the title compound.
MS calcd for (C26H31 NO4 + H)+: 422
MS found (electrospray): (M+H)+ = 422 1H NMR (CDCI3): δ 7.0 (t, 2H); 6.9 (t, 1 H); 6.8 (d, 1 H); 6.7 (m, 2H); 6.3 (d, 1 H); 4.6 (s 2H);
3.5 (s, 3H); 3.5 (t, 1 H); 3.2 (t, 1 H); 2.6 (d, 1 H); 2.4 (d, 1 H); 2.2 (d, 1 H); 2.0 (t, 1 H); 1.5 (s,
3H); 1.2 (s, 9H). Carboxylic acid proton assumed to be exchanged with moisture in the solvent.
Example 52
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid
racemic
Figure imgf000082_0003
A solution of Example 51 (13 mg) in ethanol (5 mL) was charged over 10% palladium on carbon (15 mg, wet) and stirred at room temperature in a hydrogen atmosphere for 16 hours. The mixture was filtered through celite and the organic solution evaporated to give the title compound. MS calcd for (C26H33NO4 + H)+: 424 MS found (electrospray): (M+H)+ = 424
Example 53
6-Amino-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid
Figure imgf000083_0001
Similarly prepared to Example 49 from Intermediate 76. Purified by OASIS cartridge to give the title compound. MS calcd for (C29H32N2O4 + H)+: 473 MS found (electrospray): (M+H)+ = 473
Example 54
6-(Acetylamino)-1 -{[4-(1 ,1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-l ,2,3,4-tetrahydro-2-quinolinecarboxylic acid
racemic
Figure imgf000083_0002
Acetyl chloride (8 uL, 0.11 mmol) was added dropwise to a solution of Example 53 in dry pyridine (1 mL) at 0°C under nitrogen. The mixture was allowed to warm to room temperature and stirred for 24 hours. It was then poured into 2N HCI (10 L), extracted with EtOAc (3 x10 mL) dried (Na2SO4) and evaporated to give the title compound. MS calcd for (C31H3 N2O5 +H)+: 515 MS found (electrospray): (M+H)+ = 515
Example 55
1 -{[4-(1 ,1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-6-{[( methyloxy)carbonyl]amino}-2-(phenylmethyl)-1,2,3,4-tetrahydro-2- quinolinecarboxylic acid racemic
Figure imgf000084_0001
Methyl chloroformate (9 uL, 0.11 mmol) was added dropwise to a solution of Example 53 (50 mg, 0.01 mmol) in dry pyridine (1 mL) at 0°C under nitrogen. After 3 hours, the reaction was poured into 2N HCI (10 mL), extracted with EtOAc (3 x 10 mL) and evaporated. Purification was by SPE (silica) cartridge, eluting with DCM, then EtOAc, then MeCN and finally acetone/MeOH (1 :1 v/v) to give the title compound. MS calcd for (C31H34N2O6+H)+: 531 MS found (electrospray): (M+H)+ = 531.
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 physiologically acceptable salt or solvate thereof in admixture with one or more physiologically 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. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, 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. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. For topical administration, 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 (IC50) potency, (EC50) 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.
Preferably the composition is in unit dosage form. For oral application, for example, 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. In each case, 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.
Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, 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. Where the 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. Where the 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.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
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.
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.
No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
ASSAY
The potential for compounds of the invention to inhibit NS5B wildtype HCV polymerase activity may be demonstrated, for example, using the following in vitro assay:
In Vitro Detection of inhibitors of HCV RNA-dependent RNA Polymerase Activity
Incorporation of [33P]-GMP into RNA was followed by absorption of the biotin labelled RNA polymer by streptavidin containing SPA beads. A synthetic template consisting of biotinylated 13mer-oligoG hybridised to polyrC was used as a homopolymer substrate.
Reaction Conditions were 0.5 μM [33P]-GTP (0.2 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI2, 5mM MnCI2, 20 mM Tris-HCI, pH7.5, 1.6 μg/mL polyC/0.256 μM biotinylated oligoG13, 10% glycerol, 0.01% NP-40, 0.2 u/μL RNasin and 50 mM NaCI.
HCV RNA Polymerase (Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11 ), 1997, 8416 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 10 nM final concentration. 5x concentrated assay buffer mix was prepared using 1 M MnCI2 (0.25 mL), glycerol (4mL), 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-MgCI2 (0.4 mL), glycerol (1 mL), 10% NP-40 (10 μL), 1 M DTT (20 μL) and water (7.97 mL), Total 10 mL.
Substrate Mix was prepared using 5x Concentrated assay Buffer mix (4μL), [33P]-GTP (10 μCi/μL, 0.02μL), 25 μM GTP (0.4 μL), 0.4 u/μL RNasin (0.04 μL), 20 μg/mL polyrC/biotinylated-oligorG (1.6 μL), and Water (3.94 μL), Total 10 μL.
Enzyme Mix was prepared by adding 1 mg/ml full-length NS5B polymerase (1.5 μL) to 2.811 mL 2x-concentrated enzyme buffer.
The Assay was set up using compound (1μL), Substrate Mix (10 μL), and Enzyme Mix (added last to start reaction) (10 μL), Total 21 μL.
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 1h at 22°C. After this time, the reaction was stopped by addition of 40 μL 1.875 mg/ml streptavidin SPA beads in 0.1 M EDTA. The beads were incubated with the reaction mixture for 1 h at 22°C after which 120 μL 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.
After subtraction of background levels without enzyme, any reduction in the amount of radioactivity incorporated in the presence of a compound, compared to that in the absence, was taken as a measure of the level of inhibition. Ten concentrations of compounds were tested in three- or fivefold dilutions. From the counts, percentage of inhibition at highest concentration tested or IC50s for the compounds were calculated using Grafit3 or Grafit4 software packages.
The exemplified compounds had an IC50 of <35μM in the above described assay. Preferred compounds had an IC50 of <5μM, more preferably <1μM. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.
The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies ((eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche))), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine). The 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) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

Claims

Claims
1. Use of a compound of
Figure imgf000089_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, d.6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or C1-6alkyl; RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; in the manufacture of a medicament for the treatment of viral infection.
2. Use as claimed in claim 1 , wherein the viral infection is HCV.
3. Compounds of Formula (I) represented by Formula (lb)
Figure imgf000090_0001
wherein: R1 represents hydroxy or NRBRC;
R2 represents d.6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, C1-βalkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD,
NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, d-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl; RB and Rc independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or d.6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 ,3-dihydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-oxopropyl)-, dimethyl ester.
4. A compound as claimed in claim 3 selected from the group consisting of:
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3-dihydro-1 H- indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-
1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3-dihydro-1r - indole-2,4-dicarboxylic acid;
4-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-
[(phenylmethyl)oxy]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-[(3- pyridinylmethyl)oxy]-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[(5-methyl-3- isoxazolyl)methyl]oxy}-2-(phenylmethyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(2-methylpropyl)oxy]-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(E)-2-Carboxyethenyl]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2- (phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-(2-Carboxyethyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-phenyl-2-(phenylmethyl)-2,3- dihydro-1 /-/-indole-2-carboxylic acid;
1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-(5- pyrimidinyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-4-(1 ,3-thiazol-2- yl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
5-[(Carboxymethyl)oxy]-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(3-pyridinyl)- 2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-5-(1 ,3-thiazol-2- yl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(Carboxymethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 4-[(£)-2-Carboxyethenyl]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-(2-Carboxyethyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 - -indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-phenyl-2,3- dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-phenyl-2,3- dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-
1/- -indole-2,4-dicarboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[2-(methylsulfonyl)ethyl]-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-(3-oxobutyl)-
2,3-dihydro-1 /- -indole-2-carboxylic acid;
5-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-2,3- dihydro-1H-indole-2-carboxylic acid;
5-Bromo-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3- dihydro-1 /-/-indole-2-carboxylic acid;
5-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4- ylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1 -yl)-2,3- dihydro-1 /-/-indole-2-carboxylic acid;
1-{[4-(1,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4-ylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-thiazol-4-ylmethyl)-2,3- dihydro-1H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(3-pyridinylmethyl)-2,3-dihydro-
1 H-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(1 ,3-oxazol-2-ylmethyl)-2,3- dihydro-1 H-indole-2-carboxylic acid;
4-[(Carboxymethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 4-[(2-Amino-2-oxoethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-
(phenylmethyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-[(2-Amino-2-oxoethyl)oxy]-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[2-(methylamino)-2- oxoethyl]oxy}-2-(2-methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
4-{[2-(Dimethylamino)-2-oxoethyl]oxy}-1-{[4-(1 ,1-dimethylethyl)-3-
(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
4-(Aminocarbonyl)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid; 1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-[(methylamino)carbonyl]-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1 -{[4-( 1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-4-{[( 1 - methylethyl)amino]carbonyl}-2-(2-methylpropyl)-2,3-dihydro-1r -indole-2-carboxylic acid;
4-[(Dimethylamino)carbonyl]-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1H-indole-2-carboxylic acid;
1 -{[4-(1 , 1 -Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 ,3-thiazol-
2-ylamino)carbonyl]-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1 /-/- pyrazol-3-ylamino)carbonyl]-2,3-dihydro-1/-/-indole-2-carboxylic acid; 1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-4-[(1H-1 ,2,4- triazol-3-ylamino)carbonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;
4-[(Cyanomethyl)oxy]-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-2-carboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-5-(methylsulfonyl)-2- (phenylmethyl)-2,3-dihydro-1/-/-indole-2-carboxylic acid;
2-(Aminocarbonyl)-1 -{[4-(1 , 1 -dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indole-4-carboxylic acid;
{[2-(Aminocarbonyl)-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2- methylpropyl)-2,3-dihydro-1 H-indol-4-yl]oxy}acetic acid; 1 -{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid;
6-Bromo-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid;
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methyl-2-propen-1-yl)- 1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid;
1 -{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(2-methylpropyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid; 6-Amino-1-{[4-(1,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-1 ,2,3,4- tetrahydro-2-quinolinecarboxylic acid;
6-(Acetylamino)-1-{[4-(1 ,1-dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-2-(phenylmethyl)-
1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid; and
1-{[4-(1 ,1-Dimethylethyl)-3-(methyloxy)phenyl]carbonyl}-6-{[( methyloxy)carbonyl]amino}-
2-(phenylmethyl)-1 ,2,3,4-tetrahydro-2-quinolinecarboxylic acid; and salts, solvates and esters, and individual enantiomers thereof.
5. A compound as claimed in claim 3 wherein R1 is hydroxy.
6. A compound as claimed in claim 3 wherein R2 represents C1-6alkyl, arylalkyl or heteroaryl.
7. A compound as claimed in claim 3 wherein R3 represents phenyl optionally substituted by halo, C1-6alkyl or C1-3alkoxy.
8. A compound as claimed in claim 7 wherein R3 represents tert-butylphenyl optionally 3-substituted by halo, C1-6alkyl or C1-3alkoxy.
9. A compound as claimed in claim 3 wherein R4 is positioned on the C4 or C5 positions of the indoline ring.
10. A compound as claimed in claim 3 wherein R4 is positioned on the C6 position of the tetrahydroquinoline ring.
11. A compound as claimed in claim 9 or claim 10 wherein R4 is a single subtituent.
12. A compound as claimed in claim 3 wherein R5, R6, R7 and R8 each represent hydrogen.
13. A method of treating or preventing viral infection which comprises administering to a subject in need thereof, an effective amount of a compound of Formula (I)
Figure imgf000094_0001
wherein:
R represents hydroxy or NRBRC; R2 represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, d.6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, d.6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of d.6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or C1-6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
and salts, solvates and esters thereof; provided that when R is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl.
14. A method as claimed in claim 13 which involves inhibiting HCV.
15. A method as claimed in claim 13 in which the compound is administered in an oral dosage form.
16. A compound of Formu
Figure imgf000096_0001
wherein:
R1 represents hydroxy or NRBRC;
R2 represents d.6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
R3 represents aryl or heteroaryl;
R4 represents one or two substituents independently selected from hydrogen, C1-6alkyl, halo, ORA, C(O)NRBRc, C(O)RD, CO2H, CO2RD, NRBRC, NREC(O)RD, NRECO2RD, NREC(O)NRFRG, NRESO2RD, SO2NRFRG, SO2RD, nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF3;
R5 and R6 independently represent hydrogen, d.6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R7 and R8 independently represent hydrogen, C1-6alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
n represents 0 or 1 ;
RA represents hydrogen, C1-6alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
RB and Rc independently represent hydrogen, C1-6alkyl, aryl or heteroaryl; or RB and Rc together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
RD is selected from the group consisting of d.6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
RE represents hydrogen or d-6alkyl;
RF and RG are independently selected from the group consisting of hydrogen, d^alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or RF and RG together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group; and salts, solvates and esters thereof; provided that when R1 is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl; and provided that the compound of Formula (I) is other than i) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroχyethyl] amino]propyl]-1 ,3-dihydro-, dimethyl ester; ii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-5-bromo-1 , 3-d i hydro-, dimethyl ester; and iii) 2H-indole-2,2-dicarboxylic acid, 1-benzoyl-1 ,3-dihydro-5-(2-oxopropyl)-, dimethyl ester; for use in medical therapy.
17. A compound as claimed in claim 16 wherein the medical therapy is the treatment of viral infection.
18. A compound as claimed in claim 17 wherein the viral infection is HCV.
19. A pharmaceutical formulation comprising a compound of Formula (lb) as defined in claim 3 in conjunction with a pharmaceutically acceptable diluent or carrier.
20. A process for the preparation of a compound of Formula (I) as defined in claim 1 , comprising treatment of a compound of Formula (II)
Figure imgf000097_0001
in which R1 is an alkoxy, benzyloxy or silyloxy group, and n, R2, R3, R4, R5, R6, R7 and R8 are as defined above for Formula (I), with a base.
21. A process for the preparation of a compound of Formula (I) as defined in claim 1 , comprising treatment of a compound of Formula (III)
Figure imgf000097_0002
in which R1 is hydroxy or a protected form thereof, and n, R2, R4, R5, R6, R7 and R8 are as defined above for Formula (I); with an acylating agent.
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