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WO2012007008A1 - Inhibitors of hdme - Google Patents

Inhibitors of hdme Download PDF

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Publication number
WO2012007008A1
WO2012007008A1 PCT/DK2011/050281 DK2011050281W WO2012007008A1 WO 2012007008 A1 WO2012007008 A1 WO 2012007008A1 DK 2011050281 W DK2011050281 W DK 2011050281W WO 2012007008 A1 WO2012007008 A1 WO 2012007008A1
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indole
group
alkyl
heterocyclic group
pyrido
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French (fr)
Inventor
Marc Labelle
Christian A.G.N. Montalbetti
Richard John Mears
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Epitherapeutics ApS
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Epitherapeutics ApS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds capable of modulating the activity of histone demethylases (HDMEs).
  • HDMEs histone demethylases
  • the compounds are useful for prevention and/or treatment of diseases in which genomic disregulation is involved in the pathogenesis, such as e.g. cancer.
  • Methylation of lysine and arginine residues on histone tails constitutes important epigenetic marks delineating transcriptionally active and inactive chromatin. For instance, methylation of lysine 9 on histone H3 (H3-K9) is associated with
  • the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, for treatment of a HDME dependent disease.
  • the inventors have surprisingly found that compounds of Formula (I) can be used in the treatment of HDME dependent diseases by inhibiting HDMEs. Inhibiting HDMEs would provide a novel approach to the prevention and treatment of cancer and other proliferative diseases. Accordingly, it is an object of the present invention to provide compounds that when administered alone or optionally in combination with antineoplastic compounds, increases the efficacy of the treatment of HDME dependent diseases.
  • a first aspect of the present invention relates to a compound of Formula (I)
  • Formula (I) an isomer or a mixture of isomers thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
  • Xi represents -A-B, wherein
  • A represents a bond, O, S, or NH
  • B represents
  • Ci- 6 -alkyl C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or C 3 . 5 -cycloalkyl
  • d-e-alkyl, C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or C 3 - 5 -cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 . 6 -cycloalkyl, Ci.
  • R" represents hydroxy, halogen-Ci- 4 -alkyl, Ci- 4 -alkoxy, hydroxy-Ci- 4 - alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C 3 - 4 -cycloalkyl or Ci- 4 -alkyl, wherein said C 3-4 - cycloalkyl or Ci -4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 - 6 -cycloalkyl, Ci -3 - alkoxy, hydroxy-Ci_ 3 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfon
  • R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci -6 -alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
  • sulfamoyl may optionally be substituted with one or two Ci -3 -alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci -4 -alkyl, halogen-Ci -4 -alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C 3 - 6 -cycloalkyl, Ci- 3 -alkyl-amino, di-Ci -3 - alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen
  • X 2 represents
  • X 3 represents
  • X a is -a bond, Ci-i 8 -alkyl, C 2 -i 8 -alkenyl, C 2 -i 8 -alkynyl, C 3 -i 0 -cycloalkyl, -Ci-i 8 -alkyl- 0-, -O- or -NX b - with the proviso, that when Y is O then X a is not O; and each X b is individually -H, C 3 - 6 -cycloalkyl, d- 6 alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic
  • heterocyclic group or a bicyclic heteroaromatic group which C 3 -i 0 -cycloalkyl, Ci -6 alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6- membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci- 4 -alkyl, hydroxy linear or branched Ci- 4 -alkoxy, Ci- 6 -alkoxyalkoxy, Ci_ 4 -alkoxycarbonyl, Ci.
  • C 1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 . 6 -cycloalkyl, Ci_ 4 -alkoxy, hydroxy-Ci- 4 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered
  • heterocyclic ring sulfamoyl, dimethylsulfamoyl, methylsulfonyl
  • a second aspect of the present invention relates to pharmaceutically compositions comprising an effective amount of a compound of Formula (I) as active ingredient.
  • a third aspect of the present invention relates to a compound of Formula (I) for use as a medicament, in particular for use as a medicament for the treatment of a HDME dependent disease.
  • a fourth aspect of the present invention relates to a compound of Formula (I) for treatment of a HDME dependent disease.
  • the treatment includes administering to a mammal, preferably a human, more preferably a human suffering from a HDME dependent disease, a therapeutically effective amount of a compound of the present invention.
  • a fifth aspect of the present invention relates to a compound of Formula (I) in a method for inhibiting HDMEs.
  • the method includes contacting a cell with any of the compounds of the present invention.
  • the method further provides that the compound is present in an amount effective to produce a concentration sufficient to selectively inhibit the demethylation of a histone in the cell.
  • a sixth aspect of the present invention relates to a compound of Formula (I) for the manufacture of a medicament to treat a proliferative or hyperproliferative disease, such as cancer.
  • Figure 1 The GASC1 demethylation HTRF assay used for high throughput screening of compounds.
  • Figure 2 Mass traces detected by LC-MS/MS: The demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a shift in molecular mass of the product compared to the substrate that can be measured by mass spectrometry. Quantification of substrate and product is done using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), enabling a precise and direct monitoring of the demethylation reaction.
  • Figure 3 The principle of the AlphaLISA assay used for screening of the compound inhibition of HDME activity. Detailed description of the invention
  • Ci-e-alkyl C 2 - 4 -alkenyl or C 2 - 4 -alkynyl
  • the present invention relates to compounds of Formula (I),
  • A represents a bond, O, S, or NH
  • B represents Ci_ 6 -alkyl, C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or C 3 . 5 -cycloalkyl,
  • R' represents hydroxy, Ci -4 -alkyl, cyclopropyl, halogen-Ci_ 4 -alkyl, Ci -4 - alkoxy, -NH 2 , methylamino, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group, preferably R' represents Ci- 4 -alkyl, halogen- Ci- 4 -alkyl, Ci- 4 -alkoxy, -NH 2 , methylamino or dimethylamino; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group;; or
  • R" represents hydroxy, halogen-Ci- 4 -alkyl, Ci- 4 -alkoxy, hydroxy-Ci- 4 - alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C 3 . 4 -cycloalkyl or Ci- 4 -alkyl, wherein said C 3-4 - cycloalkyl or Ci -4 alkyl optionally may be substituted with one or more
  • substituents selected from the group consisting of hydroxy, C 3 - 6 -cycloalkyl, Ci -3 - alkoxy, hydroxy-Ci_ 3 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyi, dimethylsulfamoyi, methylsulfonyl,
  • R' is as identified above; preferably R" represents hydroxyl, halogen-Ci- 4 -alkyl, Ci- 4 -alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-d- 3-alkyl-amino, a 6-membered monocyclic heterocyclic group or d-3-alkyl, even more preferably R" represents hydroxyl, trifluoromethyl, methyl, ethyl, -NH 2 , methylamino, dimethylamino or morpholinyl;
  • R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci. 6 -alkyl optionally substituted with dimethylamino;
  • Ci_ 3 -alkyl groups preferably with one or two methyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of d-4-alkyl, halogen-Ci- 4 -alkyl, carbonyl-Ci- 3 -alkyl, methylsulfamoyl, C 3 - 6 -cycloalkyl, Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group, preferably with cyclopropyl, methyl, ethyl, amino, methylamino or dimethylamino; phenyl, monocyclic or bicyclic heterocyclic group ,
  • methylsulfonyloxo, cyano, -(C 0)R ⁇ a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above, preferably the phenyl, monocyclic or bicyclic group is substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci- 3 -alkyl, Ci- 3 -alkoxy, cyano, -NH 2 , methylamino, dimethylamino and Ci- 3 -alkyl,; and X 2 represents
  • X a is -a bond, Ci-i 8 -alkyl, C 2 -i 8-alkenyl, C 2 -i 8 -alkynyl, C 3 -i 0 -cycloalkyl, -Ci-i 8 -alkyl- 0-, -O- or -NX b -, with the proviso that when Y is O, then X a is not O; and each X b is individually -H, C 3 . 6 -cycloalkyl, Ci. 6 -alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic
  • heterocyclic group or a bicyclic heteroaromatic group which C 3 .i 0 -cycloalkyl, Ci -6 - alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6- membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci- 4 -alkyl, hydroxy linear or branched Ci- 4 -alkoxy, Ci-6-alkoxyalkoxy, Ci- 4 -alkoxycarbonyl, Ci- 4 -alkylcarbonyl, COOH, cyano, -NH 2 , methylamino, dimethylamino, hydroxy and linear or branched Ci- 5 -alkyl, wherein said d-5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 - 6 -cycloalky
  • heterocyclic ring sulfamoyl, dimethylsulfamoyl, methylsulfonyl
  • R' is as defined above, preferably substituted with one or more substituents selected from the group consisting of linear or branched Ci- 4 -alkoxy, halogen, halogen-Ci- 4 -alkyl and linear or branched Ci-5-alkyl, even more preferably from the group consisting of methoxy, ethoxy, propyloxy, isopropyloxy, methyl, ethyl, propyl, isopropyl and chloro; and
  • X 4 and X 5 independently of each other represent ⁇ hydrogen, Ci- 4 -alkyl, halogen-Ci- 4 -alkyl, C 3 - 6 -cycloalkyl, halogen, nitro, -NH 2 , methoxycarbonyl, acetyl, methoxycarbamoyl or cyano;
  • phenyl monocyclic or bicyclic heterocyclic groups may be substituted at any suitable position,
  • X 3 comprises phenyl
  • said phenyl may for example be substituted once at the para position or once at the meta position.
  • X 3 comprises imidazole
  • said imidazole may for example be attached at the
  • X 3 comprises oxazolyl
  • said oxazolyl may for example be attached at the 2 position and/or be substituted at the
  • each X 3 only comprises one X b group in which case said X b is as defined above, Only in the case that X a is -NX b -, then and X 3 may comprise two X b groups, which may be individually selected from the group of different X b groups identified above in this section.
  • compounds of formula I having a particular 3-dimensional structure are more preferred than other compounds, probably because of the geometric preference for the binding of such compounds to the receptor. More particular it has been found that especially preferred compounds are those for which Xi represents a group comprising one or more polar substituents such as for example oxy, sulfonyl, sulfinyl, sulfanyl, carbonyl and cyano, and where this group is near the core. Furthermore, it has been found that especially preferred compounds are those for which X 2 represents carboxyl, amide or nitrile, and in particular X 2 may be carboxyl or amide.
  • X 3 is fairly long and comprises a lipophilic moeity such as for example phenyl, a 5 or 6 membered heterocyclic ring, a bicyclic heterocyclic ring or an aliphatic chain. Said lipophilic moiety is preferably removed from the core.
  • a preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, and B represents:
  • Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents O and B represents:
  • sulfonyl optionally may be substituted as indicated herein above in the section "Compounds of formula (I)"; or • phenyl, a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)”.
  • Another preferred embodiment of the present invention relates to compounds of
  • Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents NH and B represents
  • Yet another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents C 1-6 -alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3-5 - cycloalkyl, which C 1-6 -alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 5 -cycloalkyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)".
  • Another preferred embodiment of the present invention relates to compounds of
  • Formula (I) where Xi represents a group designated by -A-B, in which A represents a bond, O or NH and B represents sulfamoyi, sulfinyl, sulfanyl or sulfonyl, which sulfamoyi, sulfinyl, sulfanyl or sulfonyl may be substituted as indicated herein above in the section "Compounds of formula (I)".
  • Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". More preferably in this embodiment B represents a monocyclic or bicyclic heterocyclic group which optionally may be substituted as indicated herein above in the section "Compounds of formula (I)".
  • the compounds of Formula (I) where Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (
  • Formula (I) which comprises one or more monocyclic or bicyclic heterocyclic group(s) selected from the group consisting of a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered carbocyclic group, a bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6-membered carbocyclic group, a bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6-membered heterocyclic group, a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group, a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group, a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups,
  • the compound of Formula (I) comprises at least one monocyclic heterocyclic group, which is a 5-membered monocyclic heterocyclic group or a 6- membered monocyclic heterocyclic group.
  • the monocyclic heterocyclic group may be a 5-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S, more preferably comprising 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprising 1 or 2 heteroatoms each independently selected among N or O.
  • the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2- thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl.
  • the monocyclic heterocyclic group may be a 6-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S more preferably comprising 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprising 1 or 2 heteroatoms each independently selected among N or O.
  • the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H- thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
  • the compound of Formula (I) comprises at least one bicyclic heterocyclic group comprising 1 , 2, 3, or 4 heteroatoms each independently selected among N, O, and S, more preferably comprising 1 or 2 heteroatoms each
  • the compound of Formula (I) comprises a bicyclic heterocyclic group consisting of a 5- membered heterocyclic group and a 6-membered carbocyclic group, a 6-membered heterocyclic group and a 6-membered carbocyclic group, a 5-membered carbocyclic group and a 6-membered heterocyclic group, or a 5-membered heterocyclic group and a 6-membered heterocyclic group.
  • the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups.
  • the compound of Formula (I) comprises a bicyclic heterocyclic group consisting of a 5-membered group and a 6- membered group sharing a heteroatom, two 5-membered groups sharing a heteroatom or two 6-membered groups sharing a heteroatom.
  • A represents a bond and B represents Ci. 6 -alkyl, C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or C 3 . 5 -cycloalkyl, which may optionally be substituted as indicated above.
  • A represents a bond and B represents Ci-6-alkyl, which Ci_ 6 -alkyl is substituted one time with dimethylamino.
  • A represents a bond and B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl.
  • methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl may in one preferred embodiment be substituted once as indicated herein above in the section "Compounds of formula (I)", more preferably with a dimethylamino group.
  • B represents methyl, ethyl, propyl or isopropyl substituted once with a dimethylamino group.
  • FT represents hydroxy.
  • R" represents hydroxy, Ci -3 -alkyl, fluoro-Ci -4 -alkyl, -NH 2 , Ci- 3 -alkyl-amino, di-Ci-3-alkyl-amino or a 6-membered monocyclic heterocyclic aliphatic group. Even more preferably R" represents hydroxy, methyl, trifluoromethyl, -NH 2 , methylamino, dimethylamino or morpholinyl.
  • R" may also represent hydroxy, methyl, trifluoromethyl, methoxy, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which optionally may be substituted as indicated herein above in the section "Compounds of formula (I)". Very preferably R" represents methyl or trifluoromethyl.
  • A represents a bond and B represents sulfamoyl, which sulfamoyl optionally is substituted with one or more C 1-3 -alkyl.
  • B represents sulfamoyl or dimethylsulfamoyl.
  • A represents a bond and B represents sulfinyl or sulfonyl, which sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)".
  • said sulfinyl or sulfonyl may be substituted with one substituent selected from the group consisting of Ci_ 4 -alkyl or C 3-6 - cycloalkyl.
  • A represents a bond and B represents sulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, methylamino, dimethylamino, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group.
  • A represents a bond and B represents a 5- or 6-membered monocyclic heterocyclic group.
  • the 5- or 6-membered monocyclic heterocyclic group may be substituted as indicated herein above in the section
  • said 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci- 4 -alkyl, halogen, halogen-Ci- 2 -alkyl, Ci- 4 -alkoxy, Ci -4 - alkoxycarbonyl, COOH, cyano, -NH 2 , methylamino and dimethylamino.
  • the 5-membered monocyclic heterocyclic group may preferably be selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2- oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl
  • the 6-membered monocyclic heterocyclic group may be selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl, but preferably the 6-membered monocyclic heterocyclic groups is selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, and morpholin
  • 6- membered monocyclic heterocyclic group represents piperazinyl or morpholinyl.
  • A represents O and B represents d-e-alkyl, C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or C 3 - 5 -cycloalkyl, which may optionally be substituted as indicated above.
  • A represents O and B represents C 1-6 -alkyl, C 2 - 4 -alkenyl, or C 2 . 4 - alkynyl, where the C ⁇ e-alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. Most preferably the Ci_ 6 -alkyl is methyl.
  • the C 2 is methyl.
  • 4 -alkenyl is preferably selected from the group consisting of ethenyl, 1 - or 2- propenyl, 1 -, 2- and 3-butenyl, and 1 ,3- butenyl and the C 2 .
  • 4 -alkynyl is preferably selected from the group consisting of ethynyl, 1 - or 2-propynyl, 1 -, 2- or 3-butynyl, and 1 , 3-butynyl.
  • B is selected from the group consisting of methyl, isopropyl, isobutyl, isopentyl, 1 - or 2-butenyl and 1 - or 2-butynyl.
  • A represents O and B represents C 3 - 5 -cycloalkyl, wherein the C 3 - 5 -cycloalkyl is selected fromt the group consisting of cyclopropyl, cyclobutyl and cyclopentyl preferably however, the C 3 - 5 -cycloalkyl is cyclopropyl, wherein said C 3 . 5 - cycloalkyl may be substituted as indicated above or alternatively may not be substituted.
  • A represents O and B represents Ci_ 6-alkyl, which Ci_ 6 -alkyl is substituted with one cyano group.
  • B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl substituted with one cyano group, and more preferred B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl substituted with one cyano group. In some embodiments B is substituted with cyclopropyl in addition to the cyano substituent.
  • Xi designates cyanomethoxy, cyano(cyclopropyl)methoxy, 1 -cyanoethoxy, 1 -cyano-2-methylethoxy, 1 -cyanopropoxy, 3-cyanopropoxy, 1 -cyano-2-methylpropoxy, 1 -cyanobutoxy, 2-cyanobutoxy 3- cyanobutoxy, and 4-cyanobutoxy. Most preferably Xi represents cyanomethoxy.
  • A represents O and B represents Ci- 6 -alkyl, which d-e-alkyl is substituted with Ci- 4 -alkoxy, hydroxy-Ci- 4 -alkoxy, -NH 2 , methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
  • B represents butyl substituted with hydroxy.
  • B represents methyl or ethyl, which methyl or ethyl is substituted with methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, -NH 2 , methylamino, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
  • Most preferred B represents methyl substituted with pyridinyl, thiazolyl or pyrazolyl, each of which may independently be substituted with one or more
  • B represents ethyl substituted with a substituent selected from the group consisting of ethoxy, hydroxyethoxy, dimethylamino morpholinyl and piperidinyl.
  • a first substituent selected from
  • Examples of 5- or 6- membered monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, piperidinyl, pyridinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3-pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,5-oxadiazolyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 4H-1 ,4-oxazinyl, morpholinyl, and thiomorpholinyl.
  • B preferably represents butyl substituted with both a dimethylamino group and with a hydroxy group as a second substituent.
  • B represents methyl, ethyl, propyl or isopropyl and R' represents methyl, trifluoromethyl, hydroxy, -NH 2 , methylamino or dimethylamino. Most preferably B represents methyl or isopropyl and R' represents hydroxy, methyl, trifluoromethyl or dimethylamino.
  • the halo substituent is selected among fluoro and chloro and most preferred the phenyl is substituted twice with fluoro so as to form a difluorophenyl group.
  • A represents O and B represents d-e-alkyl, which d-e-alkyl is substituted with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
  • B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted once with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
  • B represents isopropyl, which is substituted once with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
  • A represents O and B represents Ci- 6 -alkyl, which d-e-alkyl is substituted with phenyl, which phenyl may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halo, cyano, acetamino, methylsulfonylamino and a 5- or 6-membered monocyclic heterocyclic group.
  • the 5- or 6-membered monocyclic heterocyclic group may be substituted as indicated above.
  • B preferably represents methyl or ethyl, when B is substituted with unsubstituted phenyl.
  • B preferably represents methyl, which is substituted with phenyl, which phenyl is substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, cyano, acetamino and methylsulfonylamino.
  • A represents O
  • R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. More preferably, R" represents Ci- 3 -alkyl, Ci- 4 -alkoxy, hydroxy-Ci- 4 -alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
  • R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Even more preferred R" is selected from the group consisting of methyl, ethoxy, dimethylamino, pyrrolidinyl and morpholinyl.
  • A represents O and B represents sulfamoyi, sulfinyl or sulfonyl, which sulfamoyi may optionally be substituted with one or two d-3-alkyl groups and said sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci- 2 -alkyl, halogen, halogen-Ci- 2 - alkyl, Ci-4-alkoxy, Ci- 4 -alkoxycarbonyl, COOH, cyano, -NH 2 , methylamino and dimethylamino.
  • said sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted as indicated above.
  • B represents sulfamoyl, methylsulfonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl or sulfonyl, which sulfonyl is substituted with oxazolyl or thiazolyl, which oxazolyl or thiazolyl may optionally be substituted with one or more methyl.
  • A represents O and B represents a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, -COOH, cyano and dimethylamino.
  • the 5-membered monocyclic heterocyclic group may be selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H- pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, oxolanyl, pyrazolyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3- oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl.
  • the 6-membered monocyclic heterocyclic group may be selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H- pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4- oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl, but preferably the 6- membered monocyclic heterocyclic groups is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and morpholinyl.
  • A represents S and B represents C 1-6 -alkyl, C 2 - 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 5 -cycloalkyl, which may optionally be substituted as indicated above.
  • R represents C 3 - 4 -cycloalkyl, Ci- 4 -alkyl, Ci- 4 -alkoxy, -NH 2 ,
  • R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Even more preferably, R" represents methyl or dimethylamino.
  • A represents NH or A represents a bond and B represents a 5-membered or 6-membered monocyclic heterocyclic group, comprising at least one nitrogen atom in its ring structure where said nitrogen is positioned so as to form the binding link between A and the rest of the compound of Formula (I).
  • R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Most preferably R" represents methyl or dimethylamino.
  • A represents NH and B represents sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, trifluoromethyl, cyclopropyl and a 5- or 6-membered monocyclic heterocyclic group.
  • R' represents methylsulfonyl.
  • X ! is selected from the group consisting of methoxy, hydroxy, acetyl, trifluoroacetyl, cyclopropylsulfonyl, cyclopropylsulfonyloxy, cyanomethoxy, methylcarbamoyl, dimethylcarbamoyl, dimethylcarbamoyloxy, morpholine-4-carboxylate, COOH, carbamoyl, morpholine-4ylcarbonyl, methylsulfonyl, methylsulfinyl, methylsulfanyl, sulfamoyl, sulfamoyloxy and dimethylsulfamoyl.
  • A represents a bond or O.
  • A represents a bond and B represents hydroxy.
  • methanesulfonyl and methoxy optionally substituted with dimethylamino, and more preferably from a group consisting of hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl and methoxy optionally substituted with dimethylamino.
  • A represents a bond and B represents sulfonyl, which sulfonyl may be substituted with methyl, ethyl, cyclopropyl methylamino,
  • sulfonyl may be substituted with methyl, cyclopropyl or dimethylaminoethyl.
  • A represents a bond and B represents sulfanyl, which may be substituted with methyl or ethyl, preferably methyl.
  • A represents a bond and B represents sulfinyl, which sulfinyl may be substituted with methyl or ethyl, preferably methyl.
  • A represents a bond and B represents sulfamoyi, which sulfamoyi may be substituted with one or two methyl groups.
  • A represents O and B represents methyl, ethyl, propyl or isopropyl, which may optionally be substituted one or two times with a group selected from the group consisting of hydroxy, cyano and NH 2 .
  • B represents methyl, which is not substituted or which is substituted one time with cyano.
  • A represents O and B represents sulfonyl, which may be substituted with methyl, hydroxymethyl, trifluoromethyl, ethyl, hydroxyethyl or cyclopropyl.
  • B represents sulfonyl substituted with trifluoromethyl or cyclopropyl.
  • A represents O and B represents sulfamoyi, which may optionally be substituted with one or two methyl groups.
  • Preferably the sulfamoyi is unsubstituted.
  • the present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)".
  • the compounds may be compounds for formula (I), wherein X ! is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X 2 is as described in this section and X 3 , X 4 , and X 5 are as described in the section "Compounds of formula (I)".
  • the invention relates to compounds of the compound of Formula (I)
  • Xi represents -A-B, wherein
  • A represents a bond, O, S, or NH
  • B represents
  • d-e-alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 - 5 cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 . 6 -cycloalkyl, Ci.
  • R" represents hydroxy, halogen-Ci- 4 -alkyl, Ci- 4 -alkoxy, hydroxy-Ci- 4 - alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C 3 - 4 -cycloalkyl or Ci- 4 -alkyl, wherein said C 3-4 - cycloalkyl or Ci -4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 - 6 -cycloalkyl, Ci -3 - alkoxy, hydroxy-Ci_ 3 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfon
  • R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci -6 -alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
  • sulfamoyl may optionally be substituted with one or two Ci -3 -alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci -4 -alkyl, halogen-Ci -4 -alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C 3 - 6 -cycloalkyl, Ci- 3 -alkyl-amino, di-Ci -3 - alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen
  • X 3 represents
  • X a is -a bond, Ci-i 8 -alkyl, C 2 -i 8 -alkenyl, C 2 -i 8 -alkynyl, C 3 -i 0 -cycloalkyl, -Ci-i 8 -alkyl 0-, -O- or -NX b -; and
  • X b is -H, C 3 - 6 -cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C 3 .i 0 -cycloalkyl, Ci.
  • 6 -alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci- 4 - alkyl, hydroxy linear or branched Ci- 4 -alkoxy, Ci- 6 -alkoxyalkoxy, Ci -4 - alkoxycarbonyl, Ci- 4 -alkylcarbonyl, COOH, cyano, -NH 2 , methylamino, dimethylamino, hydroxy and linear or branched Ci- 5 -alkyl, wherein said d-5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 .
  • 6 -cycloalkyl, Ci_ 4 -alkoxy, hydroxy-Ci_ 4 -alkoxy, - NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C 0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above; and
  • the compounds of the invention may in preferred embodiments of the invention be compounds of formula (I), wherein Xi is as described herein above in the section "Preferred compounds of formula (I) - X/', X 2 is -COOH, X 3 is as described herein below in the as described herein below in the section “Preferred compounds of formula (I) - X 3 ", X 4 and X 5 are as described herein below in the section "Preferred compounds of formula (I) - X 4 and X 5 ".
  • X 2 is -COOH
  • this designation is to be understood as also including the carboxylate ion as well as different metal salts that could be formed such as for example sodium carboxylate, potassium carboxylate and ammonium carboxylate salts of the carboxylic acid.
  • metal salts such as for example sodium carboxylate, potassium carboxylate and ammonium carboxylate salts of the carboxylic acid.
  • a skilled person would know when it is to be expected that the acid group has been dissociated and formed the salt. The dissociation and the formation of metal salt depends on the pH in the adjacent environment and on the availability of cations in the adjacent environment.
  • the present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)".
  • the compounds may be compounds of formula (I), wherein X ! is a described herein above in the section "Preferred compounds of formula (I) - X/', and X 2 is as described in the section "Preferred compounds of formula (I) - X 2 " and X 3 is as described in this section and X 4 , and X 5 are as described in the section "Compounds of formula (I)".
  • X 3 is -H.
  • the compounds of the invention may be compounds of formula (I), wherein Xi is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X 2 is as described in the section “Preferred compounds of formula (I) - X 2 " and X 3 is -H and X 4 , and X 5 are as described in the section "Preferred compounds of formula (I)" - X 4 and X 5 ".
  • X 3 is -OH.
  • the compounds of the invention may be compounds of formula (I), wherein Xi is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X 2 is as described in the section “Preferred compounds of formula (I) - X 2 " and X 3 is -OH and X 4 , and X 5 are as described in the section "Preferred compounds of formula (I)" - X 4 and X 5 ".
  • X 3 represents -Y-X a -X b , wherein Y, X a and X b are as defined herein above in the section "Compounds of formula (I)", with the proviso that when Y is -O, then X a is not -0-.
  • heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen-d- 4 alkyl, linear or branched Ci -4 - alkoxy, or linear or branched Ci -5 alkyl.
  • 6 -alkoxy, phenyl, phenoxy, a 5 or 6 membered heteroaromatic ring or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, linear or branched Ci -4 - alkoxy, or linear or branched Ci -5 alkyl.
  • Ci -5 -alkyl methylamino, dimethylamino, hydroxy and linear or branched Ci -5 -alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3-6 -cycloalkyl, Ci -4 -alkoxy, hydroxy-Ci -4 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl,
  • X 3 represents -0-X a -X b
  • X a is Ci-is-alkyl, C 2 -i 8 -alkenyl, C 2 -i 8 -alkynyl, C 3 . io-cycloalkyl or -NX b - and X b is -H, C 3 . 6 -cycloalkyl, Ci. 6 -alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C 3 . 6 -cycloalkyl, Ci.
  • 6 -alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci_ 4 - alkyl, linear or branched Ci_ 4 -alkoxy, Ci.
  • Ci_ 4 -alkoxycarbonyl Ci_ 4 -alkoxycarbonyl
  • Ci -4 - alkylcarbonyl COOH, cyano, -NH 2 , methylamino, dimethylamino, hydroxy and linear or branched Ci -5 -alkyl, wherein said C s alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 .
  • X 3 represents -0-X a -X b , where X a is -a bond, Ci-i 8 -alkyl, C 2 . 18-alkenyl, C 2 .i 8 -alkynyl, C 3 .i 0 -cycloalkyl or -NX b -; and X b is -H, C 3 .
  • Ci -6 -cycloalkyl Ci -6 - alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, which Ci -6 -alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of linear or branched C 1-5 -alkyl, Ci- 6 -alkoxycarbonyl, Ci -4 -alkylcarbonyl, -OH, linear or branched Ci -6 - alkoxy or halogen.
  • X 3 represents -0-X a -X b , wherein X a is Ci- 6 -alkyl or -Ci -6 -alkyl-0- and X b is H, Ci -6 -alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen- Ci -4 alkyl, linear or branched Ci -4 - alkoxy, or linear or branched Ci -5 alkyl.
  • Said 5 or 6 membered heteroaromatic ring may preferably comprise 1 , 2 or 3 heteroatoms each independently selected among N, O, and S, more preferably comprise 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprise 1 or 2 heteroatoms each independently selected among N or O.
  • Said bicyclic heterocyclic group may preferably comprise 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S, more preferably comprise 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprise 1 or 2 heteroatoms each independently selected among N or O.
  • the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3- oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl.
  • the 5 membered heteroaromatic ring is oxazolyl, preferably, 1 ,3-oxazolyl.
  • the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H- thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
  • the 6 membered heteroaromatic ring is pyridinyl.
  • Said bicyclic heterocyclic group may consist of a 5-membered heterocyclic group and a 6-membered carbocyclic group, a 6-membered heterocyclic group and a 6-membered carbocyclic group, a 5-membered carbocyclic group and a 6-membered heterocyclic group, or a 5-membered heterocyclic group and a 6-membered heterocyclic group.
  • the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups.
  • the bicyclic heterocyclic group is imidazolyl.
  • X 3 is selected from the group consisting of -H, hydroxyl, methoxy, phenylethoxy, pyridine-3-ylethoxy, pyridine-3ylmethoxy, ethoxyphenyl-4-ethoxy, ethoxypyridinethoxy, propan-2yloxy-phenylethoxy,
  • X 3 represents -Y-X a -X b , where
  • Y represents O.
  • X 3 represents -Y-X a -X b , where Y represents O and X a represents Ci- 6 -alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • Ci- 6 -alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • More preferred X a represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, and even more preferred X a represents methyl, ethyl, propyl or isopropyl.
  • X 3 represents -Y-X a -X b ,
  • Y represents O and X a represents Ci. 6 -alkyl, and X b represents Ci. 6 -alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group.
  • the 5-membered monocyclic heterocyclic group, or 6- membered monocyclic heterocyclic group is selected among pyridinyl, imidazolyl and oxazolyl.
  • the Ci is selected among pyridinyl, imidazolyl and oxazolyl.
  • 6 -alkoxy, phenyl, phenoxy, 5 or a 6-membered monocyclic heterocyclic group may be substituted with one or two substituents, which independently of each other is selected from the group consisting of methyl, ethyl, isopropyl, tert.-butyl, chloro, fluoro, methoxy, ethoxy and propoxy.
  • the phenyl, phenoxy, 5 or a 6-membered monocyclic heterocyclic group may be substituted with one or two substituents, which independently of each other is selected from the group consisting of methyl, tert.-butyl, chloro, ethoxy and propoxy.
  • X 3 represents -Y-X a -X b , where Y represents O and X a represents methyl, ethyl, propyl or isopropyl, and X b represents phenyl, phenoxy, pyridinyl, imidazolyl or oxazolyl, which phenyl, phenoxy, pyridinyl, imidazolyl or oxazolyl may substituted with one or two substituents, which
  • the present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)".
  • the compounds may be compounds of formula (I), wherein X ! is a described herein above in the section "Preferred compounds of formula (I) - X/', and X 2 is as described in the section “Preferred compounds of formula (I) - X 2 ", X 3 is as described in the section "Preferred compounds of formula (I) - X 3 ", and X 4 , and X 5 are as described in this section.
  • X 4 and X 5 represents independently of each other hydrogen, Ci- 4 -alkyl, halo-Ci- 4 -alkyl, C 3 - 6 -cycloalkyl, halo, nitro, -NH 2 , methoxycarbonyl, acetyl, methoxycarbamoyi or cyano.
  • X 4 and X 5 are each independently selected from the group consisting of hydrogen, Ci- 4 -alkyl, C 3 - 6 -cycloalkyl.
  • X 4 and X 5 both represents hydrogen.
  • X 4 represents hydrogen and X 5 is selected from the group consisting of d-4-alkyl, C 3 - 6 -cycloalkyl.
  • X 5 represents hydrogen and X 4 is selected from the group consisting of Ci -4 -alkyl, C 3 - 6 -cycloalkyl.
  • X 4 represents methyl, and in other preferred embodiments X 5 represents methyl.
  • X 4 and X 5 are both -H.
  • the compounds of the invention may be compounds of formula (I), wherein X !
  • Xi represents A-B, wherein A is O and B is
  • d-e-alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 5 cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 . 6 -cycloalkyl, Ci. 4 -alkoxy, hydroxy-Ci.
  • R" represents hydroxy, halogen-Ci- 4 -alkyl, Ci- 4 -alkoxy, hydroxy-Ci- 4 - alkoxy, -NH 2 , Ci- 3 -alkyl-amino, di-Ci- 3 -alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, Ci- 4 -cycloalkyl or Ci- 4 -alkyl, wherein said Ci -4 - cycloalkyl or Ci -4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C 3 - 6 -cycloalkyl, Ci -3 - alkoxy, hydroxy-Ci_ 3 -alkoxy, -NH 2 , methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl
  • R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci -6 -alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
  • sulfamoyl may optionally be substituted with one or two Ci -3 -alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci -4 -alkyl, halogen-Ci -4 -alkyl, carbonyl-Ci- 3 -alkyl , methylsulfamoyl, C 3 - 6 -cycloalkyl, Ci- 3 -alkyl-amino, di-Ci -3 - alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; or • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting
  • X a is -a bond, C - 8 -alkyl, C 2 -i 8 -alkenyl, C 2 .i 8 -alkynyl, C 3- i 0 -cycloalkyl, -C 1 18 -alkyl- 0-, -O- or -NX b -; and
  • X b is -H, C 3 -6-cycloalkyl, Ci-6-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C 3 -i 0 -cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4- alkyl, hydroxy linear or branched d -4 -alkoxy, Ci -6 -alkoxyalkoxy, Ci -4 - alkoxycarbonyl, Ci- 4 -alkylcarbonyl, COOH, cyano, -NH 2 , methylamino, dimethylamino,
  • Very preferred compounds of the invention may be selected from the group consisting of: 3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
  • alkyl refers to a saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contains of from one to eighteen carbon atoms (Ci-i 8 -alkyl), more preferred of from one to six carbon atoms (Ci- 6 -alkyl), including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a Ci_ 4 -alkyl group, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a Ci_ 2 -alkyl group, which includes methyl and ethyl.
  • cycloalkyl refers to a cyclic alkyl group, preferably containing of from three to eight carbon atoms (C 3 . 8 -cycloalkyl), preferably of from three to six carbon atoms (C 3 . 6 -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the cycloalkyl is cyclopropyl.
  • cycloalkyl as used herein may also include polycyclic groups such as for example bicycle[2.2.2]octyl and cubyl.
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes.
  • the alkenyl group of the invention comprises of from two to eighteen carbon atoms (C 2 -i 8 -alkenyl), whereas in other preferred embodiments the alkenyl group of the invention comprises of from two to eight carbon atoms (C 2 . 8 - alkenyl), more preferred of from two to four carbon atoms (C 2 - 4 -alkenyl) including at least one double bond.
  • Examples of preferred alkenyl groups of the invention include ethenyl; 1 - or 2-propenyl; 1 -, 2- or 3-butenyl, or 1 ,3- butenyl; 1 -, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexenyl, or 1 ,3, 5-hexenyl; 1 -, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 ,3-octenyl, or 1 ,3,5-octenyl, or 1 ,3,5,7-octenyl.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes.
  • the alkynyl group of the invention comprises of from two to eighteen carbon atoms (C 2 -i 8 -alkynyl), whereas in other preferred embodiments the alkynyl group of the invention comprises of from two to eight carbon atoms (C 2 -s- alkynyl), more preferred of from two to four carbon atoms (C 2 -4-alkynyl) including at least one triple bond.
  • alkynyl groups of the invention include ethynyl; 1 - or 2-propynyl; 1 -, 2- or 3-butynyl, or 1 ,3-butynyl; 1 -, 2-, 3-, 4- or 5-hexynyl, or 1 ,3-hexynyl, or 1 ,3, 5-hexynyl; 1 -, 2-, 3-, 4-, 5-, 6-, or 7-octynyl, or 1 ,3-octynyl, or 1 ,3,5-octynyl, or 1 ,3,5,7-octynyl.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • a trihalogenmethyl group represents e.g. a trifluoromethyl group, or a trichloromethyl group.
  • halogen designates fluoro or chloro.
  • halogenalkyl refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with one or more halogen.
  • Preferred halogenalkyl groups of the invention include trihalomethyl, preferably trifluoromethyl.
  • alkoxy refers to an "alkyl-O-" group, wherein alkyl is as defined above.
  • hydroxyalkoxy refers to an alkoxy group as defined herein, which alkoxy group is substituted one or more times with hydroxy.
  • Examples of hydroxyalkoxy groups include HO-CH 2 -0- and CH 3 -CH 2 OH-O-.
  • alkoxycarbonyl refers to an "alkyl-O-(CO)-" group, wherein alkyl is as defined above.
  • oxoalkyl refers to an "alkyl-(CO)-" group, wherein alkyl is as defined above.
  • 5-membered monocyclic heterocyclic group refers to a 5- membered monocyclic group holding one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • Examples of 5-membered monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl,
  • Examples of preferred 5-membered monocyclic heterocyclic groups include pyrrolidinyl, pyrazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2- thiazolyl and 1 ,3-thiazolyl.
  • 6-membered monocyclic heterocyclic group refers to a 6- membered monocyclic group holding one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • 6-membered monocyclic heterocyclic groups include piperidinyl, pyridinyl, oxanyl, 2-H- pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4- oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
  • preferred 6- membered monocyclic heterocyclic groups include piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pipe
  • bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered carbocyclic group refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic hydrocarbon group.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • Examples of bicyclic heterocyclic groups consisting of a 5-membered heterocyclic group and a 6- membered carbocyclic group include benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl and benzotriazolyl.
  • bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6-membered carbocyclic group refers to a heterocyclic ring system derived by fusion of a 6-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic hydrocarbon group.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • bicyclic heterocyclic groups consisting of a 6-membered heterocyclic group and a 6- membered carbocyclic group include quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1 H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl.
  • bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6-membered heterocyclic group refers to a heterocyclic ring system derived by fusion of a 5-membered carbocyclic group with a 6-membered monocyclic group holding one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic group holding one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • a preferred example of a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group includes purinyl or imidazolyl.
  • bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups refers to a heterocyclic ring system derived by fusion of two 6- membered monocyclic group each holding one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • Examples of bicyclic heterocyclic groups consisting of two 6-membered heterocyclic groups include naphthyridinyl and pteridinyl.
  • bicyclic heterocyclic group consisting of a 5-membered group and a 6- membered group sharing a heteroatom refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group and a 6-membered monocyclic group, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • a preferred example of a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom includes indolizinyl.
  • bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom refers to a heterocyclic ring system derived by fusion of two 5-membered monocyclic groups, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • a preferred example of a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom includes 1 H-pyrrolizinyl.
  • bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom refers to a heterocyclic ring system derived by fusion of two 6-membered monocyclic groups, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
  • a preferred example of a bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom includes 4H-quinolizinyl.
  • aryl as used herein, unless otherwise indicated, includes carbocyclic aromatic ring systems derived from an aromatic hydrocarbon by removal of a hydrogen atom.
  • Aryl furthermore includes bicyclic ring systems.
  • preferred aryl moieties to be used with the present invention include, but are not limited to phenyl, naphthyl, indenyl, and fluorenyl.
  • Preferred "aryl” is phenyl, naphthyl or indanyl, unless otherwise stated. Any aryl used in the present invention may be optionally substituted.
  • Heteroaryl refers to aromatic groups containing one or more heteroatoms selected from O, S, and N, preferably from one to four heteroatoms, and more preferably from one to three heteroatoms. Heteroaryl furthermore includes multicyclic groups, wherein at least one ring of the group is aromatic, and at least on of the rings contains a heteroatom selected from O, S, and N. Heteroaryl also include ring systems substituted with one or more oxo moieties.
  • heteroaryl moieties to be used with the present invention include, but are not limited to phenyl, biphenyl, indenyl, naphthyl, N-hydroxytetrazolyl, N-hydroxytriazolyl, N- hydroxyimidazolyl, anthracenyl, phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydro- benzo[b]thiophenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, quinolyl, carbazolyl, pyr
  • the compounds of the invention may exist as geometric isomers (i.e. cis-trans isomers), optical isomers or stereoisomers, such as diastereomers, as well as tautomers. Accordingly, the invention includes all cis-trans isomers, stereoisomers and tautomers including racemic mixtures of these and pharmaceutically acceptable salts thereof, especially all R- and S- isomers in any ratio.
  • geometric isomers i.e. cis-trans isomers
  • optical isomers such as diastereomers
  • stereoisomers such as diastereomers
  • the invention includes all cis-trans isomers, stereoisomers and tautomers including racemic mixtures of these and pharmaceutically acceptable salts thereof, especially all R- and S- isomers in any ratio.
  • Diastereoisomers i.e.,
  • nonsuperimposable stereochemical isomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
  • appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • suitable bases include, without limitation, brucine, sparteine and oc- methylbenzylamine.
  • the mixture of diastereomers can be separated by crystallization followed by liberation of the optically active acids or bases from these salts.
  • An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent
  • diastereoisomeric molecules by reacting compounds of the invention, preferably compounds of Formula (I), with an optically pure acid in an activated form or an optically pure isocyanate.
  • compounds of Formula (I) bearing an acidic function can be activated and reacted with an optically pure compound like an alcohol or an amine.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound.
  • the optically active compounds of the invention preferably compounds of formula (I)
  • the compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically acceptable salts, solvates and prodrugs of the compound of Formula (I).
  • Pharmaceutically acceptable salts refer to salts of the compounds of the invention, which are considered to be acceptable for clinical and/or veterinary use.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the invention with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively. It will be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmaceutically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. These salts may be prepared by methods known to the skilled person.
  • Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids e.g.
  • succinic maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and
  • galacturonic acid and arylsulfonic, for example benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid; and base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts.
  • arylsulfonic for example benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid
  • base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
  • the compounds of this invention may be prepared as described in the following. Useful steps that may be used in the preparation steps of the compounds will be known to the skilled person. The methods below are given as non-limiting examples on how the compounds may be prepared.
  • Method A through F shows the preparation of the compounds of this invention. Useful methods for the generation of intermediates are described afterwards.
  • the compound of Formula (I) may be prepared according to scheme 1 by use of a suitable solvent, such as DMF or THF, a base such as sodium hydride or cesium carbonate and a suitable electrophilic species such as an epoxide, a heteroaromatic chloride, an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride.
  • a suitable solvent such as DMF or THF
  • a base such as sodium hydride or cesium carbonate
  • a suitable electrophilic species such as an epoxide, a heteroaromatic chloride, an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride.
  • a purification method such as silica gel chromatography may be employed if needed.
  • the compound of formula (I) may be prepared according to Scheme 2. Using a suitable solvent such as DMF, DMSO or THF and a base such as an alkaline metal hydroxide, compounds of Formula (I) may be generated by mixing at elevated temperature.
  • a suitable solvent such as DMF, DMSO or THF
  • a base such as an alkaline metal hydroxide
  • said elevated temperature is a temperature slightly above room temperature, such as in the range of 2 to 10°C above room temperature.
  • Mixing is preferably done for a few hours, such as in the range of 2 to 5 hours.
  • a purification method such as acid-base extraction may be used if necessary, and the compounds may be
  • Compounds of Formula (I) may be prepared according to scheme 3 by use of a suitable solvent such as THF, a suitable catalyst such as palladium tetrakis
  • the compounds of Formula (I) may be generated according to Scheme 3 by mixing at a temperature slightly below room temperature, such as in the range of 2 to 10°C below room temperature, followed by warming to room temperature for a few hours, such as for 2 to 5 hours. A purification method such as acid-base extraction or chromatography may be used if necessary. Method D for the preparation of compounds of formula I
  • Compounds of Formula (I) may be prepared according to Scheme 4 using a suitable solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a suitable catalyst such as Pd 2 (dba) 3 , optionally a suitable salt such as lithium chloride and the desired nucleophile such as an amine, carbon monoxide, an ethanethionate, or an organometallic.
  • a suitable solvent such as toluene or tetrahydrofuran
  • a base such as cesium carbonate or potassium t-butoxide
  • Pd 2 (dba) 3 a suitable catalyst
  • optionally a suitable salt such as lithium chloride
  • the desired nucleophile such as an amine, carbon monoxide, an ethanethionate, or an organometallic.
  • the compounds of Formula I are generated at room temperature or by heating for several hours, such as for 2 to 5 hours.
  • a purification method
  • Compounds according to Formula (I) may be prepared using a suitable solvent such as DMF or THF, a base such as a hindered tertiary amine, a suitable dehydrating agent such as EDCI or DCC and ammonia.
  • the compounds of Formula (I) are generated by mixing at or above room temperature (such as 2 to l O 'C above room temperature) for a several hours, such as for 2 to 5 hours.
  • a purification method such as silica gel chromatography may be employed if needed.
  • the compounds of Formula (I) may be prepared according to Scheme 6.
  • An acid chloride of the compound is added, optionally dissolved in a suitable solvent such as THF, into a rapidly mixing aqueous ammonia solution, and the compound according to Formula (I) precipitates out.
  • a purification method such as silica gel chromatography may be employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 7 by use of a solvent such as DMF or THF, a base such as a hindered tertiary amine, a dehydrating agent such as EDCI or DCC and the desired amine, and by mixing at or above room temperature for several hours.
  • a purification method such as silica gel
  • the compound of Formula (I) may be prepared according to scheme 8 by use of a suitable solvent, such as ethanol, DMF or THF, a base such as sodium hydroxide and a suitable electrophilic species such as an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride.
  • a suitable solvent such as ethanol, DMF or THF
  • a base such as sodium hydroxide
  • a suitable electrophilic species such as an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride.
  • a purification method such as silica gel chromatography may be employed if needed.
  • Intermediate 1 in which X 3 represents hydrogen or methoxy, can be prepared according to scheme 9 by using an acidic solvent such as acetic acid. Intermediate 1 forms at a temperature varying from below room temperature to boiling, depending on X 3 . A silica filtration can be done if necessary. When X 3 is methoxy, this group can be elaborated into the various representations of X 3 by methods known to those skilled in the art. Pharmaceutical compositions
  • compositions comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent.
  • Said compound according to the invention is preferably the compounds according to Formula (I) described herein above.
  • Pharmaceutical compositions according to the invention may even comprise a compound selected from the group consisting of
  • compositions are useful for treatment of a HDME dependent disease.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 st Edition, 2000, Lippincott Williams & Wilkins.
  • compositions formed by combining a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, with pharmaceutically acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injectable solutions and the like.
  • the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • compositions may be specifically prepared for administration by any suitable route such as the oral and parenteral (including subcutaneous,
  • intramuscular, intrathecal, intravenous and intradermal routes. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be prepared so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • a compound of Formula (I) may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like.
  • an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like.
  • suitable binders, lubricants, disintegrating agents, flavouring agents and colourants may be added to the mixture, as appropriate.
  • suitable binders include, e.g., lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like.
  • Lubricants include, e.g., sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like.
  • Disintegrating agents include, e.g., starch, methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, croscarmellose sodium or the like. Additional excipients for capsules include macrogols or lipids.
  • Formula (I) is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid preformulation composition containing a homogenous mixture of a compound of Formula (I).
  • excipients such as the ones described above
  • other pharmaceutical diluents such as water
  • homogenous is understood to mean that the compound of Formula (I) is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules.
  • Liquid compositions for either oral or parenteral administration of the compound of the invention include, e.g., aqueous solutions, syrups, elixirs, aqueous or oil suspensions and emulsion with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrolidone.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • solutions containing a compound of this invention or a pharmaceutically acceptable salt, solvate or prodrug thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • parenteral administration for compounds of the invention, wherein the active part of the molecule contains acid labile groups, such as e.g. ester groups.
  • acid labile groups such as e.g. ester groups.
  • oral administration is preferred instead (or another appropriate administration form which result in a first-pass metabolism).
  • compositions of a compound of formula 1 are also contemplated as being within the scope of the present invention.
  • compositions of a compound of formula 1 are also contemplated as being within the scope of the present invention.
  • compositions of a compound of formula 1 are also contemplated as being within the scope of the present invention.
  • Formula (I) may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • a suitable dosage of the compound of the invention will depend on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practicing physician.
  • the compound may be administered for example either orally, parenterally or topically according to different dosing schedules, e.g. daily or with intervals, such as weekly intervals.
  • a single dose will be in the range from 0.01 to 100 mg/kg body weight, preferably from about 0.05 to 75 mg/kg body weight, more preferably between 0.1 to 50 mg/kg body weight, and most preferably between 0.1 to 25 mg/kg body weight.
  • the compound may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or more times a day. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration.
  • the compounds of the invention may also be prepared in a pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses.
  • suitable pharmaceutically acceptable carriers, diluents and excipients are as described herein above, and the one or more further active substances may be any active substances, or preferably an active substance as described in the section "combination treatment" herein below.
  • the compounds according to Formula (I) as defined herein are useful for treatment of a HDME dependent disease.
  • the treatment may include administering to a mammal, preferably a human, more preferably a human suffering from a HDME dependent disease, a therapeutically effective amount of a compound according to Formula (I) as defined herein.
  • Said HDME may be any HDME, however preferably the HDME of the present method is selected from the JmjC (Jumonji) family, as described in Cloos et. al., Genes & Development 22, 1 1 15-1 140, 2008, which is incorporated herein by reference in its entirety. More preferably said HDME is a HDME of the human JmjC family.
  • the HDME of the method is selected from the JmjC sub-family consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, more preferably from the group consisting of human GASC1 (JMJD2C), human JMJD2A, human JMJD2B, human JMJD2D and human JMJD2E.
  • said HDME is GASC1 of SEQ ID NO:1 .
  • said HDME dependent disease is a disease dependent on at least one HDME selected from the group consisting of the JmjC family, preferably from the human JmjC family, even more preferably from the group consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, yet more preferably from the group consisting of human GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E.
  • the present invention also relates to a compound of Formula (I), as defined herein, in a method for inhibiting HDMEs.
  • the method includes contacting a cell with any of the compounds of the present invention.
  • the method further provides that the compound is present in an amount effective to produce a
  • the present invention also relates to a compound of Formula (I), as defined herein, for treatment of a proliferative or hyperproliferative disease, such as cancer.
  • a proliferative or hyperproliferative disease such as cancer.
  • the disease to be treated is a HDME dependent disease.
  • HDME dependent disease is meant any disease characterized by elevated HDME expression and/or activity in at least in some instances of the disease.
  • the disease to be treated with the inhibitors of HDME according to the invention may be a proliferative or hyperproliferative disease, which includes benign or malignant tumors, for example a proliferative or hyperproliferative disease selected from the group consisting of a carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (for example gastric tumors), ovaries, esophagus, colon, rectum, prostate, pancreas, lung, vagina, thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, for example, colon carcinoma or colorectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation, for example, psoriasis, prostate hyperplasia, a neoplasia, including a neoplasia of epithelial character, including mammary carcinoma, and a leukemia.
  • a proliferative or hyperproliferative disease selected
  • the compound of Formula (I) of the present invention is useful in the treatment of one or more cancers.
  • cancer refers to any cancer caused by the proliferation of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:
  • bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibrom
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcorna, gliomatosis), brain
  • uterus endometrial carcinoma
  • cervix cervical carcinoma, pre-tumor cervical dysplasia
  • ovaries ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli- Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibro
  • lymphocytic leukemia myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome
  • Hodgkin's disease non-Hodgkin's lymphoma (malignant lymphoma)
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis
  • Adrenal glands neuroblastoma.
  • the compound of Formula (I) of the present invention are useful in the treatment of one or more cancers selected from the group consisting of: leukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T- cell lymphotrophic virus (HTLV) such as adult T- cell leukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primary central nervous system (CNS) lymphoma; multiple myeloma; childhood
  • ALL
  • the compound of Formula (I) of the present invention is useful for the treatment of squamous cell carcinomas.
  • squamous cell carcinomas are cancers of the carcinoma type of squamous epithelium that may occur in many different organs, including the skin, lips, mouth, esophagus, urinary bladder, prostate, lungs, vagina, and cervix; brain cancer, that is
  • the compound of Formula (I) of the present invention are useful for treatment of brain cancer, tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), and breast cancer.
  • head and neck cancers e.g., oral, laryngeal and esophageal
  • genito urinary cancers e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon
  • Other cancer forms for which the compounds of the present invention are useful as treatment can be found in Stedman's Medical Dictionary (Lippincott Williams & Wilkins, 28 th Ed., 2005), which is incorporated herein by reference in its entirety.
  • the disease to be treated by compounds of Formula (I) of the present invention is selected from persistent proliferative or hyperproliferative conditions such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g., stent-induced restenosis; endometriosis; Hodgkin's disease; leukemia; hemangioma; angiofibroma; eye diseases, such as neovascular glaucoma; renal diseases, such as glomerulonephritis; malignant nephrosclerosis; thrombotic microangiopathic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; mesangial cell-proliferative diseases; injuries of the nerve tissue; and inhibiting the re-occlusion of vessels after balloon catheter treatment, for use in vascular prosthetics or after inserting mechanical devices for holding vessels open, such as, e.g., s
  • the invention provides a pharmaceutical composition comprising any of the compounds of Formula (I) of the present invention and one or more pharmaceutically acceptable carrier(s) or excipient(s).
  • the compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating cellular proliferative or hyperproliferative ailments and/or ailments associated with disregulated gene expression.
  • the pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like.
  • pharmaceutically effective amount or
  • terapéuticaally effective amount indicates an amount necessary to administer to a host, or to a cell, tissue, or organ of a host, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect, for example an antitumor effect, e.g. reduction of or preferably inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells, or of any other HDME dependent disease.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of Formula (I) of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with at least one further anti-neoplastic compound, and a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a method of treating diseases in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein, to a subject in need of such treatment.
  • the disease may be any disease or disorder as mentioned herein, such as for example mentioned in the section "HDME dependent diseases", and the compound may be administered alone or in a pharmaceutical composition, such as for example mentioned in the section "Pharmaceutical compositions".
  • treating refers to reversing, alleviating, inhibiting the process of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition and includes the administration of a compound of Formula (I) to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder.
  • treatment is curative or ameliorating.
  • the method is a method of treating a HDME dependent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein, to a subject in need of such treatment.
  • the HDME dependent disease may be any HDME dependent disease as described herein above.
  • the HDME dependent disease is squamous cell carcinomas.
  • the compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein is administered in combination with one or more further active substances.
  • the active substances may be any active substances, and preferably an active substance as described herein above in the section "combination treatment". More preferably the one or more additional active substances are selected from the group consisting of anti-proliferative or antineoplastic agents.
  • a compound of the present invention may also be used to advantage in combination with one or more other anti-proliferative or anti-neoplastic agents.
  • antiproliferative agents include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase;
  • gonadorelin agonists include anti-androgens; angiostatic steroids; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMOD AL(R)); leucovorin; immune stimulating agents, such as BCG, IL-2 or IFN-a , antibodies, such as rituximab or herceptin and cancer vaccines.
  • immune stimulating agents such as BCG, IL-2 or IFN-a
  • antibodies such as rituximab or herceptin and cancer vaccines.
  • a compound of Formula (I) of the present invention may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or tumor cell damaging approaches, especially ionizing radiation.
  • a compound of Formula (I) of the present invention may also be used as a
  • radiosensitizer including, for example, the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • combination is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non- steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN.
  • Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ORIMETEN.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
  • antiestrogen as used herein relates to a compound that antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOLVADEX.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g., as disclosed in US 4,636,505.
  • gonadorelin agonist includes, but is not limited to abarelix, goserelin and goserelin acetate.
  • Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g., as disclosed in US 5,843,901 .
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecan and its analogues, 9- nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in W099/ 17804).
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g.,
  • Etoposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL.
  • ADRIBLASTIN or ADRIAMYCIN can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to taxanes, e.g., paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, including vinblastine sulfate, vincristine including vincristine sulfate, and vinorelbine,
  • taxanes e.g., paclitaxel and docetaxel
  • vinca alkaloids e.g., vinblastine, including vinblastine sulfate, vincristine including vincristine sulfate, and vinorelbine
  • Paclitaxel may be administered e.g., in the fo[pi]n as it is marketed, e.g., TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark
  • VINBLASTIN R.P Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in US 5,010,099. Also included are Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929, WO 98/08849, WO
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
  • the phrase, "histone deacetylase inhibitors" or “HDAC inhibitors” relates to compounds which inhibit at least one example of the class of enzymes known as a histone deacetylase, and which compounds generally possess antiproliferative activity.
  • HDAC inhibitors include compounds disclosed in, e.g., WO 02/22577, including N-hydroxy-3-[4- ⁇ [(2-hydroxyethyl)[2-(IH-indol-3-yl)ethyl]- amino]methyl]phenyl]-2E-2- propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-IH-indol-3-yl)- ethylJ-amino]methyl]phenyl]-2E-2- propenamide and pharmaceutically acceptable salts thereof. It further includes Suberoylanilide hydroxamic acid (SAHA).
  • SAHA Suberoylanilide hydroxamic acid
  • Other publicly disclosed HDAC inhibitors include butyric acid and its derivatives, including sodium phenylbutyrate, thalidomide, trichostatin A and trapoxin.
  • anti-plastic antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR.
  • the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See, e.g., Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993).
  • angiostatic steroids refers to agents which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 1 1 -[alpha]- epihydrocotisol, cortexolone, 17[alpha]-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • chemotherapeutic agents include, but are not limited to, plant alkaloids, hormonal agents and antagonists; biological response modifiers, preferably
  • lymphokines or interferons antisense oligonucleotides or oligonucleotide derivatives; or miscellaneous agents or agents with other or unknown mechanism of action.
  • the structure of the active agents identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g., Patents International (e.g., IMS World Publications).
  • the above-mentioned compounds, which can be used in combination with a compound of the present invention can be prepared and administered as described in the art such as in the documents cited above.
  • the aqueous phase was extracted with diethyl ether (3 x 5 ml) and the combined organic phases were then washed with water (3 x 5 ml), diluted with hexane (15 ml), dried over Na 2 S0 4 , filtered and the solvent removed in vacuo to provide the title compound as a yellow solid.
  • Procedure B From 10-(Methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid.
  • Procedure A From 3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester using dimethyl carbamyl chloride.
  • Procedure A From 3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester using dimethyl carbamyl chloride.
  • Procedure D From 3-(morpholine-4-carbonyloxy)-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
  • the GASC1 demethylation HTRF assay ( Figure 1 ) uses a truncated version of histone H3 trimethylated at lysine 9 as a substrate
  • H3K9me3 The demethylase activity of GASC1 results in loss of methyl group(s) at lysine 9 in this substrate peptide. This reaction is monitored by quantifying the amount of product (H3K9me2) formed.
  • HTRF homogeneous time resolved fluorescence
  • This type of assay is entirely homogeneous, amenable to miniaturisation to 1 ,536-well high density plate format and compatible with automated high throughput equipment.
  • the GASC1 enzyme Prior to incubation the GASC1 enzyme (in assay buffer) is added to the wells and mixed with either compound (2 mM in DMSO), control inhibitor (at either 5 ⁇ in DMSO as "IC50” control or at 500 ⁇ in DMSO as maximal inhibition control for Z' calculation) or DMSO (negative control).
  • control inhibitor at either 5 ⁇ in DMSO as "IC50” control or at 500 ⁇ in DMSO as maximal inhibition control for Z' calculation
  • DMSO negative control.
  • the enzyme substrate H2K9-me3 in assay buffer
  • the assay buffer in the 2 ⁇ reaction is 50 mM Tris pH 8.0, 0.1 % pluronic® F127, 200 mM NaCI, 0.1 mM MgCI2, 5 ⁇ FeS04, 250 ⁇ ascorbate and 250 ⁇ ⁇ - ketoglutarate. If the compound concentration during screening is 20 ⁇ , the DMSO concentration in the negative controls of the GASC1 reaction (2 ⁇ volume) is 1 %.
  • the 2-fold concentrated intermediate Eu-Abcam1220 / SA-XL665 mixture is dissolved in 50 mM NaPi pH 7.0, 800 mM KF, 0.1 % pluronic® F127 and 0.1 % BSA.
  • the 6-fold concentrated intermediate Bt-H3K9me2 solution (“Bt-me2") is dissolved in 50 mM NaPi pH 7.0, 0.1 % pluronic® F127 and 0.1 % BSA.
  • the GASC1 LC-MS based demethylation assay uses the same truncated version of histone H3 trimethylated at lysine 9 as a substrate (H3K9me3) as was used on the GASC1 HTRF assay of Example 2.
  • the demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a shift in molecular mass of the product (H3K9me2) compared to the substrate that can be measured by mass spectrometry.
  • Quantification of substrate and product is done using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), enabling a precise and direct monitoring of the demethylation reaction.
  • An example of the mass traces detected by LC-MS/MS is shown in figure 2.
  • IC50 values of compounds were determined based on 8-point concentration-response curves using LC-MS-MS detection of the demethylated product. Results are shown in Table 1 below. Assay plates were divided into control wells and compound wells. On such an assay plate the following samples were placed:
  • GASC1 protein in assay buffer was mixed with compound (8 concentrations; e.g. final concentrations from 20 ⁇ to 2,1 nm, 3,7 fold dilution) and incubated for 10 minutes at room temp.
  • Substrate, H3K9-me3 (final concentration: 50 ⁇ ) was then added and the reaction was incubated for 360 minutes at room temp.
  • 30% TCA final concentration: 5% was added to stop the reaction, which was hereafter centrifuged for 10 minutes at 3750xg. The amount of remaining substrate and dimethylated product was directly measured using LC-MS/MS.
  • the table below shows an overview of the reaction and plate set up.
  • Enzyme buffer 50 mM Tris pH 8.0, 0.1 mM MgCI2, 200 mM NaCI, 0,1 % Pluronic F- 127
  • Assay buffer 50 mM Tris pH 8.0, 0.1 mM MgCI2, 200 mM NaCI, 0,1 % Pluronic F- 127, 50 ⁇ (final: 25 ⁇ ) FeS04, 500 ⁇ (final: 250 ⁇ ) ascorbic acid, 500 ⁇ (final: 250 ⁇ ) ⁇ -ketoglutarate
  • Solvent A LC/MS grade (Baker) water containing 0.05% trifluoroacetic acid
  • Solvent B LC/MS grade (Baker) acetonitrile containing 0.1 % formic acid
  • Quantification of product is uses the AlphaLISA technology and a commercially available detection kit supplied by PerklinElmer.
  • the AlphaLISA based GASC1 demethylation assay uses the truncated version of histone H3 trimethylated at lysine 9 as was used in the GASC1 LC-MS assay (example 3) as a substrate, with an N- terminal added biotin molecule (BH3K9me3).
  • the demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a binding epitope for a specific H3K9Me2 antibody, which is part of the specific detection kit ( Figure 3). Reagents and equipment used in the assay are listed below:
  • IC50 values of compounds were determined based on 8-point concentration-response curves using the following protocol of the alphaLISA detection kit:
  • Negative controls control wells containing enzyme without inhibitor (for calculation of inhibition and Z'-values)
  • GASC1 protein in assay buffer was mixed with compound (8 concentrations; final concentrations from 100 ⁇ to 6.4 nm, 5 fold dilution) and incubated for 10 minutes at room temp.
  • Substrate (BH3K9-me3, final concentration: 10 ⁇ and cofactors) were then added and the reaction was incubated for 60 minutes at room temp.
  • An equal volume of 4mM EDTA in Enzyme buffer was added to stop the reaction, which was hereafter vortexed for 2 minutes.
  • the amount of formed dimethylated product was directly measured using the AlphaLISA method.
  • the table below shows an overview of the reaction and plate set up.
  • Enzyme buffer 50 mM HEPES pH 8.0, 0.1 % BSA, 0.003% Tween-20
  • Assay buffer 50 mM HEPES pH 8.0, 0.1 % BSA, 0.003% Tween-20, 15 ⁇ (final:
  • Detection reaction To 5 ⁇ _ reaction product in an Alphascreen 384-plate is added 10 ⁇ _ acceptor beads (1 :100 in 1 x Epigenetics Buffer). Upon 60 min incubation at RT, 10 ⁇ _ donor beads are added (1 :100 in 1 x Epigenetics Buffer). Upon 30min incubation in the dark, the Alpha signal is measured upon excitation at standard Alpha conditions. ⁇ nn
  • GASC1 AlphaLISA assay for IC50 value determination at conditions with low carrier protein and detergent concentrations The Assay was carried out as described in Example 4 using PBS (pH 7.4) instead of for enzyme buffer in entries 3, 4, 5, and 10 in the Assay Overview.
  • Table 3 GASC1 AlphaLISA assay - low carrier protein and detergent concentrations.
  • TCRKDMVKISMDIFVRKFQPDRYQLWKQGKDIYTIDHTKPT SEQ ID NO:1 is the amino acid sequence of the 386 aa GASC1 product produced in E. coli.
  • the protein has an MW of 44,765 Da and a pi of 6,43.
  • the plasmid was transformed into E. coli BL21 (DE3) strain and expressed by auto- induction following protocols according to Studier, FW, 2005.
  • cells were grown overnight in non-inducing MDG media without trace metals containing 100 ⁇ g ml ampicillin and 100 ⁇ FeCI 3 .
  • 500 ⁇ of the overnight culture was used to inoculate 500 ml of ZYM-5052 induction media without trace metals, supplemented with 100 ⁇ g ml ampicillin and 100 ⁇ FeCI 3 , for auto induction of expression (Recipes and stock solutions can be found at Studier, F.W. (2005) Protein production by auto-induction in high density shaking cultures. Protein Expr. Purif. 41 ; 207-234).
  • Cells were resuspended in 5 ml of lysis buffer per gram of cell pellet supplemented with 1 tablet of EDTA-Free Complete protease inhibitor (Roche) per litre of cell culture and 25 U of Bezonase Nuclease (Novagen) per ml of lysis buffer to reduce viscosity.
  • Cells were lysed using a Cell Disruptor (Constant Systems Ltd) 20,000 psi, then centrifuged at 2 X 50,000 X g for 30 minutes at 4°C.
  • GASC1 protein was purified from the supernatant using Talon metal affinity resin (Clontech) according to manufacturer's protocol.
  • Talon affinity resin was equilibrated using 20 X bed volumes of lysis buffer (1 ml bed volume per litre of cell culture) and then incubated with the soluble cell extract at 4°C with agitation for 30-60 minutes. The resin was then loaded onto disposable chromatography columns (Bio-Rad) and washed using 20 X bed volumes of wash buffer. Protein was eluted with 6 X (1 ml / ml resin) fractions using the elution buffer. Finally, protein concentration was measured using Protein assay reagent (Bio-Rad) and GASC1 containing fractions were pooled and buffer changed on a PD-10 desalting column (GE Healthcare) to stabilizing buffer. Protein concentration was adjusted to 1 .5 - 2.0 mg/ml and flash frozen. This E. coli expressed fragment of GASC1 contains the active site of the full length enzyme and has the capability of demethylating the trimethyl Wink-78 substrate.
  • Human tumour cells are harvested from monolayer cultered cells using appropriate enzymes, e.g. trypsin. The cells are suspended in media plus serum and quantified. The cell suspension is centrifuges and the cells are re-suspended in serum-free medium to a suitable cell concentration.
  • appropriate enzymes e.g. trypsin.
  • the cells are suspended in media plus serum and quantified.
  • the cell suspension is centrifuges and the cells are re-suspended in serum-free medium to a suitable cell concentration.
  • a human tumour is transferred to a sterile petri dish with medium plus antibiotics and tumour tissue is cut into pieces of approx. 5x5x5 mm.
  • 5-7 week old nude athymic mice (nu/nu) or SCID mice (scid/scid) are anesthetized and a volume (e.g. 100 ⁇ g) of suspended tumour cells is injected corresponding to a suitable total cell number (e.g. between 10 5 and 10 7 cells) under the skin of the lower flank of the mice or at another appropriate site.
  • the mice are anesthetized, a small incision of 5 mm in length at an appropriate site is made and a tumour piece is inserted into the incision.
  • a antibiotics solution is dropped over the incision, which is closed, e.g. using tissue adhesive.
  • mice are divided into different treatment groups for testing of compound, e.g. following the scheme below:
  • Control chemotherapy 14 + groups for testing different concentrations of compound can be included.
  • a tumour will start to appear at the site of the graft after a period of 1 -4 months, which can be measured in size at specific timepoints to determine the result of the experiment.
  • the number of metastases in different organs can alternatively be counted as a measure of tumour growth.
  • Active compounds will lead to a decreased tumour size or number of metastases.

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Abstract

The present invention relates to compounds capable of modulating the activity of histone demethylases (HDMEs), which are useful for prevention and/or treatment of diseases in which genomic disregulation is involved in the pathogenesis, such as e.g. cancer. The present invention also relates to pharmaceutical compositions comprising said compounds and to the use of such compounds as a medicament.

Description

Inhibitors of HDME
All patent and non-patent references cited in the application are hereby incorporated by reference in their entirety.
Field of invention
The present invention relates to compounds capable of modulating the activity of histone demethylases (HDMEs). The compounds are useful for prevention and/or treatment of diseases in which genomic disregulation is involved in the pathogenesis, such as e.g. cancer.
Background of invention
Methylation of lysine and arginine residues on histone tails constitutes important epigenetic marks delineating transcriptionally active and inactive chromatin. For instance, methylation of lysine 9 on histone H3 (H3-K9) is associated with
epigenetically silenced chromatin (Fischle, W., et. al., Curr. Opin. Cell Biol. 15, 172-83, 2003; Margueron, R., et. al., Curr. Opin. Genet. Dev. 15, 163-76, 2005). As
documented by studies of the SUV39H1 knockout mouse, loss of the tri-methyl variant of the H3-K9 mark results in chromosomal aberrations and predisposes to cancer (Peters, A. H. et al., Cell 107, 323-37, 2001 ). Recently, several members of the JmjC domain containing family of histone demethylase (HDME), enzymes involved in erasing methyl marks associated with gene repression or activation, have been identified (Cloos, P., et. al., Genes & Development, 22, 1 1 15-1 140, 2008, and references cited therein). Inhibitors of HDME would provide a novel approach to the prevention and treatment of cancers and other proliferative diseases. There remains a need for efficacious and specific compounds suitable for treating proliferative diseases, including cancerous tumors. Now, surprisingly, compounds of Formula (I) have shown to be highly effective in inhibiting HDMEs. Summary of invention
The present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, for treatment of a HDME dependent disease. The inventors have surprisingly found that compounds of Formula (I) can be used in the treatment of HDME dependent diseases by inhibiting HDMEs. Inhibiting HDMEs would provide a novel approach to the prevention and treatment of cancer and other proliferative diseases. Accordingly, it is an object of the present invention to provide compounds that when administered alone or optionally in combination with antineoplastic compounds, increases the efficacy of the treatment of HDME dependent diseases.
Accordingly, a first aspect of the present invention relates to a compound of Formula (I)
Figure imgf000003_0001
Formula (I) an isomer or a mixture of isomers thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
Xi represents -A-B, wherein
A represents a bond, O, S, or NH, and B represents
• Ci-6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl
which d-e-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3-5-cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci.4-alkoxy, hydroxy-Ci_4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyi, dimethylsulfamoyi, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' represents hydroxy, Ci-4-alkyl, halogen-Ci-4-alkyl, Ci-4-alkoxy, -NH2, methylamino, cyclopropyl, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group; or
-OH, with the proviso that B only represent -OH, when A is a bond; or or -(C=0)R",
where R" represents hydroxy, halogen-Ci-4-alkyl, Ci-4-alkoxy, hydroxy-Ci-4- alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C3-4-cycloalkyl or Ci-4-alkyl, wherein said C3-4- cycloalkyl or Ci-4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above;
-(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two Ci-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci-4-alkyl, halogen-Ci-4-alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3- alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci.3-alkyl, Ci.3-alkoxy, Ci.3-alkoxyalkoxy, Ci.3-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, cyclopropyl and C1-3-alkyl, wherein said cyclopropyl or d-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, cyclopropyl, Ci 3-alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; and
X2 represents
• -COOH, (C=0)NH2 and
X3 represents
• Hydrogen or -OH; or
Figure imgf000005_0001
where
Y is O, C=0 or a bond; and
Xa is -a bond, Ci-i8-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-i0-cycloalkyl, -Ci-i8-alkyl- 0-, -O- or -NXb- with the proviso, that when Y is O then Xa is not O; and each Xb is individually -H, C3-6-cycloalkyl, d-6 alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic
heterocyclic group or a bicyclic heteroaromatic group, which C3-i0-cycloalkyl, Ci-6 alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6- membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, hydroxy linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci_4-alkoxycarbonyl, Ci.4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched C1-5-alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci_4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered
heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above; and
X4 and X5 independently of each other represent
• hydrogen, C1-4-alkyl, halogen-Ci-4-alkyl, C3-6-cycloalkyl, halogen, nitro, -NH2, methoxycarbonyl, acetyl, methoxycarbamoyl or cyano; with the proviso that the compound is not
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-; or Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-methylphenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-(trifluoromethyl)phenyl]methoxy]-; or
Acetic acid, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-, ethyl ester; or
Acetamide, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(cyanomethoxy)-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-hydroxy-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-bromophenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(3-cyanophenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(phenylmethoxy)-; or Pyrido[1 ,2-a]indole-10-carbonitrile, 3-methoxy-.
A second aspect of the present invention relates to pharmaceutically compositions comprising an effective amount of a compound of Formula (I) as active ingredient.
A third aspect of the present invention relates to a compound of Formula (I) for use as a medicament, in particular for use as a medicament for the treatment of a HDME dependent disease. A fourth aspect of the present invention relates to a compound of Formula (I) for treatment of a HDME dependent disease. The treatment includes administering to a mammal, preferably a human, more preferably a human suffering from a HDME dependent disease, a therapeutically effective amount of a compound of the present invention.
A fifth aspect of the present invention relates to a compound of Formula (I) in a method for inhibiting HDMEs. The method includes contacting a cell with any of the compounds of the present invention. In a related embodiment, the method further provides that the compound is present in an amount effective to produce a concentration sufficient to selectively inhibit the demethylation of a histone in the cell.
A sixth aspect of the present invention relates to a compound of Formula (I) for the manufacture of a medicament to treat a proliferative or hyperproliferative disease, such as cancer.
Description of Drawings
Figure 1 : The GASC1 demethylation HTRF assay used for high throughput screening of compounds. Figure 2: Mass traces detected by LC-MS/MS: The demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a shift in molecular mass of the product compared to the substrate that can be measured by mass spectrometry. Quantification of substrate and product is done using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), enabling a precise and direct monitoring of the demethylation reaction. Figure 3: The principle of the AlphaLISA assay used for screening of the compound inhibition of HDME activity. Detailed description of the invention
In the present description several lists of bullitpoints are provided. These indicate various alternatives covered by the invention. Thus, by way of example:
"B represents
· Ci-e-alkyl, C2-4-alkenyl or C2-4-alkynyl,
• -OH
• -(C=0)R"' means that B may represent either Ci-6-alkyl, C2-4-alkenyl, C2-4-alkynyl, -OH or - (C=0)R"."
Compounds of formula (I)
The present invention relates to compounds of Formula (I),
Figure imgf000008_0001
and isomers or mixture of isomers thereof or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Xi represents -A-B, wherein
A represents a bond, O, S, or NH, and
B represents Ci_6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl,
which d-e-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3-5-cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyi, dimethylsulfamoyi, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group; preferably said Ci_6-alkyl may be substituted with one or more selected from the group consisting of cyano and halogen, where
R' represents hydroxy, Ci-4-alkyl, cyclopropyl, halogen-Ci_4-alkyl, Ci-4- alkoxy, -NH2, methylamino, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group, preferably R' represents Ci-4-alkyl, halogen- Ci-4-alkyl, Ci-4-alkoxy, -NH2, methylamino or dimethylamino; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group;; or
-OH, with the proviso that B only represent -OH, when A is a bond; or
-(C=0)R",
where R" represents hydroxy, halogen-Ci-4-alkyl, Ci-4-alkoxy, hydroxy-Ci-4- alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C3.4-cycloalkyl or Ci-4-alkyl, wherein said C3-4- cycloalkyl or Ci-4 alkyl optionally may be substituted with one or more
substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyi, dimethylsulfamoyi, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R\ a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; preferably R" represents hydroxyl, halogen-Ci-4-alkyl, Ci-4-alkoxy, -NH2, Ci-3-alkyl-amino, di-d- 3-alkyl-amino, a 6-membered monocyclic heterocyclic group or d-3-alkyl, even more preferably R" represents hydroxyl, trifluoromethyl, methyl, ethyl, -NH2, methylamino, dimethylamino or morpholinyl;
• -(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci.6-alkyl optionally substituted with dimethylamino;
Ifamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two Ci_3-alkyl groups, preferably with one or two methyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of d-4-alkyl, halogen-Ci-4-alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group, preferably with cyclopropyl, methyl, ethyl, amino, methylamino or dimethylamino; phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci_3-alkyl, Ci.3-alkoxy, Ci_3-alkoxyalkoxy, Ci_3-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, cyclopropyl and C1-3-alkyl, wherein said cyclopropyl or d-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, cyclopropyl, d_ 3-alkoxy, hydroxy-Ci-3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R\ a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above, preferably the phenyl, monocyclic or bicyclic group is substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-3-alkyl, Ci-3-alkoxy, cyano, -NH2, methylamino, dimethylamino and Ci-3-alkyl,; and X2 represents
• -COOH, (C=0)NH2 or -CN and represents
• Hydrogen or -OH; or
• -Y-Xa-Xb, where
Y is O, C=0 or a bond; and
Xa is -a bond, Ci-i8-alkyl, C2-i 8-alkenyl, C2-i 8-alkynyl, C3-i 0-cycloalkyl, -Ci-i 8-alkyl- 0-, -O- or -NXb-, with the proviso that when Y is O, then Xa is not O; and each Xb is individually -H, C3.6-cycloalkyl, Ci.6-alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic
heterocyclic group or a bicyclic heteroaromatic group, which C3.i0-cycloalkyl, Ci-6- alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6- membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, hydroxy linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4-alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said d-5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci_4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered
heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above, preferably substituted with one or more substituents selected from the group consisting of linear or branched Ci-4-alkoxy, halogen, halogen-Ci-4-alkyl and linear or branched Ci-5-alkyl, even more preferably from the group consisting of methoxy, ethoxy, propyloxy, isopropyloxy, methyl, ethyl, propyl, isopropyl and chloro; and
X4 and X5 independently of each other represent · hydrogen, Ci-4-alkyl, halogen-Ci-4-alkyl, C3-6-cycloalkyl, halogen, nitro, -NH2, methoxycarbonyl, acetyl, methoxycarbamoyl or cyano;
Above-mentioned phenyl, monocyclic or bicyclic heterocyclic groups may be substituted at any suitable position, Thus, for example if X3 comprises phenyl, said phenyl may for example be substituted once at the para position or once at the meta position. If X3 comprises imidazole, said imidazole may for example be attached at the
4 position and/or be substituted at the 1 and/or 2 position(s). If X3 comprises oxazolyl, said oxazolyl may for example be attached at the 2 position and/or be substituted at the
5 position.
In general each X3 only comprises one Xb group in which case said Xb is as defined above, Only in the case that Xa is -NXb-, then and X3 may comprise two Xb groups, which may be individually selected from the group of different Xb groups identified above in this section.
Preferred compounds of formula (I) - Xi
Without being bound by any theory it has been found that compounds of formula I having a particular 3-dimensional structure are more preferred than other compounds, probably because of the geometric preference for the binding of such compounds to the receptor. More particular it has been found that especially preferred compounds are those for which Xi represents a group comprising one or more polar substituents such as for example oxy, sulfonyl, sulfinyl, sulfanyl, carbonyl and cyano, and where this group is near the core. Furthermore, it has been found that especially preferred compounds are those for which X2 represents carboxyl, amide or nitrile, and in particular X2 may be carboxyl or amide. It has also been found that in some embodiments of the invention it is advantageous if X3 is fairly long and comprises a lipophilic moeity such as for example phenyl, a 5 or 6 membered heterocyclic ring, a bicyclic heterocyclic ring or an aliphatic chain. Said lipophilic moiety is preferably removed from the core.
A preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, and B represents:
• Ci-6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl, which C1-6-alkyl, C2.4- alkenyl, C2-4-alkynyl or C3.5-cycloalkyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)"; or
• -(C=0)R", where FT is as indicated herein above in the section "Compounds of formula (I)"; or
• -(C=0)NH-R"', where FT" is as indicated herein above in the section
"Compounds of formula (I); or
• sulfamoyl, sulfinyl, sulfanyl or sulfonyl, which sulfamoyl, sulfinyl, sulfanyl or
sulfonyl optionally may be substituted as indicated herein above in the section "Compounds of formula (I)"; or
• phenyl, a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group optionally may be substituted as indicated herein above in the section "Compounds of formula (I)".
Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents O and B represents:
• C1-6-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3-5-cycloalkyl, which C1-6-alkyl, C2.4- alkenyl, C2.4-alkynyl or C3-5-cycloalkyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)"; or
• -(C=0)R", where R" is as indicated herein above in the section "Compounds of formula (I)"; or
• -(C=0)NH-R"', where R'" is as indicated herein above in the section "Compounds of formula (I); or
• sulfamoyl, sulfinyl, sulfanyl or sulfonyl, which sulfamoyl, sulfinyl, sulfanyl or
sulfonyl optionally may be substituted as indicated herein above in the section "Compounds of formula (I)"; or • phenyl, a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". Another preferred embodiment of the present invention relates to compounds of
Formula (I), where Xi represents a group designated by -A-B, in which A represents S and B represents Ci.6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl, which C1-6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)".
Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents NH and B represents
• -(C=0)R", where FT is as indicated herein above in the section "Compounds of
formula (I)"; or
• sulfamoyi, sulfinyl or sulfonyl, which sulfamoyi, sulfinyl or sulfonyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)".
Yet another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents C1-6-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3-5- cycloalkyl, which C1-6-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3.5-cycloalkyl may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". Another preferred embodiment of the present invention relates to compounds of
Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O or NH and B represents -(C=0)R" or -(C=0)NH-R"\ where R" and R'" is as defined herein above in the section "Compounds of formula (I)". Another preferred embodiment of the present invention relates to compounds of
Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O or NH and B represents sulfamoyi, sulfinyl, sulfanyl or sulfonyl, which sulfamoyi, sulfinyl, sulfanyl or sulfonyl may be substituted as indicated herein above in the section "Compounds of formula (I)". Another preferred embodiment of the present invention relates to compounds of Formula (I), where Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". More preferably in this embodiment B represents a monocyclic or bicyclic heterocyclic group which optionally may be substituted as indicated herein above in the section "Compounds of formula (I)". In particular preferred embodiments of the present invention the compounds of
Formula (I) which comprises one or more monocyclic or bicyclic heterocyclic group(s) selected from the group consisting of a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered carbocyclic group, a bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6-membered carbocyclic group, a bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6-membered heterocyclic group, a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group, a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups, a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom, a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom, and a bicyclic heterocyclic group consisting of two 6- membered groups sharing a heteroatom. In some embodiments the compound of Formula (I) comprises at least one monocyclic heterocyclic group, which is a 5-membered monocyclic heterocyclic group or a 6- membered monocyclic heterocyclic group. The monocyclic heterocyclic group may be a 5-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S, more preferably comprising 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprising 1 or 2 heteroatoms each independently selected among N or O. Preferably, the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2- thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl. Alternatively, the monocyclic heterocyclic group may be a 6-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S more preferably comprising 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprising 1 or 2 heteroatoms each independently selected among N or O. Preferably, the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H- thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
In other embodiments the compound of Formula (I) comprises at least one bicyclic heterocyclic group comprising 1 , 2, 3, or 4 heteroatoms each independently selected among N, O, and S, more preferably comprising 1 or 2 heteroatoms each
independently selected among N, O, and S, even more preferably comprising 1 or 2 heteroatoms each independently selected among N or O. In some embodiments the compound of Formula (I) comprises a bicyclic heterocyclic group consisting of a 5- membered heterocyclic group and a 6-membered carbocyclic group, a 6-membered heterocyclic group and a 6-membered carbocyclic group, a 5-membered carbocyclic group and a 6-membered heterocyclic group, or a 5-membered heterocyclic group and a 6-membered heterocyclic group. In yet other embodiments the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups.
In yet other embodiments of the present invention the compound of Formula (I) comprises a bicyclic heterocyclic group consisting of a 5-membered group and a 6- membered group sharing a heteroatom, two 5-membered groups sharing a heteroatom or two 6-membered groups sharing a heteroatom.
Any of the above mentioned monocyclic or bicyclic heterocyclic groups may optionally be substituted as indicated herein above in the section "Compounds of formula (I)".
In some preferred embodiments of the present invention A represents a bond and B represents Ci.6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl, which may optionally be substituted as indicated above. In one preferred embodiment of the invention A represents a bond and B represents Ci-6-alkyl, which Ci_6-alkyl is substituted one time with dimethylamino. In a preferred embodiment of the invention A represents a bond and B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl. Said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl may in one preferred embodiment be substituted once as indicated herein above in the section "Compounds of formula (I)", more preferably with a dimethylamino group. In a more preferred embodiment B represents methyl, ethyl, propyl or isopropyl substituted once with a dimethylamino group.
In another embodiment of the invention A represents a bond and B represents methyl, which methyl has been substituted once with -(C=0)R', where FT represents hydroxy, methyl, trifluoromethyl, methoxy, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". Preferably FT represents hydroxy.
In some preferred embodiments of the invention A represents a bond and B represents -(C=0)R", where FT is as defined herein above in the section "Compounds of formula (I)".
In one preferred embodiment A represents a bond and B represents -(C=0)R", where wherein R" represents hydroxy, C3-4-cycloalkyl, Ci-4-alkyl, halogen-Ci-4-alkyl, -NH2, Ci- 3-alkyl-amino, di-Ci-3-alkyl-amino or a 5- or 6-membered monocyclic heterocyclic group. Preferably, R" represents hydroxy, Ci-3-alkyl, fluoro-Ci-4-alkyl, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino or a 6-membered monocyclic heterocyclic aliphatic group. Even more preferably R" represents hydroxy, methyl, trifluoromethyl, -NH2, methylamino, dimethylamino or morpholinyl. R" may also represent hydroxy, methyl, trifluoromethyl, methoxy, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which optionally may be substituted as indicated herein above in the section "Compounds of formula (I)". Very preferably R" represents methyl or trifluoromethyl.
In some preferred embodiment of the invention A represents a bond and B represents sulfamoyl, which sulfamoyl optionally is substituted with one or more C1-3-alkyl.
Preferably B represents sulfamoyl or dimethylsulfamoyl. In another embodiment of the invention A represents a bond and B represents sulfinyl or sulfonyl, which sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted as indicated herein above in the section "Compounds of formula (I)". In particular, said sulfinyl or sulfonyl may be substituted with one substituent selected from the group consisting of Ci_4-alkyl or C3-6- cycloalkyl.
It is also comprised within the invention that A represents a bond and B represents sulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, methylamino, dimethylamino, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group.
In some preferred embodiments of the invention A represents a bond and B represents a 5- or 6-membered monocyclic heterocyclic group. The 5- or 6-membered monocyclic heterocyclic group may be substituted as indicated herein above in the section
"Compounds of formula (I)". In particular, said 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci-4-alkyl, halogen, halogen-Ci-2-alkyl, Ci-4-alkoxy, Ci-4- alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino. The 5-membered monocyclic heterocyclic group may preferably be selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2- oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl. The 6-membered monocyclic heterocyclic group may be selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl, but preferably the 6-membered monocyclic heterocyclic groups is selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, and morpholinyl. Most preferred the 6- membered monocyclic heterocyclic group represents piperazinyl or morpholinyl. In some preferred embodiments of the present invention A represents O and B represents d-e-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3-5-cycloalkyl, which may optionally be substituted as indicated above.
In one embodiment A represents O and B represents C1-6-alkyl, C2-4-alkenyl, or C2.4- alkynyl, where the C^e-alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. Most preferably the Ci_6-alkyl is methyl. The C2.4-alkenyl is preferably selected from the group consisting of ethenyl, 1 - or 2- propenyl, 1 -, 2- and 3-butenyl, and 1 ,3- butenyl and the C2.4-alkynyl is preferably selected from the group consisting of ethynyl, 1 - or 2-propynyl, 1 -, 2- or 3-butynyl, and 1 , 3-butynyl. Most preferably B is selected from the group consisting of methyl, isopropyl, isobutyl, isopentyl, 1 - or 2-butenyl and 1 - or 2-butynyl.
In another embodiment A represents O and B represents C3-5-cycloalkyl, wherein the C3-5-cycloalkyl is selected fromt the group consisting of cyclopropyl, cyclobutyl and cyclopentyl preferably however, the C3-5-cycloalkyl is cyclopropyl, wherein said C3.5- cycloalkyl may be substituted as indicated above or alternatively may not be substituted. In another preferred embodiment of the invention A represents O and B represents Ci_ 6-alkyl, which Ci_6-alkyl is substituted with one cyano group. Preferably B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl substituted with one cyano group, and more preferred B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl substituted with one cyano group. In some embodiments B is substituted with cyclopropyl in addition to the cyano substituent. Most preferred Xi designates cyanomethoxy, cyano(cyclopropyl)methoxy, 1 -cyanoethoxy, 1 -cyano-2-methylethoxy, 1 -cyanopropoxy, 3-cyanopropoxy, 1 -cyano-2-methylpropoxy, 1 -cyanobutoxy, 2-cyanobutoxy 3- cyanobutoxy, and 4-cyanobutoxy. Most preferably Xi represents cyanomethoxy. In another embodiment of the invention A represents O and B represents Ci-6-alkyl, which d-e-alkyl is substituted with Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro. In an embodiment B represents butyl substituted with hydroxy.
Preferably B represents methyl or ethyl, which methyl or ethyl is substituted with methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, -NH2, methylamino, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro. Most preferred B represents methyl substituted with pyridinyl, thiazolyl or pyrazolyl, each of which may independently be substituted with one or more
substituents selected from the group consisting of methyl, chloro and fluoro. In yet other preferred embodiments B represents ethyl substituted with a substituent selected from the group consisting of ethoxy, hydroxyethoxy, dimethylamino morpholinyl and piperidinyl.
In another embodiment of the invention A represents O and B represents propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which propyl, isopropyl, butyl , isobutyl, secondary butyl, or tertiary butyl is substituted with a first substituent selected from the group consisting of dimethylamino or a 5- or 6-membered monocyclic heterocyclic group comprising at least one nitrogen atom in its ring structure where said nitrogen atom is positioned so as to form the binding link to said propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, and with a second substituent selected from the group consisting of hydroxy, cyano, methylsulfonyloxy and -(C=0)R', where R' represents hydroxy, methyl, trifluoromethyl, methoxy, NH2. Examples of 5- or 6- membered monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, piperidinyl, pyridinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3-pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,5-oxadiazolyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 4H-1 ,4-oxazinyl, morpholinyl, and thiomorpholinyl. In an embodiment B represents isopropyl substituted with 1 -pyrrolidinyl and with a second substituent selected from the group consisting of cyano and - (C=0)R', where R' represents an alkoxy group, preferably a methoxy group. In another embodiment B preferably represents isopropyl substituted with a dimethylamino group and with a second substituent selected from the group consisting of cyano and - (C=0)R', where R' represents hydroxy, -NH2, methyl, and trifluoromethyl. In yet another embodiment B preferably represents butyl substituted with both a dimethylamino group and with a hydroxy group as a second substituent.
In another embodiment of the invention A represents O and B represents Ci.6-alkyl, which d-e-alkyl is substituted with -(C=0)R', where R' represents Ci_4-alkyl, C3-4- cycloalkyl. halo-Ci_4-alkyl, hydroxy, -NH2, methylamino or dimethylamino. In a preferred embodiment B represents methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted once with -(C=0)R', where R' represents hydroxy, -NH2, or dimethylamino. Preferably B represents isopropyl, which isopropyl is substituted once with -(C=0)R', where R' represents hydroxy, -NH2, or dimethylamino. In other preferred embodiments B represents methyl, ethyl, propyl or isopropyl and R' represents methyl, trifluoromethyl, hydroxy, -NH2, methylamino or dimethylamino. Most preferably B represents methyl or isopropyl and R' represents hydroxy, methyl, trifluoromethyl or dimethylamino.
In another embodiment of the invention A represents O and B represents methyl, which methyl has been substituted once with -(C=0)R', where R' represents phenyl, which phenyl has been substituted once or twice with halo. In an embodiment the halo substituent is selected among fluoro and chloro and most preferred the phenyl is substituted twice with fluoro so as to form a difluorophenyl group. In another embodiment of the invention A represents O and B represents d-e-alkyl, which d-e-alkyl is substituted with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl. In a preferred embodiment B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted once with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl. Preferably B represents isopropyl, which is substituted once with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl. In another embodiment of the invention A represents O and B represents Ci-6-alkyl, which d-e-alkyl is substituted with phenyl, which phenyl may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halo, cyano, acetamino, methylsulfonylamino and a 5- or 6-membered monocyclic heterocyclic group. The 5- or 6-membered monocyclic heterocyclic group may be substituted as indicated above. B preferably represents methyl or ethyl, when B is substituted with unsubstituted phenyl. In another embodiment B preferably represents methyl, which is substituted with phenyl, which phenyl is substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, cyano, acetamino and methylsulfonylamino.
In some preferred embodiments of the invention A represents O, and B represents - (C=0)R", where R" is as defined herein above in the section "Compounds of formula (I)".
In one embodiment of the invention A represents O and B represents -(C=0)R", where R" represents C3-4-cycloalkyl, Ci-4-alkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro. Preferably R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. More preferably, R" represents Ci-3-alkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro. Yet more preferably, R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Even more preferred R" is selected from the group consisting of methyl, ethoxy, dimethylamino, pyrrolidinyl and morpholinyl.
In some preferred embodiments of the invention A represents O and B represents sulfamoyi, sulfinyl or sulfonyl, which sulfamoyi may optionally be substituted with one or two d-3-alkyl groups and said sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci-2-alkyl, halogen, halogen-Ci-2- alkyl, Ci-4-alkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino. Thus, said sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted as indicated above. Preferably B represents sulfamoyl, methylsulfonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl or sulfonyl, which sulfonyl is substituted with oxazolyl or thiazolyl, which oxazolyl or thiazolyl may optionally be substituted with one or more methyl.
In some preferred embodiments of the invention A represents O and B represents a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, -COOH, cyano and dimethylamino. The 5-membered monocyclic heterocyclic group may be selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H- pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, oxolanyl, pyrazolyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3- oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl. The 6-membered monocyclic heterocyclic group may be selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H- pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4- oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl, but preferably the 6- membered monocyclic heterocyclic groups is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and morpholinyl.
In some preferred embodiments of the present invention A represents S and B represents C1-6-alkyl, C2-4-alkenyl, C2.4-alkynyl or C3.5-cycloalkyl, which may optionally be substituted as indicated above. In some preferred embodiments of the invention A represents S and B represents - (C=0)R", where R" is as defined herein above in the section "Compounds of formula (I)". Preferably, R" represents C3-4-cycloalkyl, Ci-4-alkyl, Ci-4-alkoxy, -NH2,
methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci-2-alkyl, halo, halo- Ci-2-alkyl, Ci-4-alkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino. More preferably, R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Even more preferably, R" represents methyl or dimethylamino.
In some preferred embodiments of the invention A represents NH or A represents a bond and B represents a 5-membered or 6-membered monocyclic heterocyclic group, comprising at least one nitrogen atom in its ring structure where said nitrogen is positioned so as to form the binding link between A and the rest of the compound of Formula (I).
In some preferred embodiments of the invention A represents NH and B represents - (C=0)R", where R" represents C3-4-cycloalkyl, Ci-4-alkyl, Ci-4-alkoxy, -NH2,
methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. In a preferred embodiment R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Most preferably R" represents methyl or dimethylamino. In some preferred embodiments of the invention A represents NH and B represents sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, trifluoromethyl, cyclopropyl and a 5- or 6-membered monocyclic heterocyclic group. Most preferred R' represents methylsulfonyl.
In preferred embodiments of the invention X! is selected from the group consisting of methoxy, hydroxy, acetyl, trifluoroacetyl, cyclopropylsulfonyl, cyclopropylsulfonyloxy, cyanomethoxy, methylcarbamoyl, dimethylcarbamoyl, dimethylcarbamoyloxy, morpholine-4-carboxylate, COOH, carbamoyl, morpholine-4ylcarbonyl, methylsulfonyl, methylsulfinyl, methylsulfanyl, sulfamoyl, sulfamoyloxy and dimethylsulfamoyl. Most preferably A represents a bond or O.
In preferred embodiments of the present invention A represents a bond and B represents hydroxy, -(C=0)R", -(C=0)NH-R"', sulfonyl, sulfanyl, sulfinyl or sulfamoyl, where R" is selected from the group consisting of hydroxy, methyl, trifluoromethyl, methylamino, dimethylamino and morpholinyl, and where R'" is selected from the group consisting of hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino, and where sulfonyl may be substituted with methyl, cyclopropyl or dimethylaminoethyl, and where sulfanyl may be substituted with methyl, and where sulfinyl may be substituted with methyl, and where sulfamoyl may be substituted with one or two methyl groups.
In a preferred embodiment A represents a bond and B represents hydroxy.
In another preferred embodiment A represents a bond and B represents -(C=0)R", where R" is selected from the group consisting of hydroxy, methyl, trifluoromethyl, hydroxymethyl, NH2, methylamino, dimethylamino and a 5- or 6-membered monocyclic heterocyclic group, and more preferably from a group consisting of hydroxy, methyl, trifluoromethyl, NH2, methylamino, dimethylamino and morpholinyl.
In yet another preferred embodiment A represents a bond and B represents -(C=0)NH- R'", where R'" is selected from the group consisting of hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl,
methanesulfonyl and methoxy optionally substituted with dimethylamino, and more preferably from a group consisting of hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl and methoxy optionally substituted with dimethylamino.
In another preferred embodiment A represents a bond and B represents sulfonyl, which sulfonyl may be substituted with methyl, ethyl, cyclopropyl methylamino,
dimethylamino, methylaminomethyl or dimethylaminoethyl. More preferably sulfonyl may be substituted with methyl, cyclopropyl or dimethylaminoethyl.
In yet another embodiment A represents a bond and B represents sulfanyl, which may be substituted with methyl or ethyl, preferably methyl. In yet another embodiment A represents a bond and B represents sulfinyl, which sulfinyl may be substituted with methyl or ethyl, preferably methyl. In yet another preferred embodiment A represents a bond and B represents sulfamoyi, which sulfamoyi may be substituted with one or two methyl groups.
In other preferred embodiments of the present invention A represents O and B represents methyl, -(C=0)R", sulfonyl, sulfamoyi, where R" represents dimethylamino or morpholinyl, and where methyl optionally is substituted with cyano and where sulfonyl may be substituted with trifluoromethyl or cyclopropyl.
In a preferred embodiment A represents O and B represents methyl, ethyl, propyl or isopropyl, which may optionally be substituted one or two times with a group selected from the group consisting of hydroxy, cyano and NH2. Preferably B represents methyl, which is not substituted or which is substituted one time with cyano.
In another embodiment A represents O and B represents -(C=0)R", where R" represents NH2, methylamino, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, more preferably dimethylamino or morpholinyl.
In yet another preferred embodiment A represents O and B represents sulfonyl, which may be substituted with methyl, hydroxymethyl, trifluoromethyl, ethyl, hydroxyethyl or cyclopropyl. Preferably B represents sulfonyl substituted with trifluoromethyl or cyclopropyl.
In yet another preferred embodiment A represents O and B represents sulfamoyi, which may optionally be substituted with one or two methyl groups. Preferably the sulfamoyi is unsubstituted.
Preferred compounds of formula (I) - X2
The present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)". In particular, the compounds may be compounds for formula (I), wherein X! is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X2 is as described in this section and X3, X4, and X5 are as described in the section "Compounds of formula (I)".
X2 may be selected from the group consisting of carboxyl, amide and nitrile. In a preferred embodiment of the invention X2 is selected from the groups consisting of - (C=0)OH and -(C=0)NH2.
Thus, in a preferred embodiment the invention relates to compounds of the compound of Formula (I)
Figure imgf000027_0001
(I) an isomer or a mixture of isomers thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
Xi represents -A-B, wherein
A represents a bond, O, S, or NH, and B represents
• Ci-6-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3.5 cycloalkyl
which d-e-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3-5 cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci.4-alkoxy, hydroxy-Ci_4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' represents hydroxy, Ci-4-alkyl, C3-5 cycloalkyl, halogen-Ci-4-alkyl, Ci-4- alkoxy, -NH2, methylamino, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group; or
-OH, with the proviso that B only represent -OH, when A is a bond; or
-(C=0)R",
where R" represents hydroxy, halogen-Ci-4-alkyl, Ci-4-alkoxy, hydroxy-Ci-4- alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C3-4-cycloalkyl or Ci-4-alkyl, wherein said C3-4- cycloalkyl or Ci-4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above;
-(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two Ci-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci-4-alkyl, halogen-Ci-4-alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3- alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci.3-alkyl, Ci.3-alkoxy, Ci.3-alkoxyalkoxy, Ci.3-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, cyclopropyl, and C1-3-alkyl, wherein said d-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, cyclopropyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; and
X2 represents -COOH or (C=0)NH2 and
X3 represents
• Hydrogen or -OH; or
Figure imgf000029_0001
where
Y is O, C=0, or a bond; and
Xa is -a bond, Ci-i8-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-i0-cycloalkyl, -Ci-i8-alkyl 0-, -O- or -NXb-; and
Xb is -H, C3-6-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3.i0-cycloalkyl, Ci.6-alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4- alkyl, hydroxy linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4- alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said d-5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci_4-alkoxy, hydroxy-Ci_4-alkoxy, - NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above; and
X4 and X5 independently of each other represent
• hydrogen, C1-4-alkyl, halogen-Ci_4-alkyl, C3-6-cycloalkyl, halogen, nitro, -NH2, methoxycarbonyl, acetyl, methoxycarbamoyl or cyano;
Thus the compounds of the invention may in preferred embodiments of the invention be compounds of formula (I), wherein Xi is as described herein above in the section "Preferred compounds of formula (I) - X/', X2 is -COOH, X3 is as described herein below in the as described herein below in the section "Preferred compounds of formula (I) - X3", X4 and X5 are as described herein below in the section "Preferred compounds of formula (I) - X4 and X5".
In embodiments where X2 is -COOH, this designation is to be understood as also including the carboxylate ion as well as different metal salts that could be formed such as for example sodium carboxylate, potassium carboxylate and ammonium carboxylate salts of the carboxylic acid. A skilled person would know when it is to be expected that the acid group has been dissociated and formed the salt. The dissociation and the formation of metal salt depends on the pH in the adjacent environment and on the availability of cations in the adjacent environment. In another preferred embodiment of the invention the compounds of the invention may be compounds of formula (I), wherein Xi is as described herein above in the section "Preferred compounds of formula (I) - Xi", X2 is -(C=0)NH2, X3 is as described herein below in the as described herein below in the section "Preferred compounds of formula (I) - X3", X4 and X5 are as described herein below in the section "Preferred compounds of formula (I) - X4 and X5".
Preferred compounds of formula (I) - X3
The present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)". In particular, the compounds may be compounds of formula (I), wherein X! is a described herein above in the section "Preferred compounds of formula (I) - X/', and X2 is as described in the section "Preferred compounds of formula (I) - X2" and X3 is as described in this section and X4, and X5 are as described in the section "Compounds of formula (I)".
In one embodiment of the invention X3 is -H. Thus, the compounds of the invention may be compounds of formula (I), wherein Xi is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X2 is as described in the section "Preferred compounds of formula (I) - X2" and X3 is -H and X4, and X5 are as described in the section "Preferred compounds of formula (I)" - X4 and X5".
In another embodiment of the invention X3 is -OH. Thus, the compounds of the invention may be compounds of formula (I), wherein Xi is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X2 is as described in the section "Preferred compounds of formula (I) - X2" and X3 is -OH and X4, and X5 are as described in the section "Preferred compounds of formula (I)" - X4 and X5".
However, in other very preferred embodiments of the invention X3 represents -Y-Xa-Xb, wherein Y, Xa and Xb are as defined herein above in the section "Compounds of formula (I)", with the proviso that when Y is -O, then Xa is not -0-. Thus, the compounds of the invention may be compounds of formula (I), wherein X3 represents - Y-Xa-Xb, wherein Y is O, C=0, or a bond and Xa is d-e-alkyl, -d_6-alkyl-0- or -O- and Xb is H, Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci.6-alkoxy, phenyl, phenoxy, a 5 or 6 membered
heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen-d-4alkyl, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl. "
Thus, the compound of the invention may be a compound of formula (I), wherein X3 represents -Y-Xa-Xb, wherein Y is O, C=0 or a bond and Xa is Ci-3-alkyl, C3-4-cycloalkyl, or -Ci-2-alkyl-O- and Xb is H, Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heteroaromatic ring or a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group, which Ci.6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heteroaromatic ring or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl.
X3 may represent -Y-Xa-Xb, wherein Y is -O-or C=0 and Xa is C1- 8-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-i o-cycloalkyl, -O- or -NXb- and Xb is -H, C3-6-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3-i o- cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, linear or branched Ci-4-alkoxy, Ci-6- alkoxyalkoxy, Ci-4-alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2,
methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl,
dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R\ a halogen- phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined herein above in the section "Compounds of formula (I)". X3 may also represent -Y-Xa-Xb, wherein Y is O, or C=0 and Xa is C1-6-alkyl or -Ci-6- alkyl-O- and Xb is H, Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen- Ci-4alkyl, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl. Preferably, X3 represents -0-Xa-Xb,and Xa is Ci-is-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3. io-cycloalkyl or -NXb- and Xb is -H, C3.6-cycloalkyl, Ci.6-alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3.6-cycloalkyl, Ci.6-alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci_4- alkyl, linear or branched Ci_4-alkoxy, Ci.6-alkoxyalkoxy, Ci_4-alkoxycarbonyl, Ci-4- alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said C s alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci-4- alkoxy, hydroxy-Ci_4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined herein above in the section "Compounds of formula (I)".
In a preferred embodiment X3 represents -0-Xa-Xb, where Xa is -a bond, Ci-i8-alkyl, C2. 18-alkenyl, C2.i8-alkynyl, C3.i0-cycloalkyl or -NXb-; and Xb is -H, C3.6-cycloalkyl, Ci-6- alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, which Ci-6-alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of linear or branched C1-5-alkyl, Ci-6-alkoxycarbonyl, Ci-4-alkylcarbonyl, -OH, linear or branched Ci-6- alkoxy or halogen.
In a very preferred embodiment of the invention X3 represents -0-Xa-Xb, wherein Xa is Ci-6-alkyl or -Ci-6-alkyl-0- and Xb is H, Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen- Ci-4alkyl, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl.
Said 5 or 6 membered heteroaromatic ring may preferably comprise 1 , 2 or 3 heteroatoms each independently selected among N, O, and S, more preferably comprise 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprise 1 or 2 heteroatoms each independently selected among N or O. Said bicyclic heterocyclic group may preferably comprise 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S, more preferably comprise 1 or 2 heteroatoms each independently selected among N, O, and S, even more preferably comprise 1 or 2 heteroatoms each independently selected among N or O.
Preferably, the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3- oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl. Very preferably the 5 membered heteroaromatic ring is oxazolyl, preferably, 1 ,3-oxazolyl.
Preferably, the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H- thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl. Very preferably, the 6 membered heteroaromatic ring is pyridinyl.
Said bicyclic heterocyclic group may consist of a 5-membered heterocyclic group and a 6-membered carbocyclic group, a 6-membered heterocyclic group and a 6-membered carbocyclic group, a 5-membered carbocyclic group and a 6-membered heterocyclic group, or a 5-membered heterocyclic group and a 6-membered heterocyclic group. In yet other embodiments the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups. In a very preferred embodiment the bicyclic heterocyclic group is imidazolyl.
In very preferred embodiments of the invention X3 is selected from the group consisting of -H, hydroxyl, methoxy, phenylethoxy, pyridine-3-ylethoxy, pyridine-3ylmethoxy, ethoxyphenyl-4-ethoxy, ethoxypyridinethoxy, propan-2yloxy-phenylethoxy,
ethoxyphenylmethoxy, diethyl-imidazol-ethoxy, 5-methyl-1 ,3-oxazol-2ylpropoxyl, 2- tertbutyl-1 ,3-oxazol-5ylmethoxy and 3-chloro-phenoxyethoxymethyl. In other preferred embodiments of the present invention X3 represents -Y-Xa-Xb, where
Y represents O.
In other preferred embodiments of the present invention X3 represents -Y-Xa-Xb, where Y represents O and Xa represents Ci-6-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. More preferred Xa represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, and even more preferred Xa represents methyl, ethyl, propyl or isopropyl.
In other preferred embodiments of the present invention X3 represents -Y-Xa-Xb, where
Y represents O and Xa represents Ci.6-alkyl, and Xb represents Ci.6-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group. Preferably the 5-membered monocyclic heterocyclic group, or 6- membered monocyclic heterocyclic group is selected among pyridinyl, imidazolyl and oxazolyl. In some of the preferred embodiments the Ci.6-alkoxy, phenyl, phenoxy, 5 or a 6-membered monocyclic heterocyclic group may be substituted with one or two substituents, which independently of each other is selected from the group consisting of methyl, ethyl, isopropyl, tert.-butyl, chloro, fluoro, methoxy, ethoxy and propoxy. Preferably, the phenyl, phenoxy, 5 or a 6-membered monocyclic heterocyclic group may be substituted with one or two substituents, which independently of each other is selected from the group consisting of methyl, tert.-butyl, chloro, ethoxy and propoxy.
In very preferred embodiments of the present invention X3 represents -Y-Xa-Xb, where Y represents O and Xa represents methyl, ethyl, propyl or isopropyl, and Xb represents phenyl, phenoxy, pyridinyl, imidazolyl or oxazolyl, which phenyl, phenoxy, pyridinyl, imidazolyl or oxazolyl may substituted with one or two substituents, which
independently of each other is selected from the group consisting of methyl, tert.-butyl, chloro, ethoxy and propoxy.
Preferred compounds of formula (I) - X4 and X5
The present invention relates to compounds of formula (I) as described herein above in the section "Compounds of formula (I)". In particular, the compounds may be compounds of formula (I), wherein X! is a described herein above in the section "Preferred compounds of formula (I) - X/', and X2 is as described in the section "Preferred compounds of formula (I) - X2", X3 is as described in the section "Preferred compounds of formula (I) - X3", and X4, and X5 are as described in this section.
In some embodiments of the present invention X4 and X5 represents independently of each other hydrogen, Ci-4-alkyl, halo-Ci-4-alkyl, C3-6-cycloalkyl, halo, nitro, -NH2, methoxycarbonyl, acetyl, methoxycarbamoyi or cyano. In another embodiment X4 and X5 are each independently selected from the group consisting of hydrogen, Ci-4-alkyl, C3-6-cycloalkyl. In one embodiment X4 and X5 both represents hydrogen. In another embodiment X4 represents hydrogen and X5 is selected from the group consisting of d-4-alkyl, C3-6-cycloalkyl. In yet another embodiment X5 represents hydrogen and X4 is selected from the group consisting of Ci-4-alkyl, C3-6-cycloalkyl. In other preferred embodiments X4 represents methyl, and in other preferred embodiments X5 represents methyl. In one preferred embodiment of the invention X4 and X5 are both -H. Thus, the compounds of the invention may be compounds of formula (I), wherein X! is a described herein above in the section "Preferred compounds of formula (I) - Xi", and X2 is as described in the section "Preferred compounds of formula (I) - X2" and X3 is are as described in the section "Preferred compounds of formula (I)" - X3" and X4, and X5 are -H.
Very preferred compounds of Formula (I)
Thus very preferred compounds according to the invention are compounds of formula (I), wherein
Xi represents A-B, wherein A is O and B is
• d-e-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3-5 cycloalkyl,
which d-e-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3.5 cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3.6-cycloalkyl, Ci.4-alkoxy, hydroxy-Ci.4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' represents hydroxy, Ci-4-alkyl, halogen-Ci-4-alkyl, Ci-4-alkoxy, -NH2, methylamino, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group; or
-OH; or or -(C=0)R",
where R" represents hydroxy, halogen-Ci-4-alkyl, Ci-4-alkoxy, hydroxy-Ci-4- alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, Ci-4-cycloalkyl or Ci-4-alkyl, wherein said Ci-4- cycloalkyl or Ci-4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; or
-(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two Ci-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci-4-alkyl, halogen-Ci-4-alkyl, carbonyl-Ci-3-alkyl , methylsulfamoyl, C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3- alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; or • a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci.3-alkyl, Ci.3-alkoxy, Ci.3-alkoxyalkoxy, Ci.3-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, cyclopropyl and C1-3-alkyl, wherein said cyclopropyl or d-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, cyclopropyl, d_ 3-alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; and X2 represents -COOH or (C=0)NH2; and
X3, represents
• Hydrogen or -OH; or · -Y-Xa-Xb, where
Y is O, C=0 or a bond; and
Xa is -a bond, C - 8-alkyl, C2-i8-alkenyl, C2.i8-alkynyl, C3-i0-cycloalkyl, -C1 18-alkyl- 0-, -O- or -NXb-; and
Xb is -H, C3-6-cycloalkyl, Ci-6-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3-i0-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4- alkyl, hydroxy linear or branched d-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4- alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, - NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above; and X4 and X5 are -H.
Very preferred compounds of the invention may be selected from the group consisting of: 3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-methoxypyrido[1 ,2-a]indole-10-carboxamide;
3-hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetylpyrido[1 ,2-a]indole-10-carbonitrile;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxamide;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carbonitrile;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carbonitrile;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-cyanopyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate; 1 -(2-phenylethoxy)-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(2-phenylethoxy)-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoyl-1 -(2-phenylethoxy)pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -[2-(4-ethoxyphenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[2-(4-ethoxyphenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -[2-(4-ethoxyphenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 1 -[2-(3-ethoxyphenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[2-(3-ethoxyphenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -[2-(3-ethoxyphenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile; 1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid; 1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 1 -[2-(6-ethoxypyridin-3-yl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(6-ethoxypyridin-3-yl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -[2-(6-ethoxypyridin-3-yl)ethoxy]pyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole- 10-carboxylic acid; 10-carbamoyl-1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(4-ethoxyphenyl)methoxy-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(4-ethoxyphenyl)methoxy-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -(4-ethoxyphenyl)methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -(3-ethoxyphenyl)methoxy-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(3-ethoxyphenyl)methoxy-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -(3-ethoxyphenyl)methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2- a]indole-10-carboxylic acid;
10-carbamoyl-1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carbonitrile;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylic acid;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxamide;
1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile; 1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 1 -(2-phenylethoxy)-7-methyl-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -(2-phenylethoxy)-3-[(dimethylcarbamoyl)oxy]-7-methyl-pyrido[1 ,2-a]indole-10- carboxylic acid;
7-methyl-10-carbamoyl-1 -(2-phenylethoxy)pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -{[2-(3-chlorophenoxy)ethoxy]methyl}pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -{[2-(3-chlorophenoxy)ethoxy]methyl}-3-[(dimethylcarbamoyl)oxy]-pyrido[1 ,2-a]indole- 10-carboxylic acid;
10-carbamoyl-1 -{[2-(3-chlorophenoxy)ethoxy]methyl}pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; pyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-carbamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indole-3-carboxylic acid;
pyrido[1 ,2-a]indole-3,10-dicarboxamide;
N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxamide;
N3-methylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-sulfamoylpyrido[1 ,2-a]indole-10-carboxamide;
3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 ,3-dihydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-hydroxy-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(cyclopropylsulfonyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(cyclopropylsulfonyl)oxy]-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxy-3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -methoxy-3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(dimethylcarbamoyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid; 3-[(dimethylcarbamoyl)oxy]-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxy-3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -methoxy-3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-3-carboxylic acid;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-3-carboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -hydroxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 ,3-dihydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-hydroxy-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl cyclopropanesulfonate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl cyclopropanesulfonate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl sulfamate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl sulfamate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
3-(cyanomethoxy)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-(cyanomethoxy)-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxamide;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
pyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-carbamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid; 3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -hydroxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylic acid;
3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carbonitrile;
10-cyanopyrido[1 ,2-a]indol-3-yl trifluoromethanesulfonate; and
3-(methanesulfonylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid.
Even more preferred compounds according to the invention may be selected from the group consisting of;
3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid; and
3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid. Definition of substituents
The term "alkyl" as used herein refers to a saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains of from one to eighteen carbon atoms (Ci-i8-alkyl), more preferred of from one to six carbon atoms (Ci-6-alkyl), including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a Ci_4-alkyl group, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention alkyl represents a Ci_2-alkyl group, which includes methyl and ethyl.
The term "cycloalkyl" as used herein refers to a cyclic alkyl group, preferably containing of from three to eight carbon atoms (C3.8-cycloalkyl), preferably of from three to six carbon atoms (C3.6-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In preferred embodiments, the cycloalkyl is cyclopropyl. Furthermore, the term "cycloalkyl" as used herein may also include polycyclic groups such as for example bicycle[2.2.2]octyl and cubyl.
The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes. In a preferred embodiment the alkenyl group of the invention comprises of from two to eighteen carbon atoms (C2-i8-alkenyl), whereas in other preferred embodiments the alkenyl group of the invention comprises of from two to eight carbon atoms (C2.8- alkenyl), more preferred of from two to four carbon atoms (C2-4-alkenyl) including at least one double bond. Examples of preferred alkenyl groups of the invention include ethenyl; 1 - or 2-propenyl; 1 -, 2- or 3-butenyl, or 1 ,3- butenyl; 1 -, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexenyl, or 1 ,3, 5-hexenyl; 1 -, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 ,3-octenyl, or 1 ,3,5-octenyl, or 1 ,3,5,7-octenyl.
The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group of the invention comprises of from two to eighteen carbon atoms (C2-i8-alkynyl), whereas in other preferred embodiments the alkynyl group of the invention comprises of from two to eight carbon atoms (C2-s- alkynyl), more preferred of from two to four carbon atoms (C2-4-alkynyl) including at least one triple bond. Examples of preferred alkynyl groups of the invention include ethynyl; 1 - or 2-propynyl; 1 -, 2- or 3-butynyl, or 1 ,3-butynyl; 1 -, 2-, 3-, 4- or 5-hexynyl, or 1 ,3-hexynyl, or 1 ,3, 5-hexynyl; 1 -, 2-, 3-, 4-, 5-, 6-, or 7-octynyl, or 1 ,3-octynyl, or 1 ,3,5-octynyl, or 1 ,3,5,7-octynyl.
The term "halogen" as used herein refers to fluoro, chloro, bromo or iodo. Thus a trihalogenmethyl group represents e.g. a trifluoromethyl group, or a trichloromethyl group. Preferably, the term "halogen" designates fluoro or chloro.
The term "halogenalkyl" as used herein refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with one or more halogen. Preferred halogenalkyl groups of the invention include trihalomethyl, preferably trifluoromethyl.
The term "alkoxy" as used herein refers to an "alkyl-O-" group, wherein alkyl is as defined above.
The term "hydroxyalkoxy" as used herein refers to an alkoxy group as defined herein, which alkoxy group is substituted one or more times with hydroxy. Examples of hydroxyalkoxy groups include HO-CH2-0- and CH3-CH2OH-O-.
The term "alkoxycarbonyl" as used herein refers to an "alkyl-O-(CO)-" group, wherein alkyl is as defined above.
The term "oxoalkyl" as used herein refers to an "alkyl-(CO)-" group, wherein alkyl is as defined above.
The term "5-membered monocyclic heterocyclic group" as used herein refers to a 5- membered monocyclic group holding one or more heteroatoms in its ring structure.
Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). Examples of 5-membered monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl,
imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl. Examples of preferred 5-membered monocyclic heterocyclic groups include pyrrolidinyl, pyrazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2- thiazolyl and 1 ,3-thiazolyl.
The term "6-membered monocyclic heterocyclic group" as used herein refers to a 6- membered monocyclic group holding one or more heteroatoms in its ring structure.
Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). Examples of 6-membered monocyclic heterocyclic groups include piperidinyl, pyridinyl, oxanyl, 2-H- pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4- oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl. Examples of preferred 6- membered monocyclic heterocyclic groups include piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, and morpholinyl.
The term "bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered carbocyclic group" as used herein refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic hydrocarbon group. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). Examples of bicyclic heterocyclic groups consisting of a 5-membered heterocyclic group and a 6- membered carbocyclic group include benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl and benzotriazolyl.
The term "bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6-membered carbocyclic group" as used herein refers to a heterocyclic ring system derived by fusion of a 6-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic hydrocarbon group. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). Examples of bicyclic heterocyclic groups consisting of a 6-membered heterocyclic group and a 6- membered carbocyclic group include quinolinyl, isoquinolinyl, chromayl, isochromanyl, 4H-chromenyl, 1 H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl.
The term "bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6-membered heterocyclic group" as used herein refers to a heterocyclic ring system derived by fusion of a 5-membered carbocyclic group with a 6-membered monocyclic group holding one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S).
The term "bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group" as used herein refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group holding one or more heteroatoms in its ring structure with a 6-membered monocyclic group holding one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). A preferred example of a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group includes purinyl or imidazolyl.
The term "bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups" as used herein refers to a heterocyclic ring system derived by fusion of two 6- membered monocyclic group each holding one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). Examples of bicyclic heterocyclic groups consisting of two 6-membered heterocyclic groups include naphthyridinyl and pteridinyl. The term "bicyclic heterocyclic group consisting of a 5-membered group and a 6- membered group sharing a heteroatom" as used herein refers to a heterocyclic ring system derived by fusion of a 5-membered monocyclic group and a 6-membered monocyclic group, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). A preferred example of a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom includes indolizinyl.
The term "bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom" as used herein refers to a heterocyclic ring system derived by fusion of two 5-membered monocyclic groups, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). A preferred example of a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom includes 1 H-pyrrolizinyl. The term "bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom" as used herein refers to a heterocyclic ring system derived by fusion of two 6-membered monocyclic groups, said ring system holding at least one heteroatom in its ring structure at a position where the two cyclic groups share said at least one heteroatom. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulphur (S). A preferred example of a bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom includes 4H-quinolizinyl. The term "aryl", as used herein, unless otherwise indicated, includes carbocyclic aromatic ring systems derived from an aromatic hydrocarbon by removal of a hydrogen atom. Aryl furthermore includes bicyclic ring systems. Examples of preferred aryl moieties to be used with the present invention include, but are not limited to phenyl, naphthyl, indenyl, and fluorenyl. Preferred "aryl" is phenyl, naphthyl or indanyl, unless otherwise stated. Any aryl used in the present invention may be optionally substituted.
The term "Heteroaryl", as used herein, refers to aromatic groups containing one or more heteroatoms selected from O, S, and N, preferably from one to four heteroatoms, and more preferably from one to three heteroatoms. Heteroaryl furthermore includes multicyclic groups, wherein at least one ring of the group is aromatic, and at least on of the rings contains a heteroatom selected from O, S, and N. Heteroaryl also include ring systems substituted with one or more oxo moieties. Examples of preferred heteroaryl moieties to be used with the present invention include, but are not limited to phenyl, biphenyl, indenyl, naphthyl, N-hydroxytetrazolyl, N-hydroxytriazolyl, N- hydroxyimidazolyl, anthracenyl, phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydro- benzo[b]thiophenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, quinolyl, carbazolyl, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, azaindolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, pyrazolinyl, and pyrazolidinyl. Non-limiting examples of partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, and 1 -octalin. Isomers
The compounds of the invention may exist as geometric isomers (i.e. cis-trans isomers), optical isomers or stereoisomers, such as diastereomers, as well as tautomers. Accordingly, the invention includes all cis-trans isomers, stereoisomers and tautomers including racemic mixtures of these and pharmaceutically acceptable salts thereof, especially all R- and S- isomers in any ratio. Diastereoisomers, i.e.,
nonsuperimposable stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization or sublimation. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Examples of suitable bases include, without limitation, brucine, sparteine and oc- methylbenzylamine. The mixture of diastereomers can be separated by crystallization followed by liberation of the optically active acids or bases from these salts. An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of the invention, preferably compounds of Formula (I), with an optically pure acid in an activated form or an optically pure isocyanate. Alternatively, compounds of Formula (I) bearing an acidic function can be activated and reacted with an optically pure compound like an alcohol or an amine. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound. The optically active compounds of the invention, preferably compounds of formula (I), can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. Examples of chiral separation techniques are given in Chiral Separation Techniques, A Practical Approach, 2 ed. by G. Subramanian, Wiley-VCH, 2001 .
Pharmaceutically acceptable salts
The compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically acceptable salts, solvates and prodrugs of the compound of Formula (I).
Pharmaceutically acceptable salts refer to salts of the compounds of the invention, which are considered to be acceptable for clinical and/or veterinary use. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the invention with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively. It will be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmaceutically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. These salts may be prepared by methods known to the skilled person.
Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and
galacturonic acid; and arylsulfonic, for example benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid; and base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts.
Methods of preparation
General synthesis The compounds of this invention may be prepared as described in the following. Useful steps that may be used in the preparation steps of the compounds will be known to the skilled person. The methods below are given as non-limiting examples on how the compounds may be prepared.
Method A through F shows the preparation of the compounds of this invention. Useful methods for the generation of intermediates are described afterwards.
Preparation of Compounds of Formula (I)
Method A for the preparation of compounds of formula I
Scheme 1
Figure imgf000052_0001
The compound of Formula (I) may be prepared according to scheme 1 by use of a suitable solvent, such as DMF or THF, a base such as sodium hydride or cesium carbonate and a suitable electrophilic species such as an epoxide, a heteroaromatic chloride, an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride. A purification method such as silica gel chromatography may be employed if needed.
Method B for the preparation of compounds of Formula (I)
Scheme 2
Figure imgf000052_0002
The compound of formula (I) may be prepared according to Scheme 2. Using a suitable solvent such as DMF, DMSO or THF and a base such as an alkaline metal hydroxide, compounds of Formula (I) may be generated by mixing at elevated temperature.
Preferaby said elevated temperature is a temperature slightly above room temperature, such as in the range of 2 to 10°C above room temperature. Mixing is preferably done for a few hours, such as in the range of 2 to 5 hours. A purification method such as acid-base extraction may be used if necessary, and the compounds may be
precipitated from an aqueous phase.
Method C for the preparation of compounds of formula I
Scheme 3
Figure imgf000053_0001
Compounds of Formula (I) may be prepared according to scheme 3 by use of a suitable solvent such as THF, a suitable catalyst such as palladium tetrakis
triphenylphosphine and a suitable nucleophile such as a secondary amine. The compounds of Formula (I) may be generated according to Scheme 3 by mixing at a temperature slightly below room temperature, such as in the range of 2 to 10°C below room temperature, followed by warming to room temperature for a few hours, such as for 2 to 5 hours. A purification method such as acid-base extraction or chromatography may be used if necessary. Method D for the preparation of compounds of formula I
Scheme 4
Figure imgf000053_0002
Compounds of Formula (I) may be prepared according to Scheme 4 using a suitable solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a suitable catalyst such as Pd2(dba)3, optionally a suitable salt such as lithium chloride and the desired nucleophile such as an amine, carbon monoxide, an ethanethionate, or an organometallic. The compounds of Formula I are generated at room temperature or by heating for several hours, such as for 2 to 5 hours. A purification method such as silica gel chromatography may be employed if needed.
Method E for the preparation of compounds of formula I
Scheme 5
Figure imgf000054_0001
Compounds according to Formula (I) may be prepared using a suitable solvent such as DMF or THF, a base such as a hindered tertiary amine, a suitable dehydrating agent such as EDCI or DCC and ammonia. The compounds of Formula (I) are generated by mixing at or above room temperature (such as 2 to l O 'C above room temperature) for a several hours, such as for 2 to 5 hours. A purification method such as silica gel chromatography may be employed if needed.
Method F for the preparation of compounds of formula I
Scheme 6
Figure imgf000054_0002
The compounds of Formula (I) may be prepared according to Scheme 6. An acid chloride of the compound is added, optionally dissolved in a suitable solvent such as THF, into a rapidly mixing aqueous ammonia solution, and the compound according to Formula (I) precipitates out. A purification method such as silica gel chromatography may be employed if needed.
Method G for the preparation of compounds of Formula (I)
Scheme 7
Figure imgf000055_0001
The compound of Formula (I) may be prepared according to scheme 7 by use of a solvent such as DMF or THF, a base such as a hindered tertiary amine, a dehydrating agent such as EDCI or DCC and the desired amine, and by mixing at or above room temperature for several hours. A purification method such as silica gel
chromatography is employed if needed. Method H for the preparation of compounds of formula I
Scheme 8
Figure imgf000055_0002
The compound of Formula (I) may be prepared according to scheme 8 by use of a suitable solvent, such as ethanol, DMF or THF, a base such as sodium hydroxide and a suitable electrophilic species such as an aliphatic, allylic or benzylic bromide, chloride or sulfonate, or a carbonyl chloride. A purification method such as silica gel chromatography may be employed if needed.
Preparation of intermediates
Intermediate 1 cheme 9
Figure imgf000056_0001
Intermediate 1 , in which X3 represents hydrogen or methoxy, can be prepared according to scheme 9 by using an acidic solvent such as acetic acid. Intermediate 1 forms at a temperature varying from below room temperature to boiling, depending on X3. A silica filtration can be done if necessary. When X3 is methoxy, this group can be elaborated into the various representations of X3 by methods known to those skilled in the art. Pharmaceutical compositions
In one aspect of this invention, there is provided a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent. Said compound according to the invention is preferably the compounds according to Formula (I) described herein above. Pharmaceutical compositions according to the invention may even comprise a compound selected from the group consisting of
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-methylphenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-(trifluoromethyl)phenyl]methoxy]-;
Acetic acid, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-, ethyl ester;
Acetamide, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(cyanomethoxy)-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-hydroxy-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-bromophenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(3-cyanophenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(phenylmethoxy)-; and
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-methoxy-. Such pharmaceutical compositions are useful for treatment of a HDME dependent disease. The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 st Edition, 2000, Lippincott Williams & Wilkins.
The pharmaceutical compositions formed by combining a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, with pharmaceutically acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injectable solutions and the like. In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The pharmaceutical compositions may be specifically prepared for administration by any suitable route such as the oral and parenteral (including subcutaneous,
intramuscular, intrathecal, intravenous and intradermal) route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be prepared so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
For oral administration in the form of a tablet or capsule, a compound of Formula (I) may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like. Furthermore, suitable binders, lubricants, disintegrating agents, flavouring agents and colourants may be added to the mixture, as appropriate. Suitable binders include, e.g., lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like. Lubricants include, e.g., sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Disintegrating agents include, e.g., starch, methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, croscarmellose sodium or the like. Additional excipients for capsules include macrogols or lipids. For the preparation of solid compositions such as tablets, the active compound of
Formula (I) is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid preformulation composition containing a homogenous mixture of a compound of Formula (I). The term "homogenous" is understood to mean that the compound of Formula (I) is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules.
Liquid compositions for either oral or parenteral administration of the compound of the invention include, e.g., aqueous solutions, syrups, elixirs, aqueous or oil suspensions and emulsion with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrolidone.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. For parenteral administration, solutions containing a compound of this invention or a pharmaceutically acceptable salt, solvate or prodrug thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is preferred to use parenteral administration for compounds of the invention, wherein the active part of the molecule contains acid labile groups, such as e.g. ester groups. By using parenteral administration the acidic environment of the stomach is avoided together with the first-pass metabolism. When compounds of the invention is prepared as a prodrug, which relies on the first-pass metabolism for releasing the active part of the molecule, oral administration is preferred instead (or another appropriate administration form which result in a first-pass metabolism).
Depot injectable compositions are also contemplated as being within the scope of the present invention. In addition to the aforementioned ingredients, the compositions of a compound of
Formula (I) may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like. A suitable dosage of the compound of the invention will depend on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practicing physician. The compound may be administered for example either orally, parenterally or topically according to different dosing schedules, e.g. daily or with intervals, such as weekly intervals. In general a single dose will be in the range from 0.01 to 100 mg/kg body weight, preferably from about 0.05 to 75 mg/kg body weight, more preferably between 0.1 to 50 mg/kg body weight, and most preferably between 0.1 to 25 mg/kg body weight. The compound may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or more times a day. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration.
The compounds of the invention may also be prepared in a pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses. The suitable pharmaceutically acceptable carriers, diluents and excipients are as described herein above, and the one or more further active substances may be any active substances, or preferably an active substance as described in the section "combination treatment" herein below.
Clinical conditions and other uses of compounds
The compounds according to Formula (I) as defined herein are useful for treatment of a HDME dependent disease. The treatment may include administering to a mammal, preferably a human, more preferably a human suffering from a HDME dependent disease, a therapeutically effective amount of a compound according to Formula (I) as defined herein.
Said HDME may be any HDME, however preferably the HDME of the present method is selected from the JmjC (Jumonji) family, as described in Cloos et. al., Genes & Development 22, 1 1 15-1 140, 2008, which is incorporated herein by reference in its entirety. More preferably said HDME is a HDME of the human JmjC family. In a further embodiment, the HDME of the method is selected from the JmjC sub-family consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, more preferably from the group consisting of human GASC1 (JMJD2C), human JMJD2A, human JMJD2B, human JMJD2D and human JMJD2E. In one preferred embodiment said HDME is GASC1 of SEQ ID NO:1 .
Thus, in a preferred embodiment of the invention said HDME dependent disease is a disease dependent on at least one HDME selected from the group consisting of the JmjC family, preferably from the human JmjC family, even more preferably from the group consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, yet more preferably from the group consisting of human GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E.
The present invention also relates to a compound of Formula (I), as defined herein, in a method for inhibiting HDMEs. The method includes contacting a cell with any of the compounds of the present invention. In a related embodiment, the method further provides that the compound is present in an amount effective to produce a
concentration sufficient to selectively inhibit the demethylation of a histone in the cell. The present invention also relates to a compound of Formula (I), as defined herein, for treatment of a proliferative or hyperproliferative disease, such as cancer. In embodiments related to these uses and methods, the disease to be treated is a HDME dependent disease. By the term "HDME dependent disease" is meant any disease characterized by elevated HDME expression and/or activity in at least in some instances of the disease. Thus, the disease to be treated with the inhibitors of HDME according to the invention may be a proliferative or hyperproliferative disease, which includes benign or malignant tumors, for example a proliferative or hyperproliferative disease selected from the group consisting of a carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (for example gastric tumors), ovaries, esophagus, colon, rectum, prostate, pancreas, lung, vagina, thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, for example, colon carcinoma or colorectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation, for example, psoriasis, prostate hyperplasia, a neoplasia, including a neoplasia of epithelial character, including mammary carcinoma, and a leukemia.
In one embodiment, the compound of Formula (I) of the present invention is useful in the treatment of one or more cancers. The term "cancer" refers to any cancer caused by the proliferation of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. In particular, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:
bronchogenic carcinoma, (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcfnoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcorna, gliomatosis), brain
(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli- Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic
lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In one embodiment, the compound of Formula (I) of the present invention are useful in the treatment of one or more cancers selected from the group consisting of: leukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T- cell lymphotrophic virus (HTLV) such as adult T- cell leukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primary central nervous system (CNS) lymphoma; multiple myeloma; childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, liver cancer and thyroid cancer.
In another very preferred embodiment, the compound of Formula (I) of the present invention is useful for the treatment of squamous cell carcinomas. Preferably said squamous cell carcinomas are cancers of the carcinoma type of squamous epithelium that may occur in many different organs, including the skin, lips, mouth, esophagus, urinary bladder, prostate, lungs, vagina, and cervix; brain cancer, that is
neuroblastoma, glioblastoma and other malignant and benign brain tumors; and breast cancer. In yet another embodiment, the compound of Formula (I) of the present invention are useful for treatment of brain cancer, tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), and breast cancer. Other cancer forms for which the compounds of the present invention are useful as treatment can be found in Stedman's Medical Dictionary (Lippincott Williams & Wilkins, 28th Ed., 2005), which is incorporated herein by reference in its entirety.
In still another related embodiment, the disease to be treated by compounds of Formula (I) of the present invention is selected from persistent proliferative or hyperproliferative conditions such as angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, e.g., stent-induced restenosis; endometriosis; Hodgkin's disease; leukemia; hemangioma; angiofibroma; eye diseases, such as neovascular glaucoma; renal diseases, such as glomerulonephritis; malignant nephrosclerosis; thrombotic microangiopathic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; mesangial cell-proliferative diseases; injuries of the nerve tissue; and inhibiting the re-occlusion of vessels after balloon catheter treatment, for use in vascular prosthetics or after inserting mechanical devices for holding vessels open, such as, e.g., stents, as immunosuppressants, as an aid in scar- free wound healing, and treating age spots and contact dermatitis.
In certain embodiments, the invention provides a pharmaceutical composition comprising any of the compounds of Formula (I) of the present invention and one or more pharmaceutically acceptable carrier(s) or excipient(s). The compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating cellular proliferative or hyperproliferative ailments and/or ailments associated with disregulated gene expression. The pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like. The phrase, "pharmaceutically effective amount" or
"therapeutically effective amount" as used herein indicates an amount necessary to administer to a host, or to a cell, tissue, or organ of a host, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect, for example an antitumor effect, e.g. reduction of or preferably inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells, or of any other HDME dependent disease.
Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of Formula (I) of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with at least one further anti-neoplastic compound, and a pharmaceutically acceptable carrier or diluent.
Method of treatment
In a further aspect the present invention relates to a method of treating diseases in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein, to a subject in need of such treatment. The disease may be any disease or disorder as mentioned herein, such as for example mentioned in the section "HDME dependent diseases", and the compound may be administered alone or in a pharmaceutical composition, such as for example mentioned in the section "Pharmaceutical compositions".
The term "treating" and "treatment", as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the process of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition and includes the administration of a compound of Formula (I) to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder. Preferably treatment is curative or ameliorating.
In a preferred embodiment of this aspect of the invention the method is a method of treating a HDME dependent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein, to a subject in need of such treatment. The HDME dependent disease may be any HDME dependent disease as described herein above. Preferably the HDME dependent disease is squamous cell carcinomas. In one embodiment of the method of treatment of a HDME dependent disease according to the invention, the compound of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, as defined herein, is administered in combination with one or more further active substances. The active substances may be any active substances, and preferably an active substance as described herein above in the section "combination treatment". More preferably the one or more additional active substances are selected from the group consisting of anti-proliferative or antineoplastic agents.
Combination treatment
A compound of the present invention may also be used to advantage in combination with one or more other anti-proliferative or anti-neoplastic agents. Such antiproliferative agents include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase;
gonadorelin agonists; anti-androgens; angiostatic steroids; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMOD AL(R)); leucovorin; immune stimulating agents, such as BCG, IL-2 or IFN-a , antibodies, such as rituximab or herceptin and cancer vaccines.
A compound of Formula (I) of the present invention may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or tumor cell damaging approaches, especially ionizing radiation.
A compound of Formula (I) of the present invention may also be used as a
radiosensitizer, including, for example, the treatment of tumors which exhibit poor sensitivity to radiotherapy. By the term "combination", is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
The phrase, "aromatase inhibitor" as used herein relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non- steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN. Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
The term "antiestrogen" as used herein relates to a compound that antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors. The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g., as disclosed in US 4,636,505. The phrase, "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX. Abarelix can be formulated, e.g., as disclosed in US 5,843,901 . The phrase, "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecan and its analogues, 9- nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in W099/ 17804). Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR. Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN. The phrase, "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g.,
CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS. Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL. Doxorubicin can be
administered, e.g., in the form as it is marketed, e.g., under the trademark
ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN. Idarubicin can be
administered, e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS. Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.
The phrase, "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to taxanes, e.g., paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, including vinblastine sulfate, vincristine including vincristine sulfate, and vinorelbine,
discodermolides, cochicine and epothilones and derivatives thereof, e.g., epothilone B or D or derivatives thereof. Paclitaxel may be administered e.g., in the fo[pi]n as it is marketed, e.g., TAXOL. Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark
VINBLASTIN R.P. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN. Discodermolide can be obtained, e.g., as disclosed in US 5,010,099. Also included are Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929, WO 98/08849, WO
99/43653, WO 98/22461 and WO 00/31247. Included are Epothilone A and/or B.
The phrase, "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN. The phrase, "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit at least one example of the class of enzymes known as a histone deacetylase, and which compounds generally possess antiproliferative activity.
Previously disclosed HDAC inhibitors include compounds disclosed in, e.g., WO 02/22577, including N-hydroxy-3-[4-{[(2-hydroxyethyl)[2-(IH-indol-3-yl)ethyl]- amino]methyl]phenyl]-2E-2- propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-IH-indol-3-yl)- ethylJ-amino]methyl]phenyl]-2E-2- propenamide and pharmaceutically acceptable salts thereof. It further includes Suberoylanilide hydroxamic acid (SAHA). Other publicly disclosed HDAC inhibitors include butyric acid and its derivatives, including sodium phenylbutyrate, thalidomide, trichostatin A and trapoxin.
The term "antineoplastic antimetabolite" includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA. Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR. Also included is the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.
The phrase, "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.
Tumor cell damaging approaches refer to approaches such as ionizing radiation. The phrase, "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See, e.g., Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993). The phrase, "angiostatic steroids" as used herein refers to agents which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 1 1 -[alpha]- epihydrocotisol, cortexolone, 17[alpha]-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
Other chemotherapeutic agents include, but are not limited to, plant alkaloids, hormonal agents and antagonists; biological response modifiers, preferably
lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; or miscellaneous agents or agents with other or unknown mechanism of action.
The structure of the active agents identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of the present invention, can be prepared and administered as described in the art such as in the documents cited above.
Examples
The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting to the scope of the present invention.
Example 1
Preparatory example
HPLC methods used for characterisation of compounds:
Standard method (3 min)
MET/CR/1278
Standard 3.5 min method
Column Atlantis dC18
2.1 x 50mm, 5μηι column
40 °C
Mobile phase A = Formic acid (aq) 0.1 %
B = Formic acid
(acetonitrile) 0.1 %
Flow rate 1 mL/min
Injection 3μΙ
volume Detector 215nm (nominal)
Gradient Time (min) % Organic
0 5
2.5 100
2.7 100
2.71 5
3.0 5
Standard Hi-Res method (7 min)
Figure imgf000071_0002
Preparation of pyrido[1 ,2-a]indole C10 Nitriles
Sche -substituted pyrido[1 ,2-a]indole-10-carbonitriles
Figure imgf000071_0001
3-Hydroxypyrido[1 ,2-a]indole-10-carbonitrile
Figure imgf000072_0001
Prepared according to procedure described for 3-hydroxypyrido[1 ,2-a]indole-10- carboxylic acid ethyl ester (Aust. J. Chem. 1969, 22, 1525) on a 1 .0 mmol scale using 2-pyridylacetonitrile. The title compound (100 mg, 48% yield) was isolated as a green solid.
H NMR (500 MHz , d6-DMSO) ? 9.77 (s, 1 H), 8.92 (d, 1 H), 7.67-7.70 (m, 1 H), 7.65 (d, 1 H), 7.62 (d, 1 H), 7.37 (dd, 1 H), 7.10 (dd1 H), 6.91 (t, 1 H)
LCMS: 100% UV215 at 1 .74 min, m/z 209 (M+1 )+ 100%
3-Methoxypyrido[1 ,2-a]indole-10-carbonitrile
Figure imgf000072_0002
Procedure A:
Sodium hydride (60% dispersion in mineral oil, 8.0 mg) was added to a stirred solution of 3-hydroxy-pyrido[1 ,2-a]indole-10-carbonitrile (20 mg) in THF (1 ml) at room temperature. After 30 minutes, DMF (1 ml) was added followed by methyl iodide (18 μΙ). After 2 hours the reaction mixture was quenched by pouring into saturated aqueous NH4CI (5 ml). The aqueous phase was extracted with diethyl ether (3 x 5 ml) and the combined organic phases were then washed with water (3 x 5 ml), diluted with hexane (15 ml), dried over Na2S04, filtered and the solvent removed in vacuo to provide the title compound as a yellow solid.
H NMR (500 MHz, d6-DMSO) ? 9.1 1 (d, 1 H), 8.01 (d1 H), 7.72-7.75 (m, 1 H), 7.71 (d, 1 H), 7.39-7.45 (m, 1 H), 7.17-7.23 (m, 1 H), 6.96-7.04 (m, 1 H), 3.90 (s, 3H)
LCMS: 100% UV215 at 2.04 min, m/z 223 (M+1 )+ 100%
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile
Figure imgf000073_0001
Procedure A: Using bromoacetonitrile
Purification: Silica gel FCC (ethyl acetate / heptanes gradient)
Form: Yellow solid H NMR (500 MHz, CDCI3) δ 8.37 (d, 1 H), 7.88 (d, 1 H), 7.74 (d, 1 H), 7.51 (d, 1 H), 7.24-
7.34 (m, 2H), 6.85 (t, 1 H), 4.92 (s, 2H).
LCMS: 100% UV215 at 2.02 min, m/z 248 (M+1 )+ 100%.
10-cyanopyrido -a]indol-3-yl dimethylcarbamate
Figure imgf000073_0002
Procedure A: Using dimethyl carbamyl chloride
Purification: Silica gel FCC (ethyl acetate / heptanes gradient)
Form: Yellow solid
H NMR (500 MHz, CDCI3) 5 8.33 (d, 1 H), 7.86 (d, 1 H), 7.76 (d, 1 H), 7.73 (d, 1 H), 7.27- 7.32 (m, 2H), 6.80 (td, 1 H), 3.18 (s, 3H), 3.07 (s, 3H).
LCMS: 96% UV215 at 2.03 min, m/z 280 (M+1 )+ 100%.
10-cyanopyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate
Figure imgf000074_0001
Procedure A: Using morpholinyl carbamyl chloride
Purification: Silica gel FCC (ethyl acetate / heptanes gradient)
Form: Yellow solid H NMR (500 MHz, CDCI3) δ 8.35 (d, 1 H), 7.88 (d, 1 H), 7.76 (d, 1 H), 7.74 (d, 1 H), 7.28- 7.34 (m, 2H), 6.82 (td, 1 H), 3.78-3.84 (m, 4H), 3.76 (d, J = 3.8 Hz, 2H), 3.62 (br. S, 2H). LCMS: 100% UV215 at 1 .95 min, m/z 322 (M+1 )+ 100%.
10-cyanopyrido[1 ,2-a]indol-3-yl trif luoromethanesulf onate
Figure imgf000074_0002
A mixture of 3-hydroxypyrido[1 ,2-a]indole-10-carbonitrile (14g) and N-phenyl- bis(trifluoromethanesulfonamide (26.5g) was dissolved in 200 ml of anhydrous DCM and 200 ml of anhydrous THF and dimethylaminopyridine (105mg) was added. The mixture stirred for 10 minutes and TEA (10.77ml) was added slowly and the mixture stirred at rt for 12 hrs. The solution concentrated by rotary evaporation. The residue was purified by column chromatography (silica gel/20% EtOAc in hexanes) to obtain the title compound H NMR (300 MHz, DMSO-d6) δ ppm 9.27 (d, 1 H), 8.76 (d, 1 H), 7.96 (d, 1 H), 7.83 (d, 1 H), 7.60(m, 2H), 7.12 (t, 1 H). 9F NMR (282MHz, DMSO-d6) δ ppm 72.55 m/z 341 (M+1 )+
Synthesis of 3-acetylpyrido[1 ,2-a]indole-10-carbonitrile:
Figure imgf000075_0001
A mixture of 10-cyanopyrido[1 ,2-a]indol-3-yl trifluoromethanesulfonate (20g), tributyl(1 - ethyoxyvinyl)tin (25.43g), tetrakistriphylphosphine (40.7g), lithium chloride (24.88) were suspended in 50 ml of dioxane and heated at 125°C for 48 hours in a sealed tube. The reaction was cooled to rt and carefully depressurized and concentrated rotary evaporation. The dark brown oil was chromatographed using silica gel /20% EtOAc in hexanes to obtain the title product H NMR (300 MHz, DMSO-d6) δ ppm 9.44 (d, 1 H), 9.12 (s, 1 H), 8.12 (s, 1 H), 7.86 (d, 2H), 7.65(dd, 1 H), 7.17 (t, 1 H), 2.71 (s, 3H). m/z 235 (M+1 )+
2.0 Preparation of pyrido[1 ,2-a]indole C10 carboxylic acids from corresponding methyl and allyl esters
3-hydroxypyrido[1 ,2-a]indole-10-carboxylic acid methyl ester
Figure imgf000075_0002
H Prepared according to procedure described for 3-hydroxypyrido[1 ,2-a]indole-10- carboxylic acid ethyl ester (Aust. J. Chem. 1969, 22, 1525) on a 10 mmol scale using methyl 2-pyridylacetate. The title compound was isolated as a green solid.
3-Methoxy-pyrido[1 ,2-a]indole-10-carboxylic acid methyl ester
Figure imgf000076_0001
Procedure A: From 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid methyl ester using methyl iodide Purification: Aqueous work-up
Form: Brown solid
H NMR (500 MHz ,CDCI3) δ 8.35 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 6.9 Hz, 1 H), 8.28 (d, J = 9.1 Hz, 1 H), 7.28-7.26 (m, 1 H), 7.23 (ddd, J = 1 .3, 6.5, 9.3 Hz, 1 H), 7.18 (dd, J = 2.2, 8.8 Hz, 1 H), 6.76 (dt, J = 0.9, 6.8 Hz, 1 H), 4.00 (s, 3H), 3.94 (s, 3H).
LCMS: 87% UV215 at 2.13 min, m/z 256 (M+1 )+ 100%.
3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000076_0002
Procedure B:
3-methoxy-pyrido[1 ,2-a]indole-10-carboxylic acid methyl ester (1 .02 g) and KOH (1 .0 g) were dissolved in a mixture of DMSO (18 ml) and water (2 ml) and the reaction mixture stirred at 50 'Ό for 5 hours. Once the reaction was complete, the reaction mixture was cooled to 0°C, and then quenched with water (20 ml). The resulting solution was extracted with EtOAc (3 x 10 ml), and the combined organic phases extracted with 1 M aqueous NaOH (2 x 10 ml). The combined aqueous extracts were acidified with 1 M HCI at 0°C to pH 3-4. The precipitated solid was collected by filtration, washed with water (20 ml), and dried in a vacuum oven. The title compound was obtained as yellow- green solid. H NMR (500 MHz, cW-methanol) δ 3.88-3.95 (m, 3H) 6.79-6.86 (m, 1 H) 7.1 1 (dd, J = 8.83, 2.52 Hz, 1 H) 7.29 (dd, J = 9.14, 6.62 Hz, 1 H) 7.57 (d, J = 2.21 Hz, 1 H) 8.17 (d, J = 8.83 Hz, 1 H) 8.25 (d, J = 9.46 Hz, 1 H) 8.69 (d, J = 6.94 Hz, 1 H).
LCMS: 98% UV215 at 1 .77 min, m/z 242 (M+1 )+ 100%.
Methyl 3-{[(trif luoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000077_0001
To a solution of methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate (62.0 g) in N,N- dimethylformamide (600 ml_) was introduced /V-phenyltriflimide (1 13.4 g) and triethylamine (40.8 ml_). The reaction mixture was heated to 50 °C under an
atmosphere of nitrogen for 14 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydroxide, water and brine. The ethyl acetate extract was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by silica gel column
chromatography (eluent: heptane / ethyl acetate gradient) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.46 (d, 1 H), 8.40 - 8.44 (m, 2H), 7.83 (d, 1 H), 7.39 (ddd, 1 H), 7.42 (dd, 1 H), 6.90 (td, 1 H), 4.02 (s, 3H).
LCMS (3 min): 2.51 min with m/z 374 (M+1 )+ 100%.
Methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000077_0002
To a pressure tube containing a solution of methyl 3- {[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate (100 mg) in anhydrous 1 ,4-dioxane (1 .0 mL) was introduced tributyl(1 -ethoxyvinyl)tin (1 16 mg), lithium chloride (500 mg) and tetrakis(triphenylphosphine)palladium(0) (200 mg). The reaction tube was closed under an atmosphere of nitrogen and heated to 140 °C for 3 days. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo and was purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.64 (d, 1 H), 8.62 (s, 1 H), 8.46 (d, 1 H), 8.42 (d, 1 H), 8.10 (dd, 1 H), 7.46 (dd, 1 H), 6.94 (t, 1 H), 4.03 (s, 3H), 2.75 (s, 3H).
LCMS (3 min): 1 .98 min; m/z 268 (M+1 )+ 100%.
Potassium 3-acetylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000078_0001
To a solution of methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate (60 mg) in dimethylsulfoxide (1 .0 mL) was introduced potassium hydroxide (0.34 mL of a 1 M aqueous solution). After 16 h at 50 °C, the reaction mixture was cooled to room temperature and concentrated in vacuo to give the title compound as a brown solid which was used without further purification.
LCMS (3 min): 1 .67 min; m/z 254 (M+1 )+ parent carboxylic acid 100%.
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000078_0002
Potassium 3-acetylpyrido[1 ,2-a]indole-10-carboxylate was dissolved in water and acidified with 2N HCI solution (pH 4). Extracted with ethylacetate, dried (MgS04), filtered and evaporated. The residue obtained was dissolved in diethyl-ether and insoluble precipitates were separated by filtration, washed with diethyl ether and dried to yield the title compound which was used without further purification.
10-(Methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid
Figure imgf000079_0001
In a sealed tube, was placed methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2- a]indole-10-carboxylate (50 mg) in A/JV-dimethylformamide (1 .0 ml_), sodium formate (27.3 mg), /V,/V-diisopropylethylamine (44.3 μΙ_), acetic anhydride (25.3 μΙ_) and lithium chloride (17 mg). Nitrogen was bubbled through the reaction mixture for 3 min and then palladium acetate (3.0 mg) and 1 ,3 bis(diphenylphoshino)propane (5.5 mg) were added to the reaction mixture as nitrogen was bubbled through the reaction mixture for a further 2 min. The reaction mixture was heated to 80 °C for 17 h and then cooled to room temperature and the A/JV-dimethylformamide was removed in vacuo. The residue was dissolved in 1 M aq. sodium hydroxide, extracted with diethyl ether and
dichloromethane. The aqueous phase was acidified to pH 1 by the addition of 1 M hydrochloric acid (aq) and extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. The compound was purified by preparative-HPLC (acetonitrile/water containing 0.1 % formic acid) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 12.94 (br. s., 1 H), 9.39 (d, 1 H), 8.99 (s, 1 H), 8.32 (d, 1 H), 8.27 (d, 1 H), 8.07 (dd, 1 H), 7.63 (ddd, 1 H), 7.09 (td, 1 H), 3.91 (s, 3H).
LCMS (7 min): 3.89 min; m/z 270 (M+1 )+ 100%.
Pyrido[1 ,2-a]indole-3,10-dicarboxylic acid
Figure imgf000080_0001
Procedure B: From 10-(Methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid.
Form: Green solid
LCMS (7 min.): 3.17 min; m/z 256 (M+1 )+ 100% (mass of free acid observed). Methyl 3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000080_0002
Procedure C:
To a stirred suspension of 10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid (50 mg) and 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide (53 mg) in anhydrous N,N- dimethylformamide (2.0 ml_), was added morpholine (32.7 μΙ_), followed by N,N- diisopropylethylamine (46 μΙ_). The resulting solution was stirred at room temperature for 17.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 10% citric acid (aq), water, saturated NaHC03 (aq), water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-100% ethyl acetate / heptanes) to give the title compound as a yellow solid.
LCMS (7 min): 3.70 min; m/z 339 (M+1 )+ 100%.
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000081_0001
Procedure B: From methyl Methyl 3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10- carboxylate
Form: yellow semi solid H NMR (500 MHz, DMSO-c 6) δ ppm 9.20 (d, 1 H) 8.47 (s, 1 H) 8.30 (t, 2 H) 7.47 - 7.55 (m, 2 H) 7.02 (t, 1 H) 3.45 - 3.78 (m, 8 H) LCMS (7 min): 3.23 min; m/z 325 (M+1 )+ 100%
Methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000081_0002
Purification: Column chromatography (20-85% ethyl acetate / heptanes)
Form: Yellow solid. H NMR (500 MHz, DMSO-c 6) δ ppm 9.18 (d, 1 H), 8.90 (d, 1 H), 8.53 (br. s., 1 H), 8.31 (d, 1 H), 8.24 (d, 1 H), 8.01 (dd, 1 H), 7.61 (ddd, 1 H), 7.10 (td, 1 H), 3.91 (s, 3H), 3.48 - 3.54 (m, 4H), 3.30 (s, 3H).
LCMS (7 min): 3.72 min; m/z 327 (M+1 )+ 100%.
Potassium 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000082_0001
Procedure B from methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate (0.147 g) (50 'Ό for 50 h). Diluted with acetone (20 mL) and stirred until a yellow solid crashed out of solution. The liquor was carefully decanted off to leave a yellow solid which was dried under vacuum to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 8.81 (d, 1 H), 8.69 (s, 1 H), 8.53 - 8.59 (m, 2H), 8.39 - 8.45 (m, 1 H), 7.79 (d, 1 H), 7.08 (dd, 1 H), 6.66 (t, 1 H), 3.50 (br. s., 4H), 3.29 (s, 3H).
LCMS (3 min): 1 .52 min; m/z 313 (M+1 )+ 100% (parent carboxylic acid). Methyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000082_0002
A solution of 10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid (30 mg) in dichloromethane (1 .5 mL) containing a catalytic amount of A/JV-dimethylformamide (5 mL) was treated with oxalyl chloride (15 mL) dropwise. The solution was stirred at room temperature for 60 min. A solution of A/JV-dimethylethylenediamine (61 μί) in dichloromethane (0.5 mL) was added and the reaction was stirred at room temperature for 5 min. The reaction mixture was washed with 1 M aq sodium hydrogen carbonate solution and the organic phase was dried (magnesium sulfate), filtered and the solvent was removed in vacuo. Purification by column chromatography on silica gel
(dichloromethane / methanol [0-10%] gradient) gave the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.81 (br. s, 1 H), 8.73 (d, 1 H), 8.44 (d, 1 H), 8.40 (d, 1 H), 7.95 (d, 1 H), 7.60 (br. s, 1 H), 7.42 (ddd, 1 H), 6.92 (td, 1 H), 4.02 (s, 3H), 3.75 (d, 2H), 2.85 (br. s, 2H), 2.54 (br. s, 6H). LCMS (7 min): 2.79 min; m/z 340 (M+1 )+.
Potassium 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000083_0001
Procedure B from methyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10- carboxylate (200 mg) (50 'Ό for 15 h). Removal of the solvent in vacuo and trituration with dry acetone, gave the title compound as a yellow solid. H NMR (500 MHz, DMSO-d6) δ ppm 8.85 (d, 1 H), 8.69 (s, 1 H), 8.54 (t, 1 H), 8.53 (d, 1 H), 8.32 (t, 1 H), 7.79 (dd, 1 H), 7.1 1 (dd, 1 H), 6.69 (t, 1 H), 3.42 (t, 2H), 2.44 (t, 2H), 2.20 (s, 6H). LCMS (3 min): 1 .10 min; m/z 326 (M+1 )+.
Methyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000083_0002
Procedure C: using 2-aminoethanol
Purification: Flash column chromatography (20-100% ethyl acetate / heptanes) Form: Yellow solid H NMR (500 MHz, DMSO-c 6) δ ppm 9.18 (d, 1 H), 8.90 (s, 1 H), 8.46 (t, 1 H), 8.31 (d, 1 H), 8.23 (d, 1 H), 8.01 (dd, 1 H), 7.61 (ddd, 1 H), 7.10 (td, 1 H), 4.77 (t, 1 H), 3.91 (s, 3H), 3.57 (q, 2H), 3.41 (q, 2H). LCMS: 3.40 min; m/z 313 (M+1 )+ 100%.
Potassium 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000084_0001
Procedure B: From methyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate
Form: yellow semi solid
H NMR (500 MHz, DMSO-c/6) δ ppm 8.82 (d, 1 H), 8.79 (br. s., 1 H), 8.69 (s, 1 H), 8.62 (d, 1 H), 8.54 (d, 1 H), 7.94 (d, 1 H), 7.07 (dd, 1 H), 6.60 (t, 1 H), 5.71 (br. s., 1 H), 3.59 - 3.67 (m, 2H), 3.40 (q, 2H).
LCMS: 2.85 min; m/z 299 (M+1 )+ 100% (mass of free acid observed).
Methyl 3-(acetylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000084_0002
A mixture containing methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10- carboxylate (1 .0 g), potassium ethanethioate (459 mg),
tris(dibenzylidenacetone)dipalladium (61 mg) and 9,9-dimethyl-4,5-bis
(diphenylphosphino) xanthene (77 mg) were placed in a pressure tube capped with a rubber septum. The tube was evacuated under vacuum and re-filled with nitrogen 3 times. A/JV-Diisopropylethylamine (885 μΙ_) and degassed dry 1 ,2-dioxane (6.0 ml_) were added to the tube and the rubber septum quickly replaced with a Teflon® screw cap. The reaction mixture was heated at Ι ΟΟ'Ό for 21 .5 h. After cooling, the reaction mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organics were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (100%
dichloromethane) to give the title compound as a yellow solid.
1 H NMR (500 MHz, DMSO-c/6) δ ppm 9.21 (d, 1 H), 8.54 (s, 1 H), 8.30 (d, 1 H), 8.27 (d, 1 H), 7.57 - 7.62 (m, 1 H), 7.50 (dd, 1 H), 7.08 (t, 1 H), 3.91 (s, 3H), 2.46 (s, 3H).
LCMS (3 min): 2.15 min; m/z 300 (M+1 )+ 100%.
Methyl 3-[(2-chloroethyl)sulf anyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000085_0001
A mixture of methyl 3-(acetylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate (500 mg) in ethanol (10 mL) at 0 <€, was treated with 1 -bromo-2-chloroethane (166.16 μΙ_) and 1 M aq. sodium hydroxide (2.0 mL). The reaction mixture was stirred at 0 °C for 50 min and then warmed to room temperature and stirred for a further 4 hours. The reaction mixture was diluted with dichloromethane and water. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c 6) δ ppm 9.20 (d, 1 H), 8.51 (d, 1 H), 8.26 (d, 1 H), 8.18 (d, 1 H), 7.56 (dd, 1 H), 7.51 - 7.54 (m, 1 H), 7.04 (td, 1 H), 3.89 (s, 3H), 3.77 (t, 2H), 3.41 (t, 2H).
LCMS: 5.05 min; m/z 320 (M+1 )+ 100%. Methyl 3-{[2-(dimethylamino)ethyl]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000086_0001
To a stirred solution of methyl 3-[(2-chloroethyl)sulfanyl]pyrido[1 ,2-a]indole-10- carboxylate (276 mg) in dichloromethane (10 ml_), at 0 °C, was added m- chloroperoxybenzoic acid (426 mg, of a 70-77% wt in water) portionwise over 27 min. The reaction mixture was then stirred at 0 °C to Ι Ο 'Ό (ice/salt bath) for 2 hours, m- Chloroperoxybenzoic acid (64 mg) was added over 7 min and stirring continued for a further 3 hours. The reaction mixture was treated with 1 M aq. sodium hydroxide (30 ml_) and stirred for 10 min on ice and then extracted with dichloromethane. The combined organic extracts were washed with 1 M aq. sodium hydroxide, brine, dried (magnesium sulfate), filtered and concentrated in vacuo to give a mixture of the crude sulfone and sulfoxide.
The mixture (150 mg) in 1 ,4-dioxane (5.0 ml_) was placed in a sealed tube and treated with sodium iodide (319.6 mg). After the reaction mixture had been stirred for 5 minutes, /V-methylmethanamine (2M solution in tetrahydrofuran, 1 .07 ml_) was added. The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was partitioned between water and dichloromethane. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in-vacuo. The mixture was purified by preparative HPLC using acetonitrile / water (+ 0.1 % formic acid) to give the title compound as the formate salt as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.43 (d, 1 H), 9.00 (d, 1 H), 8.40 (d, 1 H), 8.35 (d, 1 H), 8.19 (s, 1 H), 7.97 (dd, 1 H), 7.69 (ddd, 1 H), 7.16 (td, 1 H), 3.93 (s, 3H), 3.50 - 3.53 (m, 2H), 2.53 - 2.58 (m, 2H), 2.04 (s, 6H). LCMS: 2.90 min; m/z 361 (M+1 )+ 100%. Sodium 3-{[2-(dimethylamino)ethyl]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000087_0001
To a pressure tube containing dimethylaminoethanol (445 mg) was introduced finely cut sodium (5.0 mg) followed by methyl 3-{[2-(dimethylamino)ethyl]sulfonyl}pyrido[1 ,2- a]indole-10-carboxylate (40 mg) before the reaction mixture was heated to 100 °C. After 16 hours, the reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between water and dichloromethane. Freeze drying the basic (pH = 12) aqueous extract furnished the title compound as a yellow solid. H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (d, 1 H), 8.78 (d, 1 H), 8.75 (d, 1 H), 8.62 (d, 1 H), 7.74 (dd, 1 H), 7.24 (ddd, 1 H), 6.79 (td, 1 H), 3.45 (t, 2H), 2.52 - 2.54 (m, 2H), 2.04 (s, 6H).
LCMS: 2.45 min; m/z 347 (M+1 )+ parent carboxylic acid 100%.
Pyridin-2-yl-acetic acid allyl ester
Figure imgf000087_0002
To a suspension of 4-pyridylacetic acid hydrochloride (20.0 g) in DMF (150 ml) was added allyl alcohol (33.5 g), EDCI (30.9 g), DMAP (2.81 g) and DIPEA (29.8 g) sequentially at O 'C. The resultant yellow solution was stirred at O 'C for 1 hour, and then allowed to warm up to room temperature. Stirring was continued for a further 48 hours. The solvent was removed in vacuo, and the residue dissolved in EtOAc (100 ml). The organic layer was washed with water (200 ml), and then the aqueous phase back extracted with EtOAc (2 χ 100 ml). The combined organic phases were washed with brine (100 ml), dried over Na2S04, filtered and the solvent removed in vacuo to give the title compound as a brown oil which was used in the next step without further purification.
H NMR (500 MHz, CDCI3) δ 8.57 (d, , 1 H), 7.66 (td, 1 H), 7.30 (d, 1 H), 7.20 (dd, 1 H), 5.86-5.97 (m, 1 H), 5.29 (dd, 1 H), 5.22 (dd, 1 H), 4.64 (d, 3.89 (s, 2H).
LCMS: 98% UV215 at 0.93 min, m/z 178 (M+1 )+ 100%.
3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Figure imgf000088_0001
To a solution of pyridin-2-yl-acetic acid allyl ester (20.0 g) in glacial acetic acid (80 ml) stirred under nitrogen and cooled in an ice bath, was added p-benzoquinone (12.2 g) portion wise over 90 minutes. Towards the end of the addition, the reaction mixture became partly solid. After stirring at 0°C for a further 30 minutes, the reaction mixture was quenched with water (250 ml). The precipitated solid was collected by filtration, washed with water (20 ml), dried on the filter overnight, and finally dried in a vacuum oven at 45^ for 8 hours. The title compound was isolated as a yellow-green solid. H NMR (500 MHz, cW-methanol) δ 8.57 (d, J = 6.94 Hz, 1 H), 8.22 (d,J = 9.14 Hz, 1 H), 8.10 (d, J = 8.83 Hz, 1 H), 7.40 (d, J = 2.21 Hz, 1 H), 7.30 (dd, J = 9.30, 6.46 Hz, 1 H), 7.04 (dd, J = 8.83, 2.21 Hz, 1 H), 6.79-6.87 (m, 1 H), 6.10 -6.23 (m, 1 H), 5.45 (dd, J = 17.34, 1 .58 Hz, 1 H), 5.29 (dd, J = 10.40, 1 .26 Hz, 1 H), 4.87-4.90 (m, 2H), 4.88 (d, J = 5.36 Hz, 3H).
LCMS: 95% UV215 at 1 .96 min, m/z 268 (M+1 )+ 100%.
3-Cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Figure imgf000088_0002
QQ
oo
Procedure A: From 3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester using bromoacetonitrile
Purification: Flash column chromatography (EtO Ac/Heptanes gradient)
Form: Yellow solid H NMR (500 MHz, CDCI3) δ 8.32-8.43 (m, 3H), 7.46 (d, 1 H), 7.28-7.33 (m, 1 H), 7.24 (dd, 1 H), 6.80-6.85 (m, 1 H), 6.12-6.22 (m, 1 H), , 5.48 (dd, 1 H), 5.33 (d, 1 H), 4.95 (d, 2H), 4.90 (s, 2H).
LCMS: 99% UV215 at 2.21 min, m/z 307 (M+1 )+ 100%.
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000089_0001
Procedure D:
To a solution of 3-cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester (1 .5 g, 4.9 mmol) in THF (25.0 ml) was added Pd(PPh3)4 (283 mg, 0.25 mmol) at 0 <€ under a nitrogen atmosphere. Morpholine (2.14 ml, 24.5 mmol) was then added and the reaction stirred at 0°C for 15 minutes, then warmed to room temperature for 2 hours. The precipitated solid was collected by filtration. The filtrate was concentrated under reduced pressure and the residue suspended in EtOAc (7 ml), stirred at room temperature for 30 minutes, and then filtered to yield a second crop of solid. The two solids were combined and dried on the filter to give the title compound as a yellow powder.
H NMR (500 MHz, cW-methanol) δ 8.90 (d, 1 H), 8.30-8.42 (m, 2H), 7.97 (d, 1 H), 7.43 (dd, 1 H), 7.32 (dd, 1 H), 6.98 (t, 1 H), 5.22 (s, 2H).
LCMS: 91 % UV215 at 1 .72 min, m/z 267 (M+1 )+ 100.
3-Dimethylcarbamoyloxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Figure imgf000090_0001
Procedure A (in THF): From 3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester using dimethyl carbamyl chloride.
Purification: Flash column chromatography (MeOH/DCM gradient)
Form: Yellow solid
H NMR (500 MHz, CDCI3) 5 8.32-8.42 (m, 3H), 7.25-7.33 (m, 2H), 6.79 (td, 1 H), 6.1 1 - 6.22 (m, 1 H), 5.47 (dd, 1 H), 5.28-5.34 (m, 1 H), 4.95 (dt, 2H), 3.18 (s, 3H), 3.07 (s, 3H). LCMS: 95% UV215 at 2.23 min, m/z 339 (M+1 )+ 90%.
3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000090_0002
Procedure D: From 3-dimethylcarbamoyloxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Purification: Collected by filtration and washed with EtOAc
Form: Yellow solid H NMR (500 MHz , d6-DMSO) δ 12.00 (br. s., 1 H), 9.04 (d, 1 H), 8.30-8.14 (m, 3H), 7.45 (dd, 1 H), 7.25 (dd, 1 H), 6.97 (t, 1 H), 3.1 1 (s, 3H), 2.95 (s, 3H).
LCMS: 100% UV215 at 1 .74 min, m/z 299 (M+1 )+ 100%.
3-(Morpholine-4-carbonyloxy)-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Figure imgf000091_0001
Procedure A (in THF): From 3-Hydroxy-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester using dimethyl carbamyl chloride.
Purification: Flash column chromatography (MeOH/DCM gradient)
Form: Yellow solid H NMR (500 MHz, CDCI3) δ 3.58-3.68 (m, 2H) 3.72-3.84 (m, 6H) 4.95 (dt, 2H) 5.28- 5.34 (m, 1 H) 5.47 (dd, 1 H) 6.1 1 -6.22 (m, 1 H) 6.80 (td, 1 H) 7.24-7.29 (m, 1 H) 7.31 (ddd, 1 H) 7.72 (d, 1 H) 8.35 (d, 1 H) 8.39 (dd, 2H).
LCMS: 100% UV215 at 2.17 min, m/z 381 (M+1 )+ 100%.
3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000091_0002
Procedure D: From 3-(morpholine-4-carbonyloxy)-pyrido[1 ,2-a]indole-10-carboxylic acid allyl ester
Purification: Collected by filtration and washed with THF
Form: Yellow solid H NMR (500 MHz, DMSO-d6) δ = 9.05 (d, J = 7.0 Hz, 1 H), 8.34-8.10 (m, 3H), 7.45 (dd, J = 6.7, 9.2 Hz, 1 H), 7.27 (dd, J = 2.1 , 8.8 Hz, 1 H), 7.04-6.88 (m, 1 H), 3.68 (br. s., 6H), 3.46 (br. s., 2H).
LCMS: 98% UV215 at 1 .68 min, m/z 341 (M+1 )+ 100%.
3.0 Preparation of pyrido[1 ,2-a]indole C10 amides 3-methoxypyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000092_0001
Procedure E:
To a stirred solution of 3-methoxy-pyrido[1 ,2-a]indole-10-carboxylic acid (200 mg) in THF (7.5 ml) at 0°C, was added oxalyl chloride (217 μΙ) over 10 minutes, and DMF (1 drop). The reaction was stirred at 0°C for 30 minutes, and aqueous ammonia solution (1 .0 ml) was added dropwise at O 'C. The reaction mixture was stirred at 0 'C for 3.5 hours and then left to reach room temperature. The reaction was quenched with water (20 ml), and then extracted with EtOAc (3 x 40 ml). The combined organic layer was washed with brine (55 ml), dried over MgS04, filtered and the solvent removed in- vacuo. The green residue was purified by flash column chromatography (MeOH/DCM gradient) followed by prep. HPLC (MeCN / H20 and 0.2% NH4OH) to give the title compound as a yellow solid. H NMR (500 MHz, d6-DMSO) δ 8.94 (d, J = 7.1 Hz, 1 H), 8.20 (d, J = 9.3 Hz, 1 H), 8.06 (d, J = 9.0 Hz, 1 H), 7.88 (d, J = 2.2 Hz, 1 H), 7.21 (ddd, J = 9.3, 6.5, 0.8 Hz, 1 H), 7.10 (dd, J=8.9, 2.3 Hz, 1 H), 7.02 (br. S, 2H), 6.78 - 6.84 (m, 1 H), 3.89 (s, 3H).
LCMS: 100% UV215 at 1 .61 min, m/z 241 (M+1 )+ 100%.
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000092_0002
Procedure E: From 3-cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid
Purification: Flash column chromatography (MeOH/DCM gradient)
Form: Yellow solid H NMR (500 MHz, d4-methanol) δ = 8.69 (d, J = 6.9 Hz, 1 H), 8.18 (d, J = 9.5 Hz, 1 H), 8.06 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 2.2 Hz, 1 H), 7.31 -7.19 (m, 2H), 6.81 (dd, J = 0.9, 13.6 Hz, 1 H), 5.08 (s, 2H).
LCMS: 89% UV215 at 1 .57 min, m/z 266 (M+1 )+ 100%.
Example 2
GASC1 HTRF assay for high throughput screening: Assay principle:
High throughput screening of the -260.000 compound library was done using a
GASC1 HTRF demethylation assay. The GASC1 demethylation HTRF assay (Figure 1 ) uses a truncated version of histone H3 trimethylated at lysine 9 as a substrate
(H3K9me3). The demethylase activity of GASC1 results in loss of methyl group(s) at lysine 9 in this substrate peptide. This reaction is monitored by quantifying the amount of product (H3K9me2) formed. As readout HTRF (homogeneous time resolved fluorescence) is used. Here, the assay probe is a complex consisting of fluorescently labelled biotinylated H3K9me2, XL665-labelled ("A") streptavidin and a specific Eu3+ cryptate labelled ("D") anti-H3K9me2 antibody. In the bound state part of the energy captured by europium cryptate is transferred to the acceptor molecule finally resulting in fluorescence emission at λ=665 nm. Competition by H3K9me2 formed in the enzymatic reaction will allow to quantitatively determining the reaction progress.
This type of assay is entirely homogeneous, amenable to miniaturisation to 1 ,536-well high density plate format and compatible with automated high throughput equipment.
Assay reagents and equipment:
Figure imgf000093_0001
SA-XL665 Lot 99 Cisbio Cat. #610SAXLB
Bt-(Ttds)-
Bt-H3K9me2 Wink-63 ARTKQTAR(Kme2)STGGKAPRKQ- CONH2 (SEQ ID NO:3)
(Evotec); tracer
2,4-Pyridinedicarboxylic
acid S54932-248 Aldrich cat. # P6,339-5; inhibitor
(PDA, control inhibitor)
Reader (primary assay) Envision™ reader (Perkin Elmer)
Assay plate (primary Lumitrac 200 (1536 plate),
assay; 1536 well format) Greiner bio-one cat. # 782075
EVOscreen™ Mark III Screening device for uHTS
Assay protocol and conditions:
The uHTS run was carried out on the EVOscreen™ Mark III system (Evotec, United Kingdom) in Greiner 1536 assay plates. 4 x 384-well microtiter plates were reformatted to one MicroCarrier 1536, which is subdivided into 4 compound areas (= fit zones). Each fit zone includes 32 wells, containing no compounds. These wells are used as control wells (positive, negative and "at IC50" control wells).
On such an assay plate the following samples were placed:
· negative controls: control wells without inhibitor (for Z' calculation)
• positive controls: control wells containing 500 μΜ control inhibitor (PDA) (for Z' calculation)
• "at IC50" controls: control wells containing 5 μΜ control inhibitor (PDA) which is close to its IC50 value (for quality control during screening)
· compound samples: wells containing compounds for test during screening
• sample negative controls: control wells containing no compounds but DMSO (used for hit threshold setting).
Prior to incubation the GASC1 enzyme (in assay buffer) is added to the wells and mixed with either compound (2 mM in DMSO), control inhibitor (at either 5 μΜ in DMSO as "IC50" control or at 500 μΜ in DMSO as maximal inhibition control for Z' calculation) or DMSO (negative control). Hereafter the enzyme substrate (H2K9-me3 in assay buffer) is added and the ~2 μΙ reaction mixture is incubated for 60 min at 20° C.
Following this 3 μΙ of a mix of XL665-labelled streptavidin and Eu3+ cryptate labelled anti-H3K9me2 antibody is added and the 5 μΙ reaction is further incubated for another 60 min at 20° C. Finally, 1 μΙ of fluorescently labelled biotinylated H3K9me2 is added and the 6 μΙ reaction is allowed to proceed for a final 60 min at 20° C. Fluorescence is measured at 615 and 665 nm and readout is calculated as the ratio of emission at 665 nm/615 nm x 10000. Test compounds of the compound library capable of inhibiting GASC-1 activity were selected.
The table below shows an overview of the reaction and plate set up.
Figure imgf000095_0001
*: respective assay volume: 2000 μΙ
**: respective assay volume: 6000 μΙ
The assay buffer in the 2 μΙ reaction is 50 mM Tris pH 8.0, 0.1 % pluronic® F127, 200 mM NaCI, 0.1 mM MgCI2, 5 μΜ FeS04, 250 μΜ ascorbate and 250 μΜ α- ketoglutarate. If the compound concentration during screening is 20 μΜ, the DMSO concentration in the negative controls of the GASC1 reaction (2 μΙ volume) is 1 %. The 2-fold concentrated intermediate Eu-Abcam1220 / SA-XL665 mixture is dissolved in 50 mM NaPi pH 7.0, 800 mM KF, 0.1 % pluronic® F127 and 0.1 % BSA. The 6-fold concentrated intermediate Bt-H3K9me2 solution ("Bt-me2") is dissolved in 50 mM NaPi pH 7.0, 0.1 % pluronic® F127 and 0.1 % BSA.
Example 3
GASC1 LC-MS/MS assay for IC50 value determination
Assay principle:
The GASC1 LC-MS based demethylation assay uses the same truncated version of histone H3 trimethylated at lysine 9 as a substrate (H3K9me3) as was used on the GASC1 HTRF assay of Example 2. The demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a shift in molecular mass of the product (H3K9me2) compared to the substrate that can be measured by mass spectrometry. Quantification of substrate and product is done using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), enabling a precise and direct monitoring of the demethylation reaction. An example of the mass traces detected by LC-MS/MS is shown in figure 2.
Assay reagents and equipment:
Figure imgf000096_0001
IC50 values of compounds were determined based on 8-point concentration-response curves using LC-MS-MS detection of the demethylated product. Results are shown in Table 1 below. Assay plates were divided into control wells and compound wells. On such an assay plate the following samples were placed:
• negative controls: control wells containing enzyme without inhibitor (for calculation of inhibition and Z'-values)
• positive controls: control wells containing enzyme and 50 μΜ control inhibitor PDA (for calculation of inhibition and Z'-values)
• 98% substrate / 2% product controls: containing no enzyme but both 49 μΜ substrate and 1 μΜ product (for calibration of the analytical system)
compound samples: wells containing compounds at different concentrations (for concentration-response testing).
GASC1 protein in assay buffer was mixed with compound (8 concentrations; e.g. final concentrations from 20 μΜ to 2,1 nm, 3,7 fold dilution) and incubated for 10 minutes at room temp. Substrate, H3K9-me3 (final concentration: 50 μΜ) was then added and the reaction was incubated for 360 minutes at room temp. 30% TCA (final concentration: 5%) was added to stop the reaction, which was hereafter centrifuged for 10 minutes at 3750xg. The amount of remaining substrate and dimethylated product was directly measured using LC-MS/MS. The table below shows an overview of the reaction and plate set up.
Figure imgf000097_0001
Figure imgf000098_0001
*: in 20.2 μΙ assay volume
**: in 24.2 μΙ volume after addition of TCA
***: Enzyme buffer: 50 mM Tris pH 8.0, 0.1 mM MgCI2, 200 mM NaCI, 0,1 % Pluronic F- 127
****: Assay buffer: 50 mM Tris pH 8.0, 0.1 mM MgCI2, 200 mM NaCI, 0,1 % Pluronic F- 127, 50 μΜ (final: 25 μΜ) FeS04, 500 μΜ (final: 250 μΜ) ascorbic acid, 500 μΜ (final: 250 μΜ) α-ketoglutarate
Injection volume: 5 μΙ
Solvent A: LC/MS grade (Baker) water containing 0.05% trifluoroacetic acid
Solvent B: LC/MS grade (Baker) acetonitrile containing 0.1 % formic acid
Column temperature: 90°C
Gradient: concave gradient 1 % B to 3.1 % B within 0.9 min, up to 99.9% B within 0.1 min, holding for 0.4 min, afterwards re-equilibration, flowrate: 1 .1 ml/min, note: first step of gradient is subject to changes dependent on column separation performance MS/MS-detection (MRM):
704.85 > 69.90 & 704.85 > 83.80 (Substrate, m/z = 3)
699.85 > 69.90 & 699.85 > 83.80 (Product, m/z = 3) Table 1 : GASC1 LC-MS/MS activity
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000100_0001
3-{[2-
(dimethylamino)ethyl]carb
14 +++
amoyl}pyrido[l,2- a]indole-10-carboxylic acid
3-[(2- methoxyethyl)carbamoyl]p
15 +++
yrido[l,2-a]indole- 10-carboxylic acid
3-[(2- hydroxyethyl)carbamoyl]py
16 +++
rido[l,2-a]indole- 10-carboxylic acid
Example 4
GASC1 AlphaLISA assay for IC50 value determination at conditions with high carrier protein and detergent concentration
Assay principle:
Quantification of product is uses the AlphaLISA technology and a commercially available detection kit supplied by PerklinElmer. The AlphaLISA based GASC1 demethylation assay uses the truncated version of histone H3 trimethylated at lysine 9 as was used in the GASC1 LC-MS assay (example 3) as a substrate, with an N- terminal added biotin molecule (BH3K9me3). The demethylase activity of GASC1 results in the loss of a methyl group at lysine 9 in this substrate peptide. This creates a binding epitope for a specific H3K9Me2 antibody, which is part of the specific detection kit (Figure 3). Reagents and equipment used in the assay are listed below:
Assay reagents and equipment:
Reagents and hardware Lot/Kit No Comments
GASC1 GASC1 03-03-09 EpiTherapeutics (see below)
384 well detection plate 6005350 PerkinElmer Alphascreen plate BH3K9me3 Biotin-ARTKQTAR(Kme3)STGGKAPRKQ- CONH2 (SEQ ID NO:2 N-terminally coupled to biotin)
(Substrate, CASLO)
EnSpire Alpha detector Detector, PerkinElmer
Anti-methyl-Histone H3 AL1 17M Acceptor beads coated with an Lysine 9 (H3K9me2) H3K9me2-specific antibody
AlphaLISA Acceptor
Beads
AlphaScreen 6760002 Donor beads coated with
Streptavidin-coated streptavidin
Donor Beads
AlphaLISA 5X AL008 Optimized buffer for substrate and Epigenetics Buffer product
IC50 values of compounds were determined based on 8-point concentration-response curves using the following protocol of the alphaLISA detection kit:
Assay plates were divided into control wells and compound wells. On such an assay plate the following samples were placed:
• Negative controls: control wells containing enzyme without inhibitor (for calculation of inhibition and Z'-values)
• Positive controls: control wells containing enzyme and 50 μΜ control inhibitor PDA (for calculation of inhibition and Z'-values)
• Solutions spiked with various concentrations of product but no enzyme, for calibration of the analytical system.
• Compound samples: wells containing compounds at different concentrations (for concentration-response testing).
GASC1 protein in assay buffer was mixed with compound (8 concentrations; final concentrations from 100 μΜ to 6.4 nm, 5 fold dilution) and incubated for 10 minutes at room temp. Substrate (BH3K9-me3, final concentration: 10 μΜ and cofactors) were then added and the reaction was incubated for 60 minutes at room temp. An equal volume of 4mM EDTA in Enzyme buffer was added to stop the reaction, which was hereafter vortexed for 2 minutes. The amount of formed dimethylated product was directly measured using the AlphaLISA method. The table below shows an overview of the reaction and plate set up.
Assay Overview:
Figure imgf000103_0001
*: in 30 μΙ assay volume
**: in 60 μΙ volume after addition of EDTA
***: Enzyme buffer: 50 mM HEPES pH 8.0, 0.1 % BSA, 0.003% Tween-20
****: Assay buffer: 50 mM HEPES pH 8.0, 0.1 % BSA, 0.003% Tween-20, 15 μΜ (final:
5 μΜ) FeS04, 75 μΜ (final: 25 μΜ) ascorbic acid, 30 μΜ (final: 10 μΜ) α-ketoglutarate
Detection reaction: To 5μΙ_ reaction product in an Alphascreen 384-plate is added 10 μΙ_ acceptor beads (1 :100 in 1 x Epigenetics Buffer). Upon 60 min incubation at RT, 10μΙ_ donor beads are added (1 :100 in 1 x Epigenetics Buffer). Upon 30min incubation in the dark, the Alpha signal is measured upon excitation at standard Alpha conditions. < nn
Table 2: GASC1 AlphaLISA assay - high carrier protein and detergent concentrations
Figure imgf000104_0001
Example 5
GASC1 AlphaLISA assay for IC50 value determination at conditions with low carrier protein and detergent concentrations The Assay was carried out as described in Example 4 using PBS (pH 7.4) instead of for enzyme buffer in entries 3, 4, 5, and 10 in the Assay Overview.
Table 3: GASC1 AlphaLISA assay - low carrier protein and detergent concentrations.
Activity
Compound + 5.000-15.000 nM, structure Name
no. ++ 500-5.000 nM,
+++ <500nM
3-{[2-
(dimethylamino)ethyl]carb
14 +++
amoyl}pyrido[l,2- a]indole-10-carboxylic acid
3-[(2- methoxyethyl)carbamoyl]p
15 +++
yrido[l,2-a]indole- 10-carboxylic acid
3-[(2- hydroxyethyl)carbamoyl]py
16 +++
rido[l,2-a]indole- 10-carboxylic acid
10-cyanopyrido[l,2-
17 a]indol-3-yl +
trifluoromethanesulfonate
Figure imgf000105_0001
Figure imgf000106_0001
Example 6
GASC-1 protein preparation for HTRF and LC-MS assays:
Cloning of GASC1 :
A PCR amplified DNA fragment encoding a truncation of the GASC1 enzyme
(Genbank No. NM 015061 ) was cloned into the pET100/D-TOPO expression vector (Invitrogen). The resulting plasmid encodes the 349 amino acid N-terminus of GASC1 , in fusion with a 6x his tag for Cobalt affinity purification. The amino acid sequence of the expressed product is indicated in SEQ ID NO:1 .
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTIMEVAEVESPLNPSCKIMT
FRPSMEEFREFNKYLAYMESKGAHRAGLAKVIPPKEWKPRQCYDDIDNLLIPAPIQQM
VTGQSGLFTQYNIQKKAMTVKEFRQLANSGKYCTPRYLDYEDLERKYWKNLTFVAPIY
GADINGSIYDEGVDEWNIARLNTVLDVVEEECGISIEGVNTPYLYFGMWKTTFAWHTE
DMDLYSINYLHFGEPKSWYAIPPEHGKRLERLAQGFFPSSSQGCDAFLRHKMTLISPS
VLKKYGIPFDKITQEAGEFMITFPYGYHAGFNHGFNCAESTNFATVRWIDYGKVAKLC
TCRKDMVKISMDIFVRKFQPDRYQLWKQGKDIYTIDHTKPT SEQ ID NO:1 is the amino acid sequence of the 386 aa GASC1 product produced in E. coli. The protein has an MW of 44,765 Da and a pi of 6,43. Protein expression:
The plasmid was transformed into E. coli BL21 (DE3) strain and expressed by auto- induction following protocols according to Studier, FW, 2005. In summary, cells were grown overnight in non-inducing MDG media without trace metals containing 100 μg ml ampicillin and 100 μΜ FeCI3. 500 μΙ of the overnight culture was used to inoculate 500 ml of ZYM-5052 induction media without trace metals, supplemented with 100 μg ml ampicillin and 100 μΜ FeCI3, for auto induction of expression (Recipes and stock solutions can be found at Studier, F.W. (2005) Protein production by auto-induction in high density shaking cultures. Protein Expr. Purif. 41 ; 207-234). Cells were grown at 37°C for 3-4 hours until an OD600 of 0,4 - 0,8 was reached and then transferred to 20°C for 24 hours. Finally, the cells were harvested at 4°C. The yield is approximately 10 mg truncated GASC1 protein per litre of culture.
Protein purification:
Cells were resuspended in 5 ml of lysis buffer per gram of cell pellet supplemented with 1 tablet of EDTA-Free Complete protease inhibitor (Roche) per litre of cell culture and 25 U of Bezonase Nuclease (Novagen) per ml of lysis buffer to reduce viscosity. Cells were lysed using a Cell Disruptor (Constant Systems Ltd) 20,000 psi, then centrifuged at 2 X 50,000 X g for 30 minutes at 4°C. GASC1 protein was purified from the supernatant using Talon metal affinity resin (Clontech) according to manufacturer's protocol. In summary Talon affinity resin was equilibrated using 20 X bed volumes of lysis buffer (1 ml bed volume per litre of cell culture) and then incubated with the soluble cell extract at 4°C with agitation for 30-60 minutes. The resin was then loaded onto disposable chromatography columns (Bio-Rad) and washed using 20 X bed volumes of wash buffer. Protein was eluted with 6 X (1 ml / ml resin) fractions using the elution buffer. Finally, protein concentration was measured using Protein assay reagent (Bio-Rad) and GASC1 containing fractions were pooled and buffer changed on a PD-10 desalting column (GE Healthcare) to stabilizing buffer. Protein concentration was adjusted to 1 .5 - 2.0 mg/ml and flash frozen. This E. coli expressed fragment of GASC1 contains the active site of the full length enzyme and has the capability of demethylating the trimethyl Wink-78 substrate.
Example 7
Human tumour xenografts in immunodeficient mice
Human tumour cells are harvested from monolayer cultered cells using appropriate enzymes, e.g. trypsin. The cells are suspended in media plus serum and quantified. The cell suspension is centrifuges and the cells are re-suspended in serum-free medium to a suitable cell concentration.
Alternatively, a human tumour is transferred to a sterile petri dish with medium plus antibiotics and tumour tissue is cut into pieces of approx. 5x5x5 mm. 5-7 week old nude athymic mice (nu/nu) or SCID mice (scid/scid) are anesthetized and a volume (e.g. 100 μg) of suspended tumour cells is injected corresponding to a suitable total cell number (e.g. between 105 and 107 cells) under the skin of the lower flank of the mice or at another appropriate site. Alternatively, the mice are anesthetized, a small incision of 5 mm in length at an appropriate site is made and a tumour piece is inserted into the incision. A antibiotics solution is dropped over the incision, which is closed, e.g. using tissue adhesive.
For the experiment the mice are divided into different treatment groups for testing of compound, e.g. following the scheme below:
Treatment Grafting of
Group No Treatment applied from tumour
day cells/tissue
1 - - -
2 - - +
3 Compound 0 +
4 Compound 3 +
5 Compound 14 +
6 Control chemotherapy 0 +
7 Control chemotherapy 3 +
8 Control chemotherapy 14 + In addition, groups for testing different concentrations of compound can be included. Depending on the model and the tumour types, a tumour will start to appear at the site of the graft after a period of 1 -4 months, which can be measured in size at specific timepoints to determine the result of the experiment. Depending on the model, the number of metastases in different organs can alternatively be counted as a measure of tumour growth.
Active compounds will lead to a decreased tumour size or number of metastases.

Claims

Claims
1 . A compound of Formula (I)
Figure imgf000110_0001
an isomer or a mixture of isomers thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Xi represents -A-B, wherein
A represents a bond, O, S, or NH, and
B represents
• Ci-6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5 cycloalkyl
which d-e-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3-5 cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyi, methylsulfamoyi, dimethylsulfamoyi, methylsulfonyl, methylsulfonyloxo, methylsulfinyl, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group,
R' represents hydroxy, Ci-4-alkyl, halogen-Ci_4-alkyl, Ci.4-alkoxy, -NH2, methylamino, cyclopropyl, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group; or
-OH, with the proviso that B only represent -OH, when A is a bond; or
-(C=0)R",
where R" represents hydroxy, halogen-Ci.4-alkyl, Ci.4-alkoxy, hydroxy-Ci_4- alkoxy, -NH2, Ci.3-alkyl-amino, di-Ci.3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group, C3.4-cycloalkyl or C1-4-alkyl, wherein said C3-4- cycloalkyl or Ci-4 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3- alkoxy, hydroxy-Ci_3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R\ a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above;
-(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino; sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two C1-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of Ci-4-alkyl, halogen-Ci-4-alkyl, carbonyl-Ci-3-alkyl, methylsulfamoyl, C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3- alkyl-amino, dimethylaminoethyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; a phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-3-alkyl, Ci-3-alkoxy, Ci-3-alkoxyalkoxy, Ci-3-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, cyclopropyl and Ci-3-alkyl, wherein said cyclopropyl or Ci-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, cyclopropyl, Ci- 3-alkoxy, hydroxy-Ci-3-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', , where R' is as identified above; and
X2 represents
• -COOH, (C=0)NH2 or -CN and
X3 represents
• Hydrogen or -OH; or · -Y-Xa-Xb, where
Y is O, C=0 or a bond; and
Xa is -a bond, C1- 8-alkyl, C2.i8-alkenyl, C2.i8-alkynyl, C3.i0-cycloalkyl, -C1 18-alkyl- 0-, -O- or -NXb-, with the proviso that when Y is O, then Xa is not O; and each Xb is individually -H, C3-6-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, a 5- membered monocyclic heterocyclic group, a 6-membered monocyclic
heterocyclic group or a bicyclic heteroaromatic group, which C3-i0-cycloalkyl, Ci-6- alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6- membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, hydroxy linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4-alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci.5-alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci_4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl,
methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined above; and
X4 and X5 independently of each other represent
• hydrogen, Ci-4-alkyl, halogen-Ci-4-alkyl, C3-6-cycloalkyl, halogen, nitro, - NH2,methoxycarbonyl, acetyl, methoxycarbamoyl or cyano; with the proviso that the compound is not
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-; or Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-methylphenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-(trifluoromethyl)phenyl]methoxy]-; or
Acetic acid, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-, ethyl ester; or
Acetamide, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(cyanomethoxy)-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-hydroxy-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-bromophenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(3-cyanophenyl)methoxy]-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(phenylmethoxy)-; or
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-methoxy-.
2. The compound according to claim 1 , wherein X! comprises at least one polar moeity selected from the group consisting of oxy, sulfonyl, sulfinyl, sulfanyl, carbonyl, cyano and amino, wherein each of the aforementioned polar moieties may be substituted.
3. The compound according to claim 2, wherein said polar moiety is position at the most 3 atoms away from the pyrido[1 ,2-a]indole.
4. The compound according to any one of claims 1 to 3, wherein A represents a bond, and B represents
• Ci-6-alkyl, C2-4-alkenyl, C2-4-alkynyl or C3.5-cycloalkyl, which C1-6-alkyl, C2-4-alkenyl, C2. 4-alkynyl or C3.5-cycloalkyl may optionally be substituted as indicated in claim 1 ; or
• -OH; or
• -(C=0)R", where R" is as defined in claim 1 ,
· -(C=0)NH-R"\
where R'" is as defined in claim 1 ,
• sulfamoyl, dimethylsulfamoyl, sulfinyl, sulfanyl or sulfonyl, which sulfinyl, sulfanyl and sulfonyl may optionally be substituted as indicated in claim 1 , or
• a phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
5. The compound according to any one of claims 1 to 3, wherein A represents O and B represents
• d-e-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3-5-cycloalkyl, which Ci-6-alkyl, C2.4-alkenyl, C2. 4-alkynyl or C3-5-cycloalkyl may optionally be substituted as indicated in claim 1 ,
• -(C=0)R", where R" is as defined as indicated in claim 1 ,
• -(C=0)NH-R"\ where R'" is as defined in claim 1 ;
• sulfamoyl, dimethylsulfamoyl, sulfinyl, sulfanyl or sulfonyl, which sulfinyl, sulfanyl and sulfonyl may be substituted as indicated in claim 1 , or
· phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
6. The compound according to any one of claims 1 to 3, wherein A represents S and B represents
· d-e-alkyl, C2.4-alkenyl, C2.4-alkynyl or C3-5-cycloalkyl, which d-e-alkyl, C2.4-alkenyl, C2. 4-alkynyl or C3.5-cycloalkyl may optionally be substituted as indicated in claim 1 ; or
• phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
7. The compound according to any one of claims 1 to 3, wherein A represents NH and B represents
• -(C=0)R", where R" is as defined in claim 1 , or
• sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may be substituted as indicated in claim 1 or
• phenyl, a monocyclic or bicyclic heterocyclic group, which phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
8. The compound according to any one of claims 1 to 3, wherein A represents a bond, O, S or NH and B represents Ci-6-alkyl, C2-4-alkenyl or C2-4-alkynyl which Ci-6-alkyl, C2.
4-alkenyl or C2-4-alkynyl may optionally be substituted as indicated in claim 1 .
9. The compound according to any one of claims 1 to 3, wherein A represents a bond, O or NH and B represents -(C=0)R" or -(C=0)NH-R"\ where R" and R'" is as defined in claim 1 .
10. The compound according to any one of claims 1 to 3, wherein A represents a bond, O or NH and B represents sulfamoyl, sulfinyl, sulfanyl, dimethylsulfamoyl or sulfonyl, which sulfinyl, sulfanyl or sulfonyl may be substituted as indicated in claim 1 .
1 1 . The compound according to any one of claims 1 to 3, wherein A represents a bond, O, S or NH and B represents phenyl, which phenyl may optionally be substituted as indicated in claim 1 .
12. The compound according to any one of claims 1 to 3, wherein A represents a bond, O, S or NH and B represents a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
13. The compound according to any one of claims 1 to 12, wherein the compound comprises at least one monocyclic or bicyclic heterocyclic group, which may be selected from the group consisting of
• a 5-membered monocyclic heterocyclic group,
• a 6-membered monocyclic heterocyclic group, • a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6- membered carbocyclic group,
• a bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6- membered carbocyclic group,
· a bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6- membered heterocyclic group,
• a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6- membered heterocyclic group,
• a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups, · a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom,
• a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom, and
• a bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom,
which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
14. The compound according to any one of claims 1 to 13, wherein the compound comprises at least one monocyclic heterocyclic group, which is a 5-membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group.
15. The compound according to any one of claims 1 to 14, wherein the compound comprises at least one monocyclic heterocyclic group, which is a 5-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S.
16. The compound according to any one of claims 1 to 15, wherein the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3- thiazolyl, and 1 ,2,5-oxadiazolyl.
17. The compound according to any one of claims 1 to 14, wherein the compound comprises at least one monocyclic heterocyclic group, which is a 6-membered monocyclic heterocyclic group comprising 1 , 2, or 3 heteroatoms each independently selected among N, O, and S.
18. The compound according to any one of claims 1 to 14 and 17, wherein the 6- membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4- dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
19. The compound according to any one of claims 1 to 13, wherein the compound comprises at least one bicyclic heterocyclic group comprising 1 , 2, 3, or 4 heteroatoms each independently selected among N, O, and S.
20. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered carbocyclic group.
21 . The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6-membered carbocyclic group.
22. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6-membered heterocyclic group.
23. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6-membered heterocyclic group.
24. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups.
25. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom.
26. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom.
27. The compound according to any one of claims 1 to 13 and 19, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom.
28. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl.
29. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents Ci-6 alkyl substituted one time with dimethylamino.
30. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents Ci-3 alkyl, which Ci-3 alkyl is substituted one time with -(C=0)R', where FT represents hydroxy, methyl, trifluoromethyl, methoxy, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group optionally may be substituted as indicated in claim 1 .
31 . The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents -(C=0)R", where R" is as indicated in claim 1 .
32. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents -(C=0)R", wherein R" represents hydroxy, C1-3-alkyl, halogen-Ci_4- alkyl, -NH2, Ci.3-alkyl-amino, di-Ci.3-alkyl-amino or a 5- or 6-membered monocyclic heterocyclic group.
33. The compound according to any one of claims 1 to 3, wherein A represents a bind and B represents -(C=0)R", wherein R" represents hydroxy, Ci-3-alkyl, fluoro-Ci-4- alkyl, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino or a 6-membered monocyclic heterocyclic aliphatic group.
34. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents -(C=0)R", where R" represents hydroxy, methyl, trifluoromethyl, -
NH2, methylamino, dimethylamino or morpholinyl.
35. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents sulfamoyl, which sulfamoyl optionally is substituted with one or more d-3-alkyl.
36. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represent sulfinyl, sulfanyl or sulfonyl, which sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of d. 4-alkyl or C3.6-cycloalkyl.
37. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents sulfamoyl, sulfinyl, sulfanyl or sulfonyl, which sulfamoyl, sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, methylamino, dimethylamino, dimethylaminoethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group.
38. The compound according to claim 37, wherein B represents sulfamoyl.
39. The compound according to any one of claims 1 to 3, wherein A represents a bond and B represents a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting C1-4-alkyl, halogen, halogen-Ci-2- alkyl, Ci-4-alkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
40. The compound according to any one of claims 30, 32, 37 and 39, wherein the 5- membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2- thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl.
41 . The compound according to any one of claims 30, 32, 37 and 39, wherein the 5- membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl.
42. The compound according to any one of claims 30, 32, 33, 37 and 39, wherein the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4- dioxinyl, 1 ,4-dioxanyl, 1 ,3-diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
43. The compound according to any one of claims 30, 32, 33, 37, 39 and 42, wherein the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl and morpholinyl.
44. The compound according to any one of claims 30, 32, 33, 37, 39, 42 and 43, wherein the 6-membered monocyclic heterocyclic group represents piperazinyl or morpholinyl.
45. The compound according to any one of claims 1 to 3, wherein A represents O and B represents Ci-6-alkyl, C2-4-alkenyl, or C2-4-alkynyl, where the d-e-alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
46. The compound according to claim 45, wherein the Ci_6-alkyl is methyl.
47. The compound according to claim 45, wherein the C2.4-alkenyl is selected from the group consisting of ethenyl, 1 - propenyl, 2-propenyl, 1 - butenyl, 2- butenyl, 3-butenyl, and 1 ,3- butenyl.
48. The compound according to claim 45, wherein the C2-4-alkynyl is selected from the group consisting of ethynyl, 1 - propynyl, 2-propynyl, 1 - butynyl, 2- butynyl, 3-butynyl, and1 ,3-butynyl.
49. The compound according to any of claims 45 to 48 wherein B is selected from the group consisting of methyl, isopropyl, isobutyl, isopentyl, 1 - butenyl, 2-butenyl, 1 -, butynyl and 2-butynyl.
50. The compound according to any one of claims 1 to 3, wherein A represents O and B represents C^e-alkyl, which Ci_6-alkyl is substituted one time with cyano.
51 . The compound according to claim 50, wherein B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
52. The compound according to claim 50, wherein B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl.
53. The compound according to any of claims 50-52, wherein B is substituted with cyclopropyl in addition to the cyano substituent.
54. The compound according to any of claims 50 to 52, wherein B is selected from the group consisting of cyanomethyl, cyano(cyclopropyl)methyl, 1 -cyanoethyl, 1 -cyano-2- methylethyl, 1 -cyanopropyl, 3-cyanopropyl, 1 -cyano-2-methylpropyl, 1 -cyanobutyl, 2- cyanobutyl 3-cyanobutyl, and 4-cyanobutyl.
55. The compound according to any of claims 50 to 52, wherein B represents cyanomethyl.
56. The compound according to any one of claims 1 to 3, wherein A represents O and B represents C^e-alkyl, which Ci_6-alkyl is substituted with Ci.4-alkoxy, hydroxy-Ci_4- alkoxy, -NH2, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
57. The compound according to claim 56, wherein B represents butyl substituted with hydroxy.
58. The compound according to claim 56, wherein B represents methyl or ethyl, which methyl or ethyl is substituted one or more times with a substituent selected from the group consisting of methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, -NH2, halogen, methylamino, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
59. The compound according to claim 56, wherein B represents methyl substituted with pyridinyl, thiazolyl or pyrazolyl, each of which may independently of each other be substituted with one or more substituents selected from the group consisting of methyl, chloro and fluoro.
60. The compound according to claim 56, wherein B represents ethyl, which ethyl is substituted one or more times with a substituent selected from the group consisting of ethoxy, hydroxyethoxy, dimethylamino morpholinyl and piperidinyl.
61 . The compound according to any one of claims 1 to 3, wherein A represents O and B represents propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which propyl, isopropyl, butyl , isobutyl, secondary butyl, or tertiary butyl is substituted · with a first substituent selected from the group consisting of dimethylamino and a 5- or 6-membered monocyclic heterocyclic group, comprising at least one nitrogen atom in its ring structure where said nitrogen atom is positioned so as to form the binding link between said propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl and the rest of the compound of Formula (I), and
· with a second substituent selected from the group consisting of hydroxy, cyano, methylsulfonyloxy and -(C=0)R', where FT represents hydroxy, methyl, trifluoromethyl, methoxy, NH2.
62. The compound according to any one of claims 58 to 61 , wherein the 5- or 6- membered monocyclic heterocyclic groups is selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, piperidinyl, pyridinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3-pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,5- oxadiazolyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 4H-1 ,4-oxazinyl, morpholinyl, and thiomorpholinyl.
63. The compound according to claim 61 , wherein B represents isopropyl substituted with a first substituent, which is 1 -pyrrolidinyl, and with a second substituent selected from the group consisting of cyano and -(C=0)R', where R' represents an alkoxy group, preferably a methoxy group.
64. The compound according to claim 61 , wherein B represents isopropyl substituted with a first substituent, which is dimethylamino, and with a second substituent selected from the group consisting of cyano and -(C=0)R', where R' represents hydroxy, -NH2, methyl, and trifluoromethyl.
65. The compound according to claim 61 , wherein B preferably represents butyl substituted with dimethylamino and hydroxy.
66. The compound according to any one of claims 1 to 3, wherein A represents O and B represents Ci-6-alkyl, which Ci_6-alkyl is substituted with -(C=0)R', where R' represents Ci-4-alkyl, halogen-Ci-4-alkyl, hydroxy, -NH2, methylamino or dimethylamino.
67. The compound according to claim 66, wherein B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted one time with -(C=0)R', where R' represents hydroxy, -NH2, or dimethylamino.
68. The compound according to claim 66, wherein B represents isopropyl, which isopropyl is substituted one time with -(C=0)R', where R' represents hydroxy, -NH2, or dimethylamino.
69. The compound according to claim 66, wherein B represents methyl, ethyl, propyl or isopropyl and R' represents methyl, trifluoromethyl, hydroxy, -NH2, methylamino or dimethylamino.
70. The compound according to claim 66, wherein B represents methyl or isopropyl and FT represents hydroxy, methyl, trifluoromethyl or dimethylamino.
71 . The compound according to any one of claims 1 to 3, wherein A represents O and B represents methyl, which methyl has been substituted one time with -(C=0)R', where
FT represents phenyl, which phenyl has been substituted one or two times with halo.
72. The compound according to claim 71 , wherein phenyl is substituted two times with fluoro so as to form a difluorophenyl group.
73. The compound according to any one of claims 1 to 3, wherein A represents O and B represents C^e-alkyl, which Ci_6-alkyl is substituted with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
74. The compound according to claim 73, wherein B represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted one time with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
75. The compound according to claim 73, wherein B represents isopropyl, which isopropyl is substituted one time with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl and methylsulfonyl.
76. The compound according to any one of claims 1 to 3, wherein A represents O and B represents C^e-alkyl, which Ci_6-alkyl is substituted with phenyl, which phenyl may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci_2-alkyl, halogen, halogen-Ci-2-alkyl, Ci-4-alkoxy, Ci.4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
77. The compound according to claim 76, wherein B represents methyl, which methyl is substituted with phenyl, which phenyl is substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, cyano, acetamino and methylsulfonylamino.
78. The compound according to any one of claims 1 to 3, wherein A represents O and B represents -(C=0)R", where R" represents Ci-3-alkyl, Ci-4-alkoxy, hydroxy-Ci-4- alkoxy, -NH2, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, fluoro and chloro.
79. The compound according to claim 78, wherein R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group.
80. The compound according to claim 78, wherein R" is selected from the group consisting of methyl, ethoxy, dimethylamino, pyrrolidinyl and morpholinyl.
81 . The compound according to any one of claims 1 to 3, wherein A represents O and B represents sulfamoyi, sulfinyl, sulfanyl or sulfonyl, which sulfamoyi may optionally be substituted with one or two d-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci-2-alkyl, halogen, halogen-Ci-2-alkyl, Ci-4-alkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
82. The compound according to claim 81 , wherein B represents sulfamoyi, dimethylsulfamoyl, methylsulfonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl or sulfonyl, which sulfonyl is optionally substituted with oxazolyl or thiazolyl, which oxazolyl or thiazolyl may optionally be substituted with one or more methyl.
83. The compound according to any one of claims 1 to 3, wherein A represents O and B represents a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more of the substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, -COOH, cyano and dimethylamino.
84. The compound according to claim 83, wherein the 5-membered monocyclic heterocyclic group may be selected from the group consisting of pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl, and 1 ,2,5-oxadiazolyl.
85. The compound according to claim 83, wherein the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, oxolanyl, pyrazolyl, 3H-pyrazolyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl and 1 ,3-thiazolyl.
86. The compound according to claim 83, wherein the 6-membered monocyclic heterocyclic group may be selected from the group consisting of piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1 ,2-diazinanyl, pyrimidinyl, 1 ,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1 ,3- diazinanyl, 1 ,4-oxazinyl, morpholinyl, thiomorpholinyl and 1 ,4-oxathianyl.
87. The compound according to claim 83, wherein the 6-membered monocyclic heterocyclic groups may be selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and morpholinyl.
88. The compound according to any one of claims 1 to 3, wherein A represents NH or A represents a bond and B represents a 5- or 6-membered monocyclic heterocyclic group, comprising at least one nitrogen atom in its ring structure where said nitrogen is positioned so as to form the binding link to the compound of Formula (I).
89. The compound according to any one of claims 1 to 3, wherein A represents NH and B represents -(C=0)R", where R" represents C1-4-alkyl, Ci.4-alkoxy, -NH2,
methylamino, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting Ci_2-alkyl, halo, halo- Ci_2-alkyl, Ci.4-alkoxy, Ci_4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
90. The compound according to claim 89, wherein R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group.
91 . The compound according to claim 89, wherein R" represents methyl or
dimethylamino.
92. The compound according to any one of claims 1 to 3, wherein A represents NH and B represents sulfamoyi, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfinyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, trifluoromethyl, cyclopropyl and a 5- or 6-membered monocyclic heterocyclic group, which 5- or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting d-2-alkyl, halogen, halogen-Ci-2-alkyl, Ci.4-alkoxy, Ci_4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
93. The compound according to claim 92, wherein R' represents methylsulfonyl.
94. The compound according to any one of claims 1 to 3, wherein Xi is selected from the group consisting of methoxy, hydroxy, acetyl, trifluoroacetyl, cyclopropylsulfonyl, cyclopropylsulfonyloxy, cyanomethoxy, methylcarbamoyl, dimethylcarbamoyl, dimethylcarbamoyloxy, morpholine-4-carboxylate, COOH, carbamoyl, morpholine- 4ylcarbonyl, methylsulfonyl, methylsulfinyl, methylsulfanyl, sulfamoyi, sulfamoyloxy and dimethylsulfamoyl.
95. The compound according to any one of claims 1 to 94, wherein X2 is COOH or (C=0)NH2
96. The compound according to any one of claims 1 to 95, wherein X2 is COOH.
97. The compound according to any one of claims 1 to 95, wherein X2 is (C=0)NH2
98. The compound according to any one of claims 1 to 97, wherein X3 is -H
99. The compound according to any one of claims 1 to 97, wherein X3 is -OH
100. The compound according to any one of claims 1 to 97, wherein X3 comprises a lipophilic moiety selected from the group consisting of phenyl, a 5 or 6 membered heterocyclic ring, a bicyclic heterocyclic ring or an aliphatic chain comprising in the range of 1 to 18 carbons, wherein the lipophilic moiety may be substituted.
101 . The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -Y-Xa-Xb, wherein Y is O, C=0 or a bond and Xa is C1-6-alkyl, -Ci-6-alkyl-0- or -O- and Xb is H, d.6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which d.6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen- Ci-4alkyl, linear or branched Ci-4- alkoxy, or linear or branched d-5 alkyl.
102. The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -Y-Xa-Xb, wherein Y is O, C=0 or a bond and Xa is C1-3-alkyl or -Ci-2-alkyl-0- and Xb is H, Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heteroaromatic ring or a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6- membered heterocyclic group, which Ci-e-alkoxy, phenyl, phenoxy, a 5 or 6 membered heteroaromatic ring or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl.
103. The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -Y-Xa-Xb, wherein Y is -O-or C=0 and Xa is C1-18-alkyl, C2-i8-alkenyl, C2-i8- alkynyl, C3-io-cycloalkyl, -O- or -NXb- and Xb is -H, C3-6-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3-i0-cycloalkyl, Ci-6- alkoxy, phenyl, phenoxy, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4- alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched Ci-5-alkyl, wherein said Ci-5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined in claim 1 .
104. The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -Y-Xa-Xb, wherein Y is O, or C=0 and Xa is d-6-alkyl or -Ci-6-alkyl-0- and Xb is H , Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci.6-alkoxy, phenyl, phenoxy, a 5 or 6 membered
heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen-Ci.4alkyl, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl.
105. The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -0-Xa-Xb,and Xa is C1-18-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-i 0-cycloalkyl, - O- or -NXb- and Xb is -H , C3-6-cycloalkyl, Ci-6-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heteroaromatic group, which C3-i o-cycloalkyl, Ci-e-alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heteroaromatic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, linear or branched Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4-alkoxycarbonyl, Ci-4-alkylcarbonyl, COOH , cyano, -NH2, methylamino, dimethylamino, hydroxy and linear or branched d_ 5-alkyl, wherein said C1 -5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-C1 -4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0) R\ a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, wherein R' is as defined in claim 1 .
106. The compound according to any ones of claims 1 to 97 and 100, wherein X3 represents -0-Xa-Xb, where Xa is -a bond, Ci_18-alkyl, C2-i8-alkenyl, C2-i 8-alkynyl, C3-i 0- cycloalkyl, -O- or -NXb-; and Xb is -H , C3-6-cycloalkyl, Ci-6-alkoxy, phenyl, phenoxy, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, which Ci-e-alkoxy, phenyl, phenoxy, 5- membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of linear or branched Ci-5-alkyl, Ci-6- alkoxycarbonyl, Ci-4-alkylcarbonyl, -OH, linear or branched Ci-6- alkoxy or halogen.
107. The compound according to any one of claims 1 to 97 and 100, wherein X3 represents -0-Xa-Xb, wherein Xa is C1-6-alkyl or -Ci-6-alkyl-0- and Xb is H, Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group, which Ci-6-alkoxy, phenyl, phenoxy, a 5 or 6 membered heterocyclic group or bicyclic heterocyclic group may optionally be substituted with one or more selected from the group consisting of halogen, halogen-Ci-4alkyl, linear or branched Ci-4- alkoxy, or linear or branched Ci-5 alkyl.
108. The compound according to any one of claims 100 to 107, wherein said 5 or 6 membered heteroaromatic ring or bicyclic heterocyclic group comprises 1 or 2 heteroatoms, wherein said heteroatoms individually are N or O.
109. The compound according to any one of claims 100 to 107, wherein said 5 membered heteroaromatic ring is oxazolyl.
1 10. The compound according to any one of claims 100 to 107, wherein said 6 membered heteroaromatic ring is pyridinyl.
1 1 1 . The compound according to any one of claims 100 to 107, wherein said bicyclic heterocyclic group is imidazolyl.
1 12. The compound according to any one of claimsl to 97 and 100, wherein X3 is selected from the group consisting of -H, hydroxyl, methoxy, phenylethoxy, pyridine-3- yiethoxy, pyridine-3ylmethoxy, ethoxyphenyl-4-ethoxy, ethoxypyridinethoxy, pro-2yloxy- phenylethoxy, ethoxyphenylmethoxy, diethyl-imidazol-ethoxy, 5-methyl-1 ,3-oxazol- 2ylpropoxyl, 2-tertbutyl-1 ,3-oxazol-5ylmethoxy and 3-chloro-phenoxyethoxymethyl.
1 13. The compound according to any of the preceding claims 1 to 1 12, wherein X4 and X5 represents independently of each other hydrogen, Ci-4-alkyl, halo-Ci_4-alkyl, C3-6- cycloalkyl, halogen, nitro, -NH2, methoxycarbonyl, acetyl, methoxycarbamoyl or cyano.
1 14. The compound according to any one of claims 1 to 1 12, wherein X4 and X5 independently of each other is selected from the group consisting of hydrogen, Ci-4- alkyl, and C3-6-cycloalkyl.
1 15. The compound according to any one of claims 1 to 1 12, wherein X4 and X5 both represents hydrogen.
1 16. The compound according to any one of claims 1 to 1 12, wherein X4 represents hydrogen and X5 is selected from the group consisting of C1-4-alkyl, and C3-6-cycloalkyl.
1 17. The compound according to any one of claims 1 to 1 12, wherein X5 represents hydrogen and X4 is selected from the group consisting of C1-4-alkyl, and C3-6-cycloalkyl.
1 18. The compound according to claim 1 , wherein Xi represents A-B, wherein A is O and B is
• d-e-alkyl, C2-4-alkenyl or C2-4-alkynyl,
which d-e-alkyl, C2-4-alkenyl or C2.4-alkynyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6- cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -
(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where
FT represents hydroxy, C1-4-alkyl, halogen-Ci-4-alkyl, Ci-4-alkoxy, -NH2, methylamino, dimethylamino, a phenyl group or a monocyclic or bicyclic heterocyclic group; and where the phenyl group may be substituted with one or more of the substituents selected from the group consisting of methyl, trifluoromethyl, halogen, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group; or
• -OH; or
-(C=0)R",
where R" represents hydroxy, halogen-Ci.4-alkyl, Ci.4-alkoxy, hydroxy-Ci_4- alkoxy, -NH2, Ci.3-alkyl-amino, di-Ci.3-alkyl-amino, methylsulfonyl, a monocyclic or bicyclic heterocyclic group or C1-3-alkyl, wherein said Ci-3 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-3-alkoxy, hydroxy-Ci-3-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halo-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above;
• -(C=0)NH-R"\
where R'" represents hydroxyethyl, methoxyethyl, dimethylaminoethyl, methanesulfonyl or -0-Ci-6-alkyl optionally substituted with dimethylamino;
• sulfamoyl, sulfinyl, sulfanyl or sulfonyl,
which sulfamoyl may optionally be substituted with one or two C1-3-alkyl groups and said sulfinyl, sulfanyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of C1-4-alkyl, halogen-Ci-4-alkyl,
C3-6-cycloalkyl, Ci-3-alkyl-amino, di-Ci-3-alkyl-amino, dimethylaminoehtyl, a 6 membered heterocyclic ring, and a monocyclic or bicyclic heterocyclic group; phenyl, monocyclic or bicyclic heterocyclic group , where the phenyl, monocyclic or bicyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of halogen, halogen-Ci-4-alkyl, Ci-4-alkoxy, Ci-6-alkoxyalkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino, dimethylamino and Ci-5-alkyl, wherein said Ci 5 alkyl optionally may be substituted with one or more substituents selected from the group consisting of hydroxy, C3-6-cycloalkyl, Ci-4-alkoxy, hydroxy-Ci-4-alkoxy, -NH2, methylamino, dimethylamino, 6 membered heterocyclic ring, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, cyano, -(C=0)R', a halogen-phenyl group, and a monocyclic or bicyclic heterocyclic group, where R' is as identified above; and
X2 represents -COOH or (C=0)NH2; and
X3, X4 and X5 are -H.
1 19. The compound according to claim 1 18, wherein B is C1-3-alkyl, Ci_3-alkyl substituted with cyano or (C=0)R", wherein R" is Ci.3-alkylamino or di-Ci.3-alkylamino or a 6-membered heterocyclic group.
120. The compound according to claim 1 18, wherein B is selected from the group consisting of methyl, cyanomethyl and (C=0)R", wherein R" is dimethylamin or morpholinyl.
121 . The compound according to claim 1 , wherein the compound is selected from the group consisting of
3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-methoxypyrido[1 ,2-a]indole-10-carboxamide;
3-hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetylpyrido[1 ,2-a]indole-10-carbonitrile;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxamide;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carbonitrile;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carbonitrile;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-cyanopyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
1 -(2-phenylethoxy)-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(2-phenylethoxy)-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoyl-1 -(2-phenylethoxy)pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -(2-phenylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid; 1 -(2-pyridin-3-ylethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -(pyridin-3-ylmethoxy)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -[2-(4-ethoxyphenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(4-ethoxyphenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -[2-(4-ethoxyphenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile; 1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid; 1 -[2-(4-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 1 -[2-(3-ethoxyphenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(3-ethoxyphenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -[2-(3-ethoxyphenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile;
1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -[2-(3-ethoxyphenyl)ethoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
1 -[2-(6-ethoxypyridin-3-yl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[2-(6-ethoxypyridin-3-yl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid; 10-carbamoyl-1 -[2-(6-ethoxypyridin-3-yl)ethoxy]pyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole- 10-carboxylic acid;
10-carbamoyl-1 -[2-(4-(propan-2-yloxy)phenyl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(4-ethoxyphenyl)methoxy-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(4-ethoxyphenyl)methoxy-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -(4-ethoxyphenyl)methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -(3-ethoxyphenyl)methoxy-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -(3-ethoxyphenyl)methoxy-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylic acid;
10-carbamoyl-1 -(3-ethoxyphenyl)methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]-10-cyanopyrido[1 ,2-a]indol-3-yl
dimethylcarbamate;
1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]-3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2- a]indole-10-carboxylic acid;
10-carbamoyl-1 -[2-(1 ,2-diethyl-1 H-imidazol-4-yl)ethoxy]pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carbonitrile;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylic acid;
1 -[3-(5-methyl-1 ,3-oxazol-2-yl)propoxy]-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxamide;
1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carbonitrile; 1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -[(2-tert-butyl-1 ,3-oxazol-5-yl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide; 1 -(2-phenylethoxy)-7-methyl-10-cyanopyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -(2-phenylethoxy)-3-[(dimethylcarbamoyl)oxy]-7-methyl-pyrido[1 ,2-a]indole-10- carboxylic acid; 7-methyl-10-carbamoyl-1 -(2-phenylethoxy)pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -{[2-(3-chlorophenoxy)ethoxy]methyl}pyrido[1 ,2-a]indol-3-yl dimethylcarbamate; 1 -{[2-(3-chlorophenoxy)ethoxy]methyl}-3-[(dimethylcarbamoyl)oxy]-pyrido[1 ,2-a]indole- 10-carboxylic acid;
10-carbamoyl-1 -{[2-(3-chlorophenoxy)ethoxy]methyl}pyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
pyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-carbamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoylpyrido[1 ,2-a]indole-3-carboxylic acid;
pyrido[1 ,2-a]indole-3,10-dicarboxamide;
N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxamide;
N3-methylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxamide;
3-sulfamoylpyrido[1 ,2-a]indole-10-carboxamide;
3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 ,3-dihydroxypyrido[1 ,2-a]indole-10-carboxylic acid; 3-hydroxy-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(cyclopropylsulfonyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(cyclopropylsulfonyl)oxy]-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxy-3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -methoxy-3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(dimethylcarbamoyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(dimethylcarbamoyl)oxy]-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxy-3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -methoxy-3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid; 3-(cyanomethoxy)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-3-carboxylic acid;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-3-carboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -hydroxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 ,3-dihydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-hydroxy-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl cyclopropanesulfonate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl cyclopropanesulfonate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl sulfamate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl sulfamate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl dimethylcarbamate;
10-carbamoyl-1 -hydroxypyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
10-carbamoyl-1 -methoxypyrido[1 ,2-a]indol-3-yl morpholine-4-carboxylate;
3-(cyanomethoxy)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-(cyanomethoxy)-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxamide;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxamide; 3-(cyclopropylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
pyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-carbamoylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(morpholin-4-ylcarbonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(methylsulfinyl)pyrido[1 ,2-a]indole-10-carboxylic acid;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-carbamoyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(dimethylcarbamoyl)-1 -methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetyl-1 -hydroxypyrido[1 ,2-a]indole-10-carboxamide;
3-acetyl-1 -methoxypyrido[1 ,2-a]indole-10-carboxamide;
1 -hydroxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxypyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -hydroxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
1 -methoxy-N3,N3-dimethylpyrido[1 ,2-a]indole-3,10-dicarboxamide;
3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylic acid;
3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylic acid; 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid;
3-acetylpyrido[1 ,2-a]indole-10-carbonitrile;
10-cyanopyrido[1 ,2-a]indol-3-yl trifluoromethanesulfonate; and
3-(methanesulfonylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylic acid.
122. The compound according to claim 1 , wherein the compound is selected from the group consisting of
3-methoxypyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid;
3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide;
3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid; and
3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylic acid.
123. A compound according to any of the preceding claims 1 to 122 or a compound selected from the group consisting of
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-methylphenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[[3-(trifluoromethyl)phenyl]methoxy]-;
Acetic acid, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-, ethyl ester;
Acetamide, 2-[(10-cyanopyrido[1 ,2-a]indol-3-yl)oxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(cyanomethoxy)-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-hydroxy-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(4-bromophenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-[(3-cyanophenyl)methoxy]-;
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-(phenylmethoxy)-; and
Pyrido[1 ,2-a]indole-10-carbonitrile, 3-methoxy- for the treatment of a HDME dependent disease.
124. The compound according to any one of claims 1 to 123, wherein said compound is for the treatment of cancer.
125. The compound according to any one of claims 1 to 123, wherein said compound is for the treatment of squamous cell carcinomas.
126. The compound according to any one of claims 1 to 123, wherein said compound is for the treatment of a tumour in the brain.
127. The compound according to any one of claims 1 to 123, wherein said compound is for the treatment of breast cancer.
128. The compound according to any one of claims 1 to 123, wherein said compound is for the treatment of prostate cancer.
129. The compound according to any of claims 123 to 129, wherein the compound is prepared for administration in combination with one or more further substances.
130. The compound according to claim 129, wherein the one or more further active substances are one or more medications for treatment of cancer.
131 . The compound according to claim 129, wherein the one or more further active substances are anti-neoplastic agents.
132. The compound according to claim 129, wherein the one or more further active substances are selected from the group consisting of immune stimulating agents, and cancer vaccines.
133. Use of a compound according to any one of claims 1 to 123 for the preparation of a medicament for treatment of a HDME dependent disease.
134. Use according to claim 133, wherein the HDME dependent disease is as defined in any of claims 124-128.
135. A pharmaceutical composition comprising at least one compound of Formula (I) according to any of claims 1 -123 as an active ingredient and optionally one or more pharmaceutically acceptable excipients, diluents or carriers.
136. The pharmaceutical composition according to claim 135, further comprising one or more further active substances.
137. The pharmaceutical composition according to claim 136, wherein the one or more further active substance are as defined in any of claims 130-132.
138. The pharmaceutical composition according to any one of claims 135 to 137, wherein said composition is for the treatment of a HDME dependent disease.
139. A method of treating a HDME dependent disease in a subject, said method comprises administering to said subject a therapeutically effective amount of at least one compound as defined in any one of claims 1 to 123 to a subject in need of such treatment.
140. The method according to claim 139, wherein the compound is administered in combination with one or more further active substances as defined in claims 130-132.
141 . The method according to any one of claims 139 to 140, wherein the HDME dependent disorder is as defined in any of claims 124 to 128.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI3023415T1 (en) * 2012-10-02 2018-01-31 Gilead Sciences, Inc. Inhibitors of histone demethylases
JP6514117B2 (en) 2013-02-27 2019-05-15 エピセラピューティクス アーペーエス Inhibitors of histone demethylase
EP3126345A1 (en) * 2014-03-31 2017-02-08 Gilead Sciences, Inc. Inhibitors of histone demethylases
TW201625536A (en) 2014-08-27 2016-07-16 艾比療法公司 Compounds and methods for inhibiting histone demethylases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043721A1 (en) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2010043866A2 (en) * 2008-10-15 2010-04-22 Isis Innovation Limited Histone lysine demethylase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043866A2 (en) * 2008-10-15 2010-04-22 Isis Innovation Limited Histone lysine demethylase inhibitors
WO2010043721A1 (en) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SPANNHOFF, A. ET AL.: "The Emerging Therapheutic Potential of Histone Methyltransferase and Demethylase Inhibitors", CHEMMEDCHEM, vol. 4, 2009, pages 1568 - 1582, XP002610580, DOI: doi:10.1002/cmdc.200900301 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
JP2016520528A (en) * 2013-03-15 2016-07-14 ジェネンテック， インコーポレイテッド Cancer treatment and anticancer drug resistance prevention method

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