WO2012007007A1 - Inhibitors of hdme - Google Patents

Inhibitors of hdme Download PDF

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Publication number
WO2012007007A1
WO2012007007A1 PCT/DK2011/050280 DK2011050280W WO2012007007A1 WO 2012007007 A1 WO2012007007 A1 WO 2012007007A1 DK 2011050280 W DK2011050280 W DK 2011050280W WO 2012007007 A1 WO2012007007 A1 WO 2012007007A1
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Prior art keywords
indole
pyrido
carboxylate
ethyl
methyl
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PCT/DK2011/050280
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French (fr)
Inventor
Marc Labelle
Christian A.G.N. Montalbetti
Richard John Mears
Julia Vile
Danny M. Gelman
Xinjie Gai
Oliver Robin Barker
Hervé Jean Claude DEBOVES
Stephen Peter East
Thomas Boesen
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Epitherapeutics Aps
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Publication of WO2012007007A1 publication Critical patent/WO2012007007A1/en

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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), which are useful for prevention and/or treatment of diseases in which genomic disregulation is involved in the pathogenesis, such as e.g. cancer.
  • HDMEs histone demethylases
  • 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)
  • Xi represents -A-B, wherein
  • A represents a bond, O, S or NH
  • B represents
  • R' represents hydroxy, Ci- 4 -alkyl, halo-Ci- 4 -alkyl, Ci- 4 -alkoxy, -NH 2 , 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, halo, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group;
  • R" represents hydrogen, hydroxy, Ci- 4 -alkyl, cyclopropyl, halo-Ci- 4 -alkyl, Ci_ 4 -alkoxy, -COOH, -NH 2 , methylamino, dimethylamino, methylsulfonyl, or a monocyclic or bicyclic heterocyclic group; or where R" represents Ci- 4 -alkyl, Ci- 4 -alkoxy, oxy, carbamoyl, amine or a monocyclic or bicyclic heterocyclic group, which is substituted with one or more substituents selected from the group consisting of hydroxy, methyl, ethyl, -0-Ci -6 - alkyl, hydroxymethyl, hydroxymethyl, methoxyethyl, acetyl, cyano,
  • ethoxycarbonyl dimethylamino, N-[3-(dimethylamino)propyl]- N'ethylcarbamimidoyl, methylsulfinyl, methylsulfanyl, methylsulfonyl,
  • methoxyethoxyethyl (dimethylamino)ethyl and methylsulfanylethyl, which -0-Ci_ 6-alkyl may optionally be substituted with hydroxy, methoxy or dimethylamino;
  • R'" represents -NH 2 , methylamino or dimethylamino
  • R" represents hydroxy or methoxy
  • sulfamoyl dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may optionally be substituted with one or more substituents selected from the group consisting of Ci- 4 -alkyl, halo-Ci- 4 -alkyl, methoxy-Ci- 4 -alkyl, dimethylamino, (dimethylamino)methyl, (dimethylamino)ethyl, C 3 - 6 -cycloalkyl, C 2 - 4 -alkenyl and a monocyclic or bicyclic heterocyclic group;
  • a monocyclic or bicyclic heterocyclic group where the monocyclic or bicyclic 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, -NH 2 , methylamino and dimethylamino; and
  • X 2 represents
  • Ci-18-alkyl C 2 .i 8 -alkenyl, or C 2 .i 8 -alkynyl
  • Ci-18-alkyl, C 2 .i 8 -alkenyl, C 2 _i 8 -alkynyl may optionally be substituted with one or more substituents selected from the group consisting of C 3 . 6 -cycloalkyl, hydroxy, halo, trifluoromethyl, Ci. 6 -alkoxy, hydroxy-Ci. 6 -alkoxy, C ⁇ e-alkyl -Ci_ 6 - alkoxy, trifluoromethyl-Ci. 6 -alkoxy, oxo-Ci.
  • Ci-18-alkyl, C 2 -i 8 -alkenyl, C 2 -i 8 -alkynyl, C 3 - 6 -cycloalkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of C 3 - 6 -cycloalkyl, hydroxy, halo, trifluoromethyl, Ci- 4 -alkyl, Ci-e-alkoxy, Ci- 6 -alkoxycarbonyl, Ci -4 - alkylamino, hydroxy-Ci- 6 -alkoxy, Ci- 6 -alkyl-Ci- 6 -alkoxy, trifluoro- Ci-e-alkoxy, triflu
  • X j , X j2 , X k , X m , X n independently of each other represent methyl, ethyl, propyl, amino, methylamino or dimethylamino,
  • methyl, ethyl or propyl may optionally be substituted with one or more substituents selected from the group consisting of methoxycarbonyl, dimethylamino, carbamoyl, phenyl, cyanophenyl, and a 5- or 6-membered monocyclic heterocyclic group;
  • X 3 represents hydrogen, Ci- 4 -alkyl, C 2 - 4 -alkenyl, C 2 - 4 -alkynyl or
  • X 4 and X 5 independently of each other represent ⁇ hydrogen, Ci- 4 -alkyl, halo-Ci- 4 -alkyl, C 3 - 6 -cycloalkyl, halo, nitro, -NH 2 , or cyano; with the proviso that the compound is not ethyl 3-[(3-chlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
  • a second aspect of the present invention relates to pharmaceutically compositions comprising an effective amount of a compound of Formula (I).
  • a third aspect of the present invention relates to a compound of Formula (I) for use as a medicament.
  • a forth 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.
  • FIG. 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.
  • LC-MS/MS liquid chromatography coupled to tandem mass spectrometry
  • Figure 3 The principle of the AlphaLISA assay used for screening of the compound inhibition of HDME activity.
  • the present invention relates to compounds of Formula (I),
  • Xi represents a group designated by -A-B, in which A represents a bond, O, S or NH and B represents Ci- 6 -alkyl, C 2 -4-alkenyl or C 2 - 4 -alkynyl, which Ci- 6 -alkyl, C 2-4 - alkenyl or C 2 - 4 -alkynyl may optionally be substituted as indicated above, -OH, -
  • X 3 represents hydrogen, C 1-4 -alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl, or -O-X 9 , -S-X h or - NX i X i2 , where X 9 , X h , X i , and X i2 , are as defined above, and
  • X 4 and X 5 represents independently of each other hydrogen, C 1-4 -alkyl, halo-Ci_ 4 -alkyl, C 3 - 6 -cycloalkyl, halo, nitro, -NH 2 , or cyano.
  • especially preferred compounds are those for which X 2 represents a hydrocarbon, which preferably comprises one or more double and/or triple bonds, and which may be substituted with one or more aromatic groups, such as for example phenyl, or heteroaromatic groups such as for example pyridine. It has further been found that especially preferred compounds are those for which X 2 is fairly long, with a polar group near the core and lipophilicity 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 C 1-6 -alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl, which Ci_ 6 -alkyl, C 2 . 4 -alkenyl or C 2 .
  • 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 S and B represents C 1-6 -alkyl, C 2 . 4 -alkenyl or C 2 . 4 -alkynyl, which C 1-6 -alkyl, C 2 . 4 -alkenyl or C 2 . 4 -alkynyl may optionally be substituted as indicated above.
  • 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 Ci- 6 -alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl, which Ci -6 - alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl may optionally be substituted as indicated above.
  • 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 sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may be substituted as indicated above.
  • 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 and B represents fluoro, chloro, bromo or cyano.
  • 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 a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated above.
  • the compounds of Formula (I) 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, 3 or 4 heteroatoms each independently selected among N, O, and S.
  • 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, 1 ,2,5-oxadiazolyl and tetrazolyl.
  • the monocyclic heterocyclic group may be a 6-membered monocyclic heterocyclic group comprising 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S.
  • 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.
  • 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 d-e-alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl, 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, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted once with a dimethylamino group.
  • B represents methyl, ethyl, propyl or isopropyl substituted once with a dimethylamino group.
  • A represents a bond and B represents C 1-6 -alkyl, which Ci_ 6 -alkyl is substituted one or more substituents selected from the group consisting of hydroxy, fluoro, trifluoromethyl, cyano, dimethylamino and methylsulfinyl.
  • B represents methyl, ethyl, propyl or isopropyl substituted with two substituents, which independently of each other are selected from the group cionsisting of hydroxy, fluoro, trifluoromethyl, cyano, dimethylamino and methylsulfinyl.
  • A represents a bond and B represents C 2 - 4 -alkenyl, which C 2 - 4 -alkenyl may optionally be substituted with methylsulfinyl.
  • B represents unsubstituted ethenyl or ethenyl substituted once with methylsulfinyl.
  • unsubstituted d-e-alkyl preferably methyl or ethyl.
  • R' represents hydroxy.
  • A represents a bond and B represent hydroxy.
  • R" represents methyl, ethyl, trifluoromethyl or trifluoroethyl.
  • R" represents methyl, ethyl, propyl or isopropyl substituted with one substituted selected from the group consisting of hydroxy, methoxy, cyano, ethoxycarbonyl, dimethylamino, methylsulfinyl and morpholinyl.
  • R" represents methyl substituted with one substituent selected from the group consisting of hydroxy, cyano, ehtoxybarbonyl, methylsulfinyl and morpholinyl.
  • R" represents ethyl substituted with one substituent selected from the group consisting of methoxy, cyano and
  • R" represents propyl substituted with one substituent selected from the group consisting methoxy and dimethylamino.
  • R" represents ethoxy substituted with one substituent selected from the group consisting of methoxy, dimethylamino, methylsulfinyl and methylsulfanyl.
  • A represents a bond and B represents sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxyethyl, dimethylaminoethyl, cyclopropyl, ethenyl 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
  • A represents a bond and B represents sulfamoyl.
  • B represents unsubstituted sulfamoyl.
  • B represents sulfamoyl, which is substituted once with methyl or which is substituted twice with methyl and methoxyethyl.
  • A represents a bond and B represents dimethylsulfamoyl.
  • A represents a bond and B represents sulfonyl or sulfinyl, which sulfonyl or sulfinyl is substituted with one substituent selected from the group consisting of methyl, methoxyethyl, dimethylaminoethyl and ethenyl.
  • A represents a bond and B represents sulfonyl, which is substituted with one substituent selected from the group consisting of methyl, chloroethyl, methoxyethyl and dimethylaminoethyl.
  • A represents a bond and B represents sulfinyl, which is substituted with one substituent selected from the group consisting of methyl, methoxyethyl, dimethylaminoethyl and ethenyl.
  • A represents a bond and B represents bromo or cyano.
  • 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 above.
  • 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, 1 ,2,5-oxadiazolyl and tetrazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, imidazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,
  • heterocyclic group represents imidazolyl substituted with methyl or tetrazolyl.
  • 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
  • A represents O and B represents d-e-alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl, which may optionally be substituted as indicated above.
  • A represents O and B represents Ci_ 6 -alkyl, C 2 - 4 -alkenyl, or C 2 .
  • 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.
  • the Ci_ 6 -alkyl is methyl.
  • the C 2 .
  • 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 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, and more preferred B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl.
  • B is substituted with cyclopropyl in addition to the cyano substituent.
  • B 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 B is substituted with 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 propyl or 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.
  • 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.
  • 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 butyl, which is substituted with pyrrolidinyl and methylsulfonyloxy.
  • B represents methyl, ethyl, propyl or isopropyl and R' represents methyl, trifluoromethyl, hydroxy, -NH 2 , methylamino or dimethylamino. Most preferably B represent 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 Ci- 6 -alkyl, which d-e-alkyl is substituted with a substituent selected from the group consisting of sulfamoyi, dimethylsulfamoyi, methylsulfanyl 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 sulfamoyi, dimethylsulfamoyi, methylsulfanyl and methylsulfonyl.
  • B represents ethyl or isopropyl, which is substituted once with a substituent selected from the group consisting of sulfamoyi, dimethylsulfamoyi, methylsulfanyl 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,
  • R" is selected from the group consisting of methyl, ethoxy, dimethylamino, pyrrolidinyl and morpholinyl.
  • A represents O and B represents sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which 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
  • 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, and pyrazinyl.
  • pyridinyl, pyrimidinyl, and pyrazinyl may be substituted with one substituent selected from the group consisting of methyl, methoxy, methoxycarbonyl, -COOH, cyano and dimethylamino.
  • A represents S and B represents Ci. 6 -alkyl, C 2 - 4 -alkenyl or C 2 - 4 -alkynyl, which may optionally be substituted as indicated above.
  • B represents methyl or ethyl, which may optionally be substituted with one substituent selected from the group consisting of hydroxy, methoxy, fluoro and chloro.
  • B represents
  • B represents ethyl, which is substituted with one substituted selected from the group consisting of methoxy and chloro.
  • 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, propoxy, butoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Most preferably R" represents methyl, butoxy 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 b represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl or tertiary pentyl.
  • X b represents a linear or branched Ci -6 - alkyl, which Ci -6 -alkyl may optionally be substituted with one or two substituents selected from the group consisting hydroxy, chloro, methoxy, ethoxy, trifluoromethoxy, oxo-methyl, NH 2 , methylamino, dimethylamino, cyano, phenyl, methylphenyl, chlorophenyl, or a 5- or a 6-membered monocyclic heterocyclic group, preferably pyrrolidinyl or morpholinyl.
  • X b represents a linear or branched C 2 -i 8 -alkynyl, more preferred a linear or branched C 2 - 8 -alkynyl, even more preferred a linear or branched C 3 . 8 -alkynyl, which C 3 . 6 -alkynyl may optionally be substituted with hydroxy.
  • X c represents methyl, ethyl, propyl or isopropyl.
  • X c represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl substituted with one substituent selected from the group consisting of chloro, hydroxy and dimethylamino.
  • X c represents methyl, which is substituted with one substituent selected from the group consisting of dimethylamino, (methoxyethyl)(methyl) amino,
  • the 5- or 6-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl.
  • X e and X e2 represent independently of each other hydrogen, methyl or ethyl, which may optionally be substituted with one substituent selected from the group consisting of methoxy and dimethylamino.
  • X e and X e2 represent independently of each other hydrogen, methyl or ethyl, which methyl or ethyl is substituted with phenyl or a 5- or 6-membered monocyclic heterocyclic group, preferably pyridinyl.
  • X e and X e2 represent
  • X f represents methyl or ethyl, which methyl or ethyl is substituted with -O-methyl-phenyl, -O-ethyl-phenyl, phenyl, methylphenyl or a 5- or 6-membered monocyclic heterocyclic group.
  • X f represents methyl, which is substituted with phenyl, methylphenyl or pyridinyl. In other embodiments X f represents phenyl, which may be substituted with methyl.
  • NX j and/or X j2 represents methyl
  • said methyl is either unsubstituted or substituted with one substituent selected from the group consisting of
  • X 2 represents -S-X k , where X k represents methyl, ethyl or propyl, which methyl, ethyl or propyl may optionally be substituted with dimethylamino.
  • X k represents ethyl substituted with one sunstituent, which is dimethylamino.
  • X m represents ethyl substituted with one substituent, which is dimethylamino.
  • X 3 represents hydrogen, C 1-4 - alkyl, C 2 _ 4 -alkenyl, C 2 _ 4 -alkynyl, or -O-X 9 , -S-X h or -NX i X i2 , where X 9 , X h , X i , and X i2 , are as defined above.
  • X 3 represents hydrogen or C 1-4 -alkyl, more preferred hydrogen or methyl, but most preferably X 3 represents hydrogen.
  • X 3 represents -O-X 9 , where X 9 represents -(CH 2 ) n -CH 3 , or -(CH 2 ) n -COOH, where n is 0, 1 , 2, 3 or 4.
  • X 9 represents -(CH 2 ) n -COOH, where n is 0, 1 , 2, 3 or 4, in which the -(CH 2 ) n - may be linear or branched.
  • 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 , 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 Ci -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.
  • the compounds of Formula (I) include:
  • 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.
  • 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 . 8 - 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.
  • halo refers to fluoro, chloro, bromo or iodo.
  • a trihalomethyl group represents e.g. a trifluoromethyl group, or a trichloromethyl group.
  • halo designates fluoro or chloro.
  • haloalkyi refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with one or more halo. Preferred haloalkyi groups of the invention include trihalomethyl, preferably trifluoromethyl.
  • alkoxy refers to an "alkyl-O-" group, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with hydroxy.
  • Examples of hydroxyalkyl groups include HO-CH 2 -, CH 2 OH-CH 2 - and CH 3 -CH 2 OH-.
  • 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-0-.
  • alkoxycarbonyl refers to an "alkyl-O-(CO)-" group, wherein alkyl is as defined above.
  • amine refers to primary (R-NH 2 , R ⁇ H), secondary (R 2 -NH, R 2 ⁇ H) and tertiary (R 3 -N, R ⁇ H) amines.
  • a substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent.
  • 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, piperazinyl, and morpholinyl.
  • 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.
  • 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. 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.
  • 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.
  • 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.
  • the mixture of diastereomers can be separated by crystallization followed by liberation of the optically active 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.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation,
  • optically active compounds of the invention preferably compounds of formula (I)
  • optically active starting materials preferably optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • 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.
  • 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 compound of Formula (I) may be prepared according to scheme 1 by use of a 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 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 is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 2 either at room temperature or by heating for several hours by use of a solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a catalyst such as Pd 2 (dba) 3 , optionally a salt such as lithium chloride and the desired nucleophile such as an amine, an ethanethionate, a cyanide, carbon monoxide, or an
  • organometallic A purification method such as silica gel chromatography is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 3 either at approximately 5 ' ⁇ , at room temperature or by heating for several hours by use of a solvent such as dichloromethane, DMF or dioxane, a base such as
  • the compound of Formula (I) may be prepared according to scheme 4 by use of a solvent such as tetrahydrofuran, a base such as a hindered amine and the desired electrophile, and mixing at room temperature for a few hours. A purification method such as silica gel chromatography or trituration is employed if needed. Method E for the preparation of compounds of Formula (I)
  • the compound of Formula (I) may be prepared according to scheme 5 by use of the desired alcohol as the reactive solvent, optionally using a solvent such as THF or DMF, and a strong base such as sodium, n-BuLi, KOH or potassium t-butoxide, and by mixing at minus 40 °C or above room temperature for several hours or applying microwaves. A purification method such as silica gel chromatography or trituration is employed if needed. Method F for the preparation of compounds of Formula (I)
  • the compound of Formula (I) may be prepared according to scheme 6 by use of the desired alcohol as the reactive solvent, optionally using a solvent such as THF or DMF, and a strong base such as sodium, n-BuLi, KOH or potassium t-butoxide, and by mixing at minus 40 °C or above room temperature for several hours or applying microwaves.
  • a purification method such as silica gel chromatography or trituration is 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 cesium carbonate and an electrophile such as an alkyl halide, heteroaromatic halide, alkenyl halide, etc., and by mixing at or above room temperature for several hours.
  • a purification method such as silica gel chromatography or trituration is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 8 by use of a solvent such as DMF or THF, a base such as cesium carbonate and an electrophile such as an alkyl halide, heteroaromatic halide, alkenyl halide, etc., and by mixing at or above room temperature for several hours.
  • a purification method such as silica gel chromatography or trituration is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 9 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 10 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 1 1 by use of a solvent such as DMF, DCM or THF, optionally a base such as a hindered tertiary amine, and the desired nucleophile such as an alkoxide, a sulfonamide or an amine, and by mixing below or at room temperature for one to a few hours.
  • a purification method such as silica gel chromatography is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 12 by use of a solvent such as DMF, DCM or THF, optionally a base such as a hindered tertiary amine, and the desired nucleophile such as an alkoxide or an amine, and by mixing above room temperature for a few hours.
  • a purification method such as silica gel chromatography is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 13 by use of a solvent such as methanol and a reducing agent such as sodium borohydride, and by mixing at room temperature for a few hours. A purification method such as silica gel chromatography is employed if needed.
  • the compound of Formula (I) may be prepared according to scheme 14 by use of a solvent such as THF, optionally a base such as triethylamine and a salt such as lithium chloride and an electrophile such as an acetyl halide and by mixing at or above room temperature for several hours.
  • a solvent such as THF
  • a base such as triethylamine and a salt such as lithium chloride and an electrophile
  • a purification method such as silica gel
  • the compound of Formula (I) may be prepared according to scheme 15 by use of a solvent such as THF, a nucleophile such as a thiol or an alcohol, a catalyst such as palladium and by mixing at or above room temperature for several hours.
  • a purification method such as silica gel chromatography or trituration is employed if needed.
  • said one or more HDMEs may be any HDME, however preferably the one or more HDMEs are selected from the JmjC (Jumonji) family, more preferably said one or more HDME(s) are HDME of the human JmjC family.
  • the one or more HDME(s) are selected from the group consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, and even more preferably from the group consisting of human GASC1 (JMJD2C), human JMJD2A, human JMJD2B, human JMJD2D and human JMJD2E.
  • said HDME is GASC1 and preferably said HDME is GASC1 comprising or even consisting of SEQ ID NO:1 .
  • 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
  • preferred compounds of Formula (I) according to the invention are compounds capable of reducing or preferably inhibiting said demethylation by said HDME.
  • Said histone substrate may be any histone, but preferably is histone H3 or a fragment thereof, and more preferably histone H3 methylated at lysine 9, even more preferably trimethylated histone H3, which is methylated at lysine 9.
  • Said demethylation is preferably demethylation of histone H3, lysine 9.
  • said inhibition is determined as the IC 50 of said compound according to Formula (I) in respect of the said demethylation assay.
  • Preferred compounds of the present invention are compounds of Formula (I) which have an IC 50 at or below 1 ⁇ , more preferably less than 300 nM, for example less than 100 nM, such as less than 50 nM in respect of demethlation of any of said histone substrates by any of said HDME.
  • very preferred compounds of the present invention are compounds of Formula (I) which have an IC 50 at or below 1 ⁇ , more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM in respect of demethylation of histone H3 methylated at least on lysine 9 by GASC1 .
  • IC 5 o is determined as described in Example 3, 4 and 5 herein below.
  • very preferred compounds of the present invention are compounds of Formula (I) which have an IC 50 at or below 1 ⁇ , more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM when said IC 50 is determined as described in Example 3, 4 and 5 herein below.
  • Very preferred compounds according to the invention are compounds that lead to a decreased tumour size and/or decreased number of metastases when tested as described herein below in Example 7.
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent.
  • 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,
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. In a related embodiment, 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.
  • the disease to be treated is a HDME dependent disease.
  • HDME dependent disease 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 hyperplasi
  • 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.
  • phrases, "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
  • 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.
  • 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,
  • 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.
  • 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.
  • Ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared on an 50 mmol scale according to Aust. J. Chem. 1969, 22, 1525.
  • Methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared by an analogous procedure to the ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate preparation using methyl pyridine-2-acetate on an 10.0 mmol scale.
  • H NMR 500 MHz, CDCI 3 ) ⁇ 8.33-8.38 (m, 1 H), 8.24-8.30 (m, 2H), 7.33 (d, , 1 H), 7.23- 7.27 (m, 1 H), 7.09 (dd, 2.3 Hz, 1 H), 6.75-6.79 (m, 1 H), 4.92 (s, 1 H), 4.00 (s, 3H).
  • LCMS 93% UV 215 at 1 .79 minutes with m/z 242 (M+1 ) + 100%.
  • Prop-2-en-1 -yl hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared by a procedure adapted from Aust. J. Chem. 1969, 22, 1525.
  • Reagents and conditions a. i. NaH, DMF, ii. RX, DMF or K-.2C03, RX, DMF, RT.
  • Procedure A Sodium hydride (60% dispersion in mineral oil, 0.3 mmol) was added to a stirring solution of the hydroxyl starting material (0.1 mmol) in DMF (1 ml_) at room temperature. After 30 min electrophile (0.2 mmol) was added as a solution in DMF (1 ml_) and stirring was maintained overnight. If starting material remained the reaction was heated to 50 °C for 8h. The reaction was quenched with water and extracted with diethyl ether (3 x 1 ml_).
  • Triflic anhydride (0.494 ml_, 3.0 mmol) was added to a stirring solution of ethyl 3- hydroxypyrido[1 ,2-a]indole-10-carboxylate (500 mg,) and pyridine (0.320 ml_) in 3:1 DCM:THF (40 ml_) at 0 °C under an atmosphere of nitrogen. After 10 min DMAP (36 mg) was added and the reaction allowed to warm to room temperature overnight (18h). The reaction was diluted with DCM (60 ml) and the organic was washed with saturated aqueous NaHC0 3 (20 ml_), 1 M HCI (2 x 20 ml_) and 1 M NaOH (2 x 20 ml_).
  • Haloheteroaromatic 2-chloropyrazine
  • Haloheteroaromatic 4-chloro-2-methoxypyrimidine
  • Haloheteroaromatic 4-chloro-6-methylpyrimidine (2 equivalents used)
  • Haloheteroaromatic 2,4-dichloropyrimidine
  • Haloheteroaromatic 2-chloro-3-cyanopyrazine
  • reaction conditions 20 °C for 10 minutes.
  • Workup & Purification The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (2 x 15 mL) and brine (1 x 5 mL), dried over MgS0 4 and filtered under vacuum. The filtrate was evaporated in vacuo, acetonitrile (0.5 mL) introduced to the residue and the slurry slowly stirred for 10 minutes. The solid was collected by vacuum filtration and air dried on the filter to furnish the title compound as a yellow-brown solid.
  • Haloheteroaromatic methyl 5-chloropyrazine-2-carboxylate
  • Haloheteroaromatic 2-chloropyrimidine
  • reaction mixture was diluted with ethyl acetate and the aqueous phase separated and washed with further ethyl acetate.
  • the combined ethyl acetate extracts were dried (sodium sulfate), filtered through a Celite® plug and the filtrate concentrated in vacuo to give the title compound as a yellow foam.
  • This material was used without further purification, but could be further purified by preparative- LC to furnish the title compound as a formate salt.
  • the reaction was stirred for 60 min, before water (2 mL), tetra-n-butylammonium fluoride (1 .0 mL of a 0.1 M solution in tetrahydrofuran) and ethyl acetate (100 mL) were introduced.
  • the solution was washed with water and brine, dried (sodium sulfate) and filtered.
  • the filtrate was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient followed by ethyl acetate containing 5-10% tetrahydrofuran, all eluent mixtures contained 1 % by volume triethylamine) to give the title compound as a yellow wax which was used without further purification.
  • the dry-loaded substrate was purified by flash column chromatography (silica gel, eluent: hexane containing a 0-50% gradient of ethyl acetate) to furnish the title compound as a yellow solid.
  • H NMR 500 MHz, CDCI 3 ) 5 8.61 (d, 1 H), 8.59 (s, 1 H), 8.45 (d, 1 H), 8.41 (d, 1 H), 8.06 (dd1 H), 7.44 (dd, 1 H), 6.92 (t, 1 H), 4.50 (q, 2H), 2.74 (s, 3H), 1 .52 (t, 3H).
  • the tiltle compound was prepared by Procedure E (at 140 °C for 3 days) from methyl 3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ pyrido[1 ,2-a]indole-10-carboxylate (100 mg). After work up, purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient) to give the title compound as a yellow solid.
  • the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate added and the resulting thick suspension filtered and the precipitate washed on the filter with ethyl acetate.
  • the organic phase was separated, dried (sodium sulfate) and filtered.
  • the filtrate was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient containing 1 % by volume triethylamine) to give the title compound which was used without further purification.

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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), which 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 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
xi 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
• d-e-alkyl, C2-4-alkenyl or C2-4-alkynyl,
which Ci-6-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, halo, trifluoromethyl, -NH2, methylamino, dimethylamino, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, methylsulfonyloxo, methylsulfinyl, methylsulfanyl, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where
R' represents hydroxy, Ci-4-alkyl, halo-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, halo, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group;
OH or -(C=0)R",
where R" represents hydrogen, hydroxy, Ci-4-alkyl, cyclopropyl, halo-Ci-4-alkyl, Ci_4-alkoxy, -COOH, -NH2, methylamino, dimethylamino, methylsulfonyl, or a monocyclic or bicyclic heterocyclic group; or where R" represents Ci-4-alkyl, Ci-4-alkoxy, oxy, carbamoyl, amine or a monocyclic or bicyclic heterocyclic group, which is substituted with one or more substituents selected from the group consisting of hydroxy, methyl, ethyl, -0-Ci-6- alkyl, hydroxymethyl, hydroxymethyl, methoxyethyl, acetyl, cyano,
ethoxycarbonyl, dimethylamino, N-[3-(dimethylamino)propyl]- N'ethylcarbamimidoyl, methylsulfinyl, methylsulfanyl, methylsulfonyl,
methoxyethoxyethyl, (dimethylamino)ethyl and methylsulfanylethyl, which -0-Ci_ 6-alkyl may optionally be substituted with hydroxy, methoxy or dimethylamino;
(C=S)R"\
where R'" represents -NH2, methylamino or dimethylamino;
C(CH3)=N-R"",
where R"" represents hydroxy or methoxy;
• sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may optionally be substituted with one or more substituents selected from the group consisting of Ci-4-alkyl, halo-Ci-4-alkyl, methoxy-Ci-4-alkyl, dimethylamino, (dimethylamino)methyl, (dimethylamino)ethyl, C3-6-cycloalkyl, C2-4-alkenyl and a monocyclic or bicyclic heterocyclic group;
• fluoro, chloro, bromo or cyano; or
• a monocyclic or bicyclic heterocyclic group, where the monocyclic or bicyclic 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; and
X2 represents
• Ci-18-alkyl, C2.i8-alkenyl, or C2.i8-alkynyl,
which Ci-18-alkyl, C2.i8-alkenyl, C2_i8-alkynyl may optionally be substituted with one or more substituents selected from the group consisting of C3.6-cycloalkyl, hydroxy, halo, trifluoromethyl, Ci.6-alkoxy, hydroxy-Ci.6-alkoxy, C^e-alkyl -Ci_6- alkoxy, trifluoromethyl-Ci.6-alkoxy, oxo-Ci.6-alkyl, -NH2, dimethylamino, cyano, phenyl, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group, which phenyl, 5-membered monocyclic heterocyclic group, or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of Ci-6-alkyl or halo; or · -0-Xa, -(C=0)-0-Xb, -(C=0)-Xc, -NXd Xd2, -(CO)-NXe Xe2, or -(C=0)-NH-S02-Xf, where Xa, Xb, Xc, Xd , Xd2, Xe , Xe2 or Xf independently of each other represent hydrogen, d is-alkyl, C2.i8-alkenyl, C2_i8-alkynyl, C3.6-cycloalkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group; which Ci-18-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-6-cycloalkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of C3-6-cycloalkyl, hydroxy, halo, trifluoromethyl, Ci-4-alkyl, Ci-e-alkoxy, Ci-6-alkoxycarbonyl, Ci-4- alkylamino, hydroxy-Ci-6-alkoxy, Ci-6-alkyl-Ci-6-alkoxy, trifluoro- Ci-e-alkoxy, trifluoromethyl-O-Ci-6-alkyl, oxo-Ci-6-alkyl, -NH2, methylamino, dimethylamino, (methoxyethyl)(methyl) amino,
[(dimethylamino)ethyl](methyl)amino, cyano, -0-Ci.6-alkyl-phenyl, phenyl, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group, which phenyl, 5-membered monocyclic heterocyclic group, or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of C1-6-alkyl,
Figure imgf000006_0001
or halo; or where Xe and Xe2 independently of each other represent hydrogen, hydroxy, d. 18-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-6-cycloalkyl, -0-Ci-6-alkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group, which -O-Ci-6-alkyl may optionally be substituted with hydroxy, methoxy, or dimethylamino; with the proviso that Xe and Xe2 cannot both represent hydrogen; and
with the proviso that Xb cannot represent hydrogen; or
• -(C=0)-0-CH2-CH2-NXi Xi2, -S-Xk, -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn,
where Xj , Xj2, Xk, Xm, Xn independently of each other represent methyl, ethyl, propyl, amino, methylamino or dimethylamino,
which methyl, ethyl or propyl may optionally be substituted with one or more substituents selected from the group consisting of methoxycarbonyl, dimethylamino, carbamoyl, phenyl, cyanophenyl, and a 5- or 6-membered monocyclic heterocyclic group; X3 represents hydrogen, Ci-4-alkyl, C2-4-alkenyl, C2-4-alkynyl or
• -O-X9, -S-Xh or -NXi Xi2, where X9, Xh, Xi , and Xi2 independently of each other represent hydrogen, -(CH2)n-CH3, or -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4 and
X4 and X5 independently of each other represent · hydrogen, Ci-4-alkyl, halo-Ci-4-alkyl, C3-6-cycloalkyl, halo, nitro, -NH2, or cyano; with the proviso that the compound is not ethyl 3-[(3-chlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-amino-2-oxoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-chloro-6-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}acetic acid,
ethyl 3-[(2,6-dichlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-ethoxy-2-oxoethoxy)]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-chloro-5-trifluoromethyl-pyridine-2-yl)oxy] pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(3-trifluoromethyl-benzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 2-hydroxy-3-phenylmethoxypyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate, and
ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate.
A second aspect of the present invention relates to pharmaceutically compositions comprising an effective amount of a compound of Formula (I).
A third aspect of the present invention relates to a compound of Formula (I) for use as a medicament. A forth 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
The present invention relates to compounds of Formula (I),
Figure imgf000009_0001
where Xi represents a group designated by -A-B, in which 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 above, -OH, -
(C=0)R", where R" is as defined above and where R" optionally may be substituted as indicated above, -(C=S)R"\ where R'" is as defined above, -C(CH3)=N-R"", where R"" is as defined above, sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfinyl or sulfonyl may be substituted as indicated above, fluoro, chloro, bromo or cyano, or a monocyclic or bicyclic heterocyclic group, which may optionally be substituted as indicated above,
X2 represents d_18-alkyl, C2_18-alkenyl, or C2_18-alkynyl, or -0-Xa, -(C=0)-0-Xb, -(C=0)- Xc, NXd Xd2, -(C=0)-NXe Xe2, or -(C=0)-NH-S02-Xf, where Xa, Xb, Xc, Xd , Xd , Xe , Xe2 and Xf is as defined above, or -(C=0)-0-CH2-CH2-NXi Xj2, -S-Xk, -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn, where Xj , Xj2, Xk, Xm, Xn and is as defined above,
X3 represents hydrogen, C1-4-alkyl, C2.4-alkenyl, C2.4-alkynyl, or -O-X9, -S-Xh or - NXi Xi2, where X9, Xh, Xi , and Xi2, are as defined above, and
X4 and X5 represents independently of each other hydrogen, C1-4-alkyl, halo-Ci_4-alkyl, C3-6-cycloalkyl, halo, nitro, -NH2, or cyano.
Without being bound by any theory it has been found that compounds 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 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 a hydrocarbon, which preferably comprises one or more double and/or triple bonds, and which may be substituted with one or more aromatic groups, such as for example phenyl, or heteroaromatic groups such as for example pyridine. It has further been found that especially preferred compounds are those for which X2 is fairly long, with a polar group near the core and lipophilicity 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 C1-6-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 above, -OH or -(C=0)R", where R" is as defined above and where R" optionally may be substituted as indicated above, - (C=S)R"\ where R'" is as defined above, -C(CH3)=N-R"", where R"" is as defined above, sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may optionally be substituted as indicated above, bromo or cyano, or a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated above. 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 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 above, -(C=0)R", where R" is as defined above, sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may be substituted as indicated above, or a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated above.
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 C1-6-alkyl, C2.4-alkenyl or C2.4-alkynyl, which C1-6-alkyl, C2.4-alkenyl or C2.4-alkynyl may optionally be substituted as indicated above.
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 R" is as defined above, or sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may be substituted as indicated above.
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 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 above.
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", where R" is as defined above and where R" optionally may be substituted as indicated above.
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 and B represents -(C=S)R"', where R'" is as defined above.
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 and B represents -C(CH3)=N-R"", where R"" is as defined above.
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 sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may be substituted as indicated above.
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 and B represents fluoro, chloro, bromo or cyano.
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 a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated above. In particular preferred embodiments of the present invention the compounds of Formula (I) 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, 3 or 4 heteroatoms each independently selected among N, O, and S. 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, 1 ,2,5-oxadiazolyl and tetrazolyl. Alternatively, the monocyclic heterocyclic group may be a 6-membered monocyclic heterocyclic group comprising 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S. 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. 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 above.
In some preferred embodiments of the present invention A represents a bond and B represents d-e-alkyl, C2-4-alkenyl or C2-4-alkynyl, 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, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, or tertiary butyl is substituted once with a dimethylamino group. In a more preferred embodiment B represents methyl, ethyl, propyl or isopropyl substituted once with a dimethylamino group.
In other preferred embodiments A represents a bond and B represents C1-6-alkyl, which Ci_6-alkyl is substituted one or more substituents selected from the group consisting of hydroxy, fluoro, trifluoromethyl, cyano, dimethylamino and methylsulfinyl. Preferably, B represents methyl, ethyl, propyl or isopropyl substituted with two substituents, which independently of each other are selected from the group cionsisting of hydroxy, fluoro, trifluoromethyl, cyano, dimethylamino and methylsulfinyl. In other preferred embodiments A represents a bond and B represents C2-4-alkenyl, which C2-4-alkenyl may optionally be substituted with methylsulfinyl. In preferred embodiments B represents unsubstituted ethenyl or ethenyl substituted once with methylsulfinyl.
In yet other preferred embodiments A represents a bond and B represents
unsubstituted d-e-alkyl, preferably methyl or ethyl.
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 above. Preferably R' represents hydroxy. In other preferred embodiments A represents a bond and B represent hydroxy.
In some preferred embodiments of the invention A represents a bond and B represents -(C=0)R", where R" designates the substituents as indicated above. In one preferred embodiment A represents a bond and B represents -(C=0)R", where R" represents hydroxy, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, dimethylamino or a 5- or 6-membered monocyclic heterocyclic group, which optionally may be substituted as indicated above. Most preferably R" represents methyl, ethyl, trifluoromethyl or trifluoroethyl.
In other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents methoxy, -COOH or dimethylamino. In yet other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents cyclopropyl. In yet other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents a 5- or 6-membered monocyclic heterocyclic group, preferably morpholinyl. In some preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents hydrogen.
In other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents Ci-4-alkyl, which is substituted with one or more substituents selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxymethyl, methoxyethyl, acetyl, cyano, ethoxycarbonyl, dimethylamino, N-[3-(dimethylamino)propyl]-N'ethylcarbamimidoyl, methylsulfinyl, methylsulfanyl, methylsulfonyl, methoxyethoxyethyl, dimethylaminoethyl and
methylsulfanylethyl. Preferably R" represents methyl, ethyl, propyl or isopropyl substituted with one substituted selected from the group consisting of hydroxy, methoxy, cyano, ethoxycarbonyl, dimethylamino, methylsulfinyl and morpholinyl. In some preferred embodiments R" represents methyl substituted with one substituent selected from the group consisting of hydroxy, cyano, ehtoxybarbonyl, methylsulfinyl and morpholinyl. In other preferred embodiments R" represents ethyl substituted with one substituent selected from the group consisting of methoxy, cyano and
dimethylamino. In other preferred embodiments R" represents propyl substituted with one substituent selected from the group consisting methoxy and dimethylamino. In other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents Ci.4-alkoxy, which is substituted with one or more substituents selected from the group consisting of methoxy, dimethylamino, methylsulfinyl and methylsulfanyl. Preferably R" represents ethoxy substituted with one substituent selected from the group consisting of methoxy, dimethylamino, methylsulfinyl and methylsulfanyl.
In yet other embodiments A represents a bond and B represents -(C=0)R", where R" represents an oxy group, which is substituted with one substituent selected from the group consisting of N-[3-(dimethylamino)propyl]-N'ethylcarbamimidoyl,
methoxyethoxyethyl, dimethylaminoethyl and methylsulfanylethyl. In other
embodiments A represents a bond and B represents -(C=0)R", where R" represents carbamoyl substituted with two substituents selected from the group consisting of methyl and methoxy. In other embodiments A represents a bond and B represents - (C=0)R", where R" represents imidazolyl substituted with methyl.
In other preferred embodiments A represents a bond and B represents -(C=0)R", where R" represents amine, which is subsistuted one or more times with a substituent which is independently selected from the group consisting of hydroxy, methyl, methoxy, hydroxyethyl, methoxyethyl, acetyl, (dimethylamino)ethyl and methylsulfonyl. When R" is substituted with two substituents, one of the substituent is always methyl. In some preferred embodiments of the invention A represents a bond and B represents -(C=S)R"\ where FT" represents methylamino or dimethylamino. In some preferred embodiments of the invention A represents a bond and B represents -C(CH3)=N-R"", where FT" represents hydroxy or methoxy.
In some preferred embodiments of the invention A represents a bond and B represents sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxyethyl, dimethylaminoethyl, cyclopropyl, ethenyl 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.
In some embodiments of the invention A represents a bond and B represents sulfamoyl. In some preferred embodiments B represents unsubstituted sulfamoyl. In other embodiments B represents sulfamoyl, which is substituted once with methyl or which is substituted twice with methyl and methoxyethyl. In other embodiments of the invention A represents a bond and B represents dimethylsulfamoyl.
In other embodiments of the invention A represents a bond and B represents sulfonyl or sulfinyl, which sulfonyl or sulfinyl is substituted with one substituent selected from the group consisting of methyl, methoxyethyl, dimethylaminoethyl and ethenyl. In some preferred embodiments of the invention A represents a bond and B represents sulfonyl, which is substituted with one substituent selected from the group consisting of methyl, chloroethyl, methoxyethyl and dimethylaminoethyl. In other preferred embodiments of the invention A represents a bond and B represents sulfinyl, which is substituted with one substituent selected from the group consisting of methyl, methoxyethyl, dimethylaminoethyl and ethenyl.
In some preferred embodiments of the invention A represents a bond and B represents bromo or cyano. 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 above. 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, 1 ,2,5-oxadiazolyl and tetrazolyl, but preferably the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, imidazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl and tetrazolyl, and most preferred the 5-membered monocyclic
heterocyclic group represents imidazolyl substituted with methyl or tetrazolyl. 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 substituted with butyloxycarbonyl or morpholinyl.
In some preferred embodiments of the present invention A represents O and B represents d-e-alkyl, C2-4-alkenyl or C2-4-alkynyl, which may optionally be substituted as indicated above. In one embodiment A represents O and B represents Ci_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 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, and more preferred B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl. In some embodiments B is substituted with cyclopropyl in addition to the cyano substituent. Most preferred B 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 B is substituted with 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 propyl or 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 ethyl or isopropyl substituted with 1 - pyrrolidinyl and with a second substituent selected from the group consisting of hydroxy or cyano and -(C=0)R', where R' represents hydroxy or 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 yet another embodiment B represents butyl, which is substituted with pyrrolidinyl and methylsulfonyloxy.
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, halo-Ci-4- alkyl, hydroxy, -NH2, methylamino or dimethylamino. 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 -(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 represent 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 Ci-6-alkyl, which d-e-alkyl is substituted with a substituent selected from the group consisting of sulfamoyi, dimethylsulfamoyi, methylsulfanyl 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 sulfamoyi, dimethylsulfamoyi, methylsulfanyl and methylsulfonyl.
Preferably B represents ethyl or isopropyl, which is substituted once with a substituent selected from the group consisting of sulfamoyi, dimethylsulfamoyi, methylsulfanyl 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 above.
In one embodiment of the invention A represents O and B represents -(C=0)R", where R" represents C1-4-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,
hydroxym ethoxy, hydroxyethoxy, 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 sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which 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 is substituted with two methyl groups.
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, and pyrazinyl. In some of the embodiments pyridinyl, pyrimidinyl, and pyrazinyl may be substituted with one substituent selected from the group consisting of methyl, methoxy, methoxycarbonyl, -COOH, cyano and dimethylamino.
In some preferred embodiments of the present invention A represents S and B represents Ci.6-alkyl, C2-4-alkenyl or C2-4-alkynyl, which may optionally be substituted as indicated above. Preferably, B represents methyl or ethyl, which may optionally be substituted with one substituent selected from the group consisting of hydroxy, methoxy, fluoro and chloro. In some preferred embodiments B represents
unsubstituted methyl, and in other preferred embodiments B represents ethyl, which is substituted with one substituted selected from the group consisting of methoxy and chloro.
In other preferred embodiments of the invention A represents S and B represents - (C=0)R", where R" is as defined above. 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 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, propoxy, butoxy, dimethylamino, or a 5- or 6-membered monocyclic heterocyclic group. Most preferably R" represents methyl, butoxy 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 some preferred embodiments of the present invention X2 represents C1- 8-alkyl, C2-i8- alkenyl, or C2_18-alkynyl, or -0-Xa, -(C=0)-0-Xb, -(C=0)-Xc, NXd Xd2, -(C=0)-NXe Xe2, or -(C=0)-NH-S02-Xf, where Xa, Xb, Xc, Xd , Xd , Xe , Xe2 and Xf is as defined above, or - (C=0)-0-CH2-CH2-NXi Xi2, -S-Xk, -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn, where Xj , Xj2, Xk, Xm, Xn and is as defined above. In one preferred embodiment, however, X2 represents -0-Xa, -(C=0)-0-Xb, -(C=0)-Xc, NXd Xd2, -(C=0)-NXe Xe2, or -(C=0)-NH-S02-Xf, where Xa, Xb, Xc, Xd , Xd , Xe , Xe2 and Xf is as defined above. In other preferred embodiments of the present invention X2 represents -(C=0)-0-CH2- CH2-NXi Xi2, -S-Xk, -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn, where Xj , Xj2, Xk, Xm, Xn and is as defined above.
In a particular preferred embodiment of the invention X2 represents -(C=0)-0-Xb, where Xb is as defined above.
In one preferred embodiment of the invention X2 represents -(C=0)-0-Xb, where Xb represents a linear or branched C1- 8-alkyl, more preferred a linear or branched Ci-6- alkyl. In other preferred embodiments Xb represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl or tertiary pentyl. In an even more preferred embodiment Xb represents a linear or branched Ci-6- alkyl, which Ci-6-alkyl may optionally be substituted with one or two substituents selected from the group consisting hydroxy, chloro, methoxy, ethoxy, trifluoromethoxy, oxo-methyl, NH2, methylamino, dimethylamino, cyano, phenyl, methylphenyl, chlorophenyl, or a 5- or a 6-membered monocyclic heterocyclic group, preferably pyrrolidinyl or morpholinyl.
In another preferred embodiment of the invention X2 represents -(C=0)-0-Xb, where Xb represents a linear or branched C2-i8-alkenyl, more preferred a linear or branched C2.8- alkenyl, even more preferred a linear or branched C3-6-alkenyl, which C3-6-alkenyl may optionally be substituted with hydroxy.
In yet another preferred embodiment of the invention X2 represents -(C=0)-0-Xb where Xb, represents a linear or branched C2-i8-alkynyl, more preferred a linear or branched C2-8-alkynyl, even more preferred a linear or branched C3.8-alkynyl, which C3.6-alkynyl may optionally be substituted with hydroxy.
In other preferred embodiments of the invention X2 represents -(C=0)-0-Xb, where Xb represents C3.6-cycloalkyl, more preferred cyclopropyl or cyclobutyl. In other preferred embodiments of the invention X2 represents -(C=0)-0-Xb, where Xb represents a 5-membered monocyclic heterocyclic group, more preferred piperazinyl or tetrahydrofuranyl. In another preferred embodiment of the present invention X2 represents -(C=0)-Xc, where Xc represents hydrogen.
In other preferred embodiments of the present invention X2 represents -(C=0)-Xc, where Xc represents Ci.6-alkyl, which Ci_6-alkyl may be substituted with one or more substituents selected from the group consisting of chloro, hydroxy, dimethylamino, (methoxyethyl)(methyl) amino, and [(dimethylamino)ethyl](methyl)amino. In one preferred embodiment Xc represents methyl, ethyl, propyl or isopropyl. In another embodiment Xc represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl substituted with one substituent selected from the group consisting of chloro, hydroxy and dimethylamino. In yet another embodiment Xc represents methyl, which is substituted with one substituent selected from the group consisting of dimethylamino, (methoxyethyl)(methyl) amino,
and[(dimethylamino)ethyl](methyl)amino. In yet other preferred embodiments of the present invention X2 represents -(C=0)-Xc, where Xc represents a 5- or 6-membered monocyclic heterocyclic group. Preferably, the 5- or 6-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl. The 5- or 6- membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of Ci-6-alkyl,-(C=0)-0-Ci-6-alkyl and halo, preferably butoxycarbonyl.
In other particular preferred embodiments of the invention X2 represents -(C=0)- NXe Xe2, where Xe and Xe2 independently of each other represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, methoxy, dimethylamino, phenyl and a 5- or 6-membered monocyclic heterocyclic group with the proviso that Xe and Xe2 cannot both represent hydrogen. In one preferred embodiment Xe and Xe2 represent independently of each other hydrogen, methyl or ethyl, which may optionally be substituted with one substituent selected from the group consisting of methoxy and dimethylamino. Preferably Xe and Xe2 represent independently of each other hydrogen, methyl or ethyl, which methyl or ethyl is substituted with phenyl or a 5- or 6-membered monocyclic heterocyclic group, preferably pyridinyl. In other preferred embodiments Xe and Xe2 represent
independently of each other hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl or -0-Ci-6-alkyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl or -0-Ci.6-alkyl may optionally be substituted with hydroxy, methoxy or dimethylamino.
In a particular preferred embodiment of the invention X2 represents -(C=0)-NH-S02-Xf, where Xf represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl or phenyl, which groups may optionally be substituted with one or more of Ci-4-alkyl, Ci_4-alkoxy or Ci.6-alkylamino. In one embodiment Xf represents methyl or ethyl, which methyl or ethyl is substituted with -O-methyl-phenyl, -O-ethyl-phenyl, phenyl, methylphenyl or a 5- or 6-membered monocyclic heterocyclic group.
Preferably, Xf represents methyl, which is substituted with phenyl, methylphenyl or pyridinyl. In other embodiments Xf represents phenyl, which may be substituted with methyl.
In a preferred embodiment X2 represents -(C=0)-0-CH2-CH2-NXi Xi2, where NXj and Xj2 independently of each other each represents methyl or ethyl, which methyl or ethyl may be substituted with one or two substituents selected from the group consisting of methoxycarbonyl, dimethylamino, carbamoyl, phenyl, cyanophenyl, and a 5- or 6- membered monocyclic heterocyclic group, preferably pyridinyl or indolyl. Preferably, when NXj and/or Xj2 represents methyl, said methyl is either unsubstituted or substituted with one substituent selected from the group consisting of
methoxycarbonyl, carbamoyl, phenyl, cyanophenyl, pyridinyl and indolyl. When NXj and/or Xj2 represents ethyl, this group is substituted with dimethylamino.
In other embodiments X2 represents -S-Xk, where Xk represents methyl, ethyl or propyl, which methyl, ethyl or propyl may optionally be substituted with dimethylamino.
Preferably Xk represents ethyl substituted with one sunstituent, which is dimethylamino. In other embodiments X2 represents -(C=S)-N(CH3)-Xm, where Xm represents methyl, ethyl or propyl, which methyl, ethyl or propyl may optionally be substituted with dimethylamino. Preferably Xm represents ethyl substituted with one substituent, which is dimethylamino.
In yet another embodiment X2 represents -(C=S)-N-Xn, where Xn represents amino, methylamino or dimethylamino, preferably amino.
In some preferred embodiments of the present invention X3 represents hydrogen, C1-4- alkyl, C2_4-alkenyl, C2_4-alkynyl, or -O-X9, -S-Xh or -NXi Xi2, where X9, Xh, Xi , and Xi2, are as defined above.
In one preferred embodiment X3 represents hydrogen or C1-4-alkyl, more preferred hydrogen or methyl, but most preferably X3 represents hydrogen.
In one preferred embodiment X3 represents -O-X9, where X9 represents -(CH2)n-CH3, or -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4. In a preferred embodiment of the invention, X9 represents -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4, in which the -(CH2)n- may be linear or branched.
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, 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 Ci-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 a most preferred embodiment the compounds of Formula (I) include:
methyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate,
[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]acetic acid,
propyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 2-methyl-3-[(methylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate,
cyclopropyl 3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
benzyl 3-[(dimethylamino)methyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-[cyano(cyclopropyl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -cyanobutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -cyano-2-methylpropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-(1 -cyanopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-[1 -(dimethylamino)propan-2-yl]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)propyl]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(acetyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(2-oxopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-morpholinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-piperidinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(2-hydroxyethoxy)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(2-ethoxyethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(acetylamino)pyrido[1 ,2-a]indole-10-carboxylate,
3-methyl-phenylmethyl 3-[(dimethylcarbamoyl)amino]pyrido[1 ,2-a]indole-10- carboxylate,
(2Z)-pent-2-en-1 -yl 3-[(methylsulfonyl)amino]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(4-t-butyloxycarbonylpiperazyl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(morpholin-4-yl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(1 -cyanopropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(1 -cyanobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)-2-oxoethoxy]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[4-(dimethylamino)-4-oxobutan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(4-amino-4-oxobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
3-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid, propyl 3-{[1 -(methylsulfonyl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, butyl 3-{[2-(methylsulfonyl)propan-1 -yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, propyl 3-[(1 -sulfamoylpropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[1 -(dimethylsulfamoyl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[4-amino-1 -(dimethylamino)-4-oxobutan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
4-(dimethylamino)-3-{[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid, methyl 3-{[1 -cyano-3-(dimethylamino)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
ethyl 3-{[1 -(dimethylamino)-4-hydroxybutan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[1 -(dimethylamino)-4-oxopentan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, propyl 3-{[1 -(dimethylamino)-4-oxo-5,5,5-trifluoropentan-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate,
propyl 3-[(4-amino-4-oxobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
3-{[10-(butoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid,
pentyl 3-[(1 -cyanopropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(4-hydroxybutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(4-oxopentan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(5,5,5-trifluoro-4-oxopentan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(3-cyanopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(ethoxycarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2,6-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2,5-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(6-chloropyridin-3-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-methylprop-2-en-1 -yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
propan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, tert-butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3-methylbutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2,2-dimethylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -chloropropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- chloroethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- chloropropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, cyclopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
(2Z)-hex-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3Z)-hex-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2Z)-pent-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, cyclobutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
(2E)-hex-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3E)-hex-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2E)-pent-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3E)-pent-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2Z)-but-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 3-methylbut-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, benzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
4- methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 4-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-oxopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-phenylethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -phenylethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -phenylpropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-phenylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, pent-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hex-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, pent-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hex-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hept-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, oct-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
but-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -phenylethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylbut-3-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-hydroxybut-3-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(pyrrolidin-1 -ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
2-cyanoethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-hydroxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-ethoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-(trifluoromethoxy)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-hydroxybut-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-amino-3-hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 3-hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- hydroxybutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3-cyanopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
tetrahydrofuran-3-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
1 -methoxypropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}acetic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}propanoic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}butanoic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}-2- methylpropanoic acid,
3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}-2-methylbutanoic acid,
ethyl 3-(cyanomethoxy)-7-methylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-ethylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-(propan-2-yl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-cyclopropylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-methylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-ethylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-(propan-2-yl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-cyclopropylpyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(pyridin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(6-methylpyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[2-(dimethylamino)pyrimidin-4-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(pyrimidin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-methoxypyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(pyrazin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanopyrazin-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[5-(methoxycarbonyl)pyrazin-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, 5-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}pyrazine-2-carboxylic acid, ethyl 3-[2-(3,4-difluorophenyl)-2-oxoethoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(1 ,3-dimethyl-1 H-pyrazol-5-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(2-methyl-1 ,3-thiazol-4-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(3-methylbutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(cyclopropylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(4-cyanobutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[1 -methoxy-1 -oxo-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(piperazin-1 -yl)methanone,
ethyl 3-[(methylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[(3,5-dimethyl-1 ,2-oxazol-4-yl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, 3-methoxy-N-[2-(pyridin-3-yl)ethyl]pyrido[1 ,2-a]indole-10-carboxamide,
N-benzyl-3-methoxypyrido[1 ,2-a]indole-10-carboxamide,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(morpholin-4-yl)methanone,
t-butyl-4-[(3-methoxypyrido[1 ,2-a]indol-10-yl)carbonyl]piperazine-1 -carboxylate, (3-methoxypyrido[1 ,2-a]indol-10-yl)(piperidin-1 -yl)methanone,
3-methoxy-N,N-dimethylpyrido[1 ,2-a]indole-10-carboxamide,
N-butyl-3-methoxypyrido[1 ,2-a]indole-10-carboxamide,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(pyrrolidin-1 -yl)methanone,
3-(cyanomethoxy)-N-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(ethylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(propylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(butylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-[(4-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-(cyanomethoxy)-N-[(3-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, N-(benzylsulfonyl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-[(4-methylbenzyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-(cyanomethoxy)-N-[(pyridin-3-ylmethyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-acetyl-N-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(ethylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(propylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(butylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(4-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(3-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(benzylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(4-methylbenzyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(pyridin-3-ylmethyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, ethyl 3-[(3-acetaminobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-methylsulfonylaminobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-{[(2,4-dimethyl-1 ,3-thiazol-5-yl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, prop-2-en-1 -yl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, prop-2-en-1 -yl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, 2-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}-3-(pyrrolidin-1 -yl)propanoic acid ethyl 3-{[1 -hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
ethyl 3-{[1 -(methanesulfonyloxy)-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate,
ethyl 3-{[1 -cyano-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(tert-butoxycarbonyl)amino]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate,
prop-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
prop-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
cyanomethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylprop-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(1 -hydroxypropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid,
methyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(morpholin-4-yl)carbonyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(trifluoromethane)sulfonyloxy]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(dimethylcarbamoyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylate, 3-N-[3-(dimethylamino)propyl]-N'-ethylcarbamimidoyl 10-methyl pyrido[1 ,2-a]indole- 3,10-dicarboxylate,
methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-methanesulfinylpyrido[1 ,2-a]indole-10-carboxylate,
3,10-dimethyl pyrido[1 ,2-a]indole-3,10-dicarboxylate,
methyl 3-methanesulfonylpyrido[1 ,2-a]indole-10-carboxylate,
3-(cyanomethoxy)-N-(2-methoxyethyl)pyrido[1 ,2-a]indole-10-carboxamide,
N-benzyl-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide,
3-(dimethylamino)propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-(pyrrolidin-1 -yl)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- (morpholin-4-yl)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- (cyanomethoxy)-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxamide, 2-[benzyl(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-[(carbamoylmethyl)(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate,
2-[methyl(pyridin-3-ylmethyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate,
2-{methyl[(1 -methyl-1 H-indol-3-yl)methyl]amino}ethyl 3-(cyanomethoxy)pyrido[1 ,2- a]indole-10-carboxylate,
1 -(dimethylamino)propan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-{[(3-cyanophenyl)methyl](methyl)amino}ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole- 10-carboxylate,
2-(dimethylamino)propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-(methylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3-N,10-N-bis[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-3,10-dicarboxamide, 2-(dimethylamino)ethyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
methyl 2-[(2-{[3-(cyanomethoxy)pyrido[1 ,2-a]indol-10- yl]carbonyloxy}ethyl)(methyl)amino]acetate, [2-({3-acetylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl][2-
(dimethylamino)ethyl]dimethylazanium,
2-({10-acetylpyrido[1 ,2-a]indol-3-yl}oxy)acetonitrile,
2-(dimethylamino)ethyl 3-(3-cyanopropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3-methoxypropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-[3-(dimethylamino)propanoyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(4-methoxybutanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-[4-(dimethylamino)butanoyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethyl](methyl)carbamoyl}pyrido[1 ,2- a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
3,10-bis[2-(dimethylamino)ethyl] pyrido[1 ,2-a]indole-3,10-dicarboxylate,
10-[2-(dimethylamino)ethyl] 3-(2-methoxyethyl) pyrido[1 ,2-a]indole-3,10-dicarboxylate, 10-[2-(dimethylamino)ethyl] 3-(2-methanesulfinylethyl) pyrido[1 ,2-a]indole-3,10- dicarboxylate,
2-(dimethylamino)ethyl 3-methanesulfinylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[2-(methylsulfanyl)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3-cyano-1 -hydroxypropyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-cyanopyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-[(1 -methyl-1 H-imidazol-2-yl)carbonyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(1 -methyl-1 H-imidazol-2-yl)pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(hydroxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(methoxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-methylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(1 H-1 ,2,3,4-tetrazol-5-yl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(2,2,2-trifluoro-1 -hydroxyethyl)pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3,3,3-trifluoropropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-cyclopropanecarbonylpyrido[1 ,2-a]indole-10-carboxylate, 10-[2-(dimethylamino)ethyl] 3-[2-(methylsulfanyl)ethyl] pyrido[1 ,2-a]indole-3,10- dicarboxylate,
10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3-carboxylic acid,
2-(dimethylamino)ethyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-bromopyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[(2-methoxyethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate, [2-({3-methanesulfonylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl]dimethylamine oxide, [2-({3-methanesulfinylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl]dimethylamine oxide, 2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10- carboxylate,
10-[2-(dimethylamino)ethyl] 3-[2-(2-methoxyethoxy)ethyl] pyrido[1 ,2-a]indole-3,10- dicarboxylate,
methyl 3-(2-cyanoacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[2-(dimethylamino)-1 -hydroxyethyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(3-ethoxy-3-oxopropanoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-formylpyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(difluoromethyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(2-methanesulfinylacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethane)sulfonyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(dimethylcarbamoyl)carbonyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethyl)(methyl)sulfamoyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(2,2,2-trifluoro-1 -hydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-propanoylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-ethylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-ethenylpyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(2-methoxyethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(ethenesulfonyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(acetylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethane)sulfinyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-chloroethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate,
2-[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]-2-oxoacetic acid,
methyl 3-[methoxy(methyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-{[methoxy(methyl)carbamoyl]carbonyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[2-(dimethylamino)ethane]sulfinyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(2-chloroethane)sulfinyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -hydroxy-2-methanesulfinylethyl)pyrido[1 ,2-a]indole-10-carboxylate,
2- (dimethylamino)ethyl 3-(difluoromethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(E)-2-methanesulfinylethenyl]pyrido[1 ,2-a]indole-10-carboxylate,
3- [2-(dimethylamino)ethyl] 10-methyl pyrido[1 ,2-a]indole-3,10-dicarboxylate, 10-methyl 3-[2-(methylsulfanyl)ethyl] pyrido[1 ,2-a]indole-3,10-dicarboxylate, methyl 3-(2-hydroxyacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methoxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[2-(morpholin-4-yl)acetyl]pyrido[1 ,2-a]indole-10-carboxylate,
2- (dimethylamino)ethyl 3-[methoxy(methyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
methyl 3-[methoxy(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate,
3- (cyanomethoxy)-N-methanesulfonylpyrido[1 ,2-a]indole-10-carboxamide,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-(dimethylamino)ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-[(2-methoxyethyl)(methyl)amino]ethan-1 -one, 1 -(10-{[2-(dimethylamino)ethyl]sulfanyl}pyrido[1 ,2-a]indol-3-yl)ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-5-(dimethylamino)pentan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-3-(dimethylamino)propan-1 -one,
3-acetylpyrido[1 ,2-a]indole-10-carbaldehyde,
methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-chloroethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-{[2-(dimethylamino)ethyl](methyl)amino}ethan-1 - one,
2- {[2-(dimethylamino)ethyl](methyl)amino}ethyl 3-acetylpyrido[1 ,2-a]indole-10- carboxylate,
3- acetyl-N-[2-(dimethylamino)ethyl]-N-methylpyrido[1 ,2-a]indole-10-carbothioamide, 3-acetyl-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carbothioamide,
3-acetyl-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[2-(dimethylamino)ethyl]-N-methylpyrido[1 ,2-a]indole-10-carboxamide, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}propan-1 -one,
2- [(2-methoxyethyl)(methyl)amino]-1 -{3-[1 -(methoxyimino)ethyl]pyrido[1 ,2-a]indol-10- yl}ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-4-hydroxybutan-1 -one,
3- hydroxypyrido[1 ,2-a]indole-10-carboximidamide,
1 -{3-[(1 -(hydroxyimino)ethyl]pyrido[1 ,2-a]indol-10-yl}-2-[(2- methoxyethyl)(methyl)amino]ethan-1 -one,
2-(dimethylamino)-1 -{3-[1 -(hydroxyimino)ethyl]pyrido[1 ,2-a]indol-10-yl}ethan-1 -one, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}ethan-1 -one
methyl 3-(methanesulfonylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, and
N-methanesulfonylpyrido[1 ,2-a]indole-3-carboxamide.
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. 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 (C2.8- 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 "halo" as used herein refers to fluoro, chloro, bromo or iodo. Thus a trihalomethyl group represents e.g. a trifluoromethyl group, or a trichloromethyl group. Preferably, the term "halo" designates fluoro or chloro.
The term "haloalkyi" as used herein refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with one or more halo. Preferred haloalkyi 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 "hydroxyalkyl" as used herein refers to an alkyl group as defined herein, which alkyl group is substituted one or more times with hydroxy. Examples of hydroxyalkyl groups include HO-CH2-, CH2OH-CH2- and CH3-CH2OH-.
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-0-.
The term "alkoxycarbonyl" as used herein refers to an "alkyl-O-(CO)-" group, wherein alkyl is as defined above.
The term "oxy" as used herein refers to an "-0-" group.
The term "amine" as used herein refers to primary (R-NH2, R≠ H), secondary (R2-NH, R2≠ H) and tertiary (R3-N, R≠ H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent. The term "carbamoyl" as used herein refers to a "H2N(C=0)-" group.
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. 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.
The mixture of diastereomers can be separated by crystallization followed by liberation of the optically active 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. 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, 2nd 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
Preparation of Compounds of Formula (I)
Method A for the preparation of compounds of Formula (I)
Scheme 1
Figure imgf000044_0001
The compound of Formula (I) may be prepared according to scheme 1 by use of a 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 is employed if needed.
Method B for the preparation of compounds of Formula (I)
Scheme 2
Figure imgf000045_0001
The compound of Formula (I) may be prepared according to scheme 2 either at room temperature or by heating for several hours by use of a solvent such as toluene or tetrahydrofuran, a base such as cesium carbonate or potassium t-butoxide, a catalyst such as Pd2(dba)3, optionally a salt such as lithium chloride and the desired nucleophile such as an amine, an ethanethionate, a cyanide, carbon monoxide, or an
organometallic. A purification method such as silica gel chromatography is employed if needed.
Method C for the preparation of compounds of Formula (I)
Scheme 3
Figure imgf000045_0002
The compound of Formula (I) may be prepared according to scheme 3 either at approximately 5 'Ό, at room temperature or by heating for several hours by use of a solvent such as dichloromethane, DMF or dioxane, a base such as
diisopropylethylamine, a catalyst such as Pd2(dba)3 or
tetrakis(triphenylphoshine)palladium(0), a ligand such as tri-ieri-butylphosphine, optionally a salt suchas as copper(l)iodide), and the desired electrophile such as an acid halide, alkyl halide, heteroaromatic halide, alkenyl halide, or bromine. A purification method such as silica gel chromatography is employed if needed. Method D for the preparation of compounds of Formula (I)
Scheme 4
Figure imgf000046_0001
The compound of Formula (I) may be prepared according to scheme 4 by use of a solvent such as tetrahydrofuran, a base such as a hindered amine and the desired electrophile, and mixing at room temperature for a few hours. A purification method such as silica gel chromatography or trituration is employed if needed. Method E for the preparation of compounds of Formula (I)
Scheme 5
Figure imgf000046_0002
The compound of Formula (I) may be prepared according to scheme 5 by use of the desired alcohol as the reactive solvent, optionally using a solvent such as THF or DMF, and a strong base such as sodium, n-BuLi, KOH or potassium t-butoxide, and by mixing at minus 40 °C or above room temperature for several hours or applying microwaves. A purification method such as silica gel chromatography or trituration is employed if needed. Method F for the preparation of compounds of Formula (I)
Scheme 6
Figure imgf000047_0001
The compound of Formula (I) may be prepared according to scheme 6 by use of the desired alcohol as the reactive solvent, optionally using a solvent such as THF or DMF, and a strong base such as sodium, n-BuLi, KOH or potassium t-butoxide, and by mixing at minus 40 °C or above room temperature for several hours or applying microwaves. A purification method such as silica gel chromatography or trituration is employed if needed.
Method G for the preparation of compounds of Formula (I)
Scheme 7
Figure imgf000047_0002
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 cesium carbonate and an electrophile such as an alkyl halide, heteroaromatic halide, alkenyl halide, etc., and by mixing at or above room temperature for several hours. A purification method such as silica gel chromatography or trituration is employed if needed.
Method H for the preparation of compounds of Formula (I)
Scheme 8
Figure imgf000048_0001
The compound of Formula (I) may be prepared according to scheme 8 by use of a solvent such as DMF or THF, a base such as cesium carbonate and an electrophile such as an alkyl halide, heteroaromatic halide, alkenyl halide, etc., and by mixing at or above room temperature for several hours. A purification method such as silica gel chromatography or trituration is employed if needed.
Figure imgf000048_0002
The compound of Formula (I) may be prepared according to scheme 9 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 J for the preparation of compounds of Formula (I)
Scheme 10
Figure imgf000049_0001
The compound of Formula (I) may be prepared according to scheme 10 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 K for the preparation of compounds of Formula (I)
Scheme 1 1
Figure imgf000049_0002
The compound of Formula (I) may be prepared according to scheme 1 1 by use of a solvent such as DMF, DCM or THF, optionally a base such as a hindered tertiary amine, and the desired nucleophile such as an alkoxide, a sulfonamide or an amine, and by mixing below or at room temperature for one to a few hours. A purification method such as silica gel chromatography is employed if needed. Method L for the preparation of compounds of Formula (I)
Scheme 12
Figure imgf000050_0001
The compound of Formula (I) may be prepared according to scheme 12 by use of a solvent such as DMF, DCM or THF, optionally a base such as a hindered tertiary amine, and the desired nucleophile such as an alkoxide or an amine, and by mixing above room temperature for a few hours. A purification method such as silica gel chromatography is employed if needed.
Method M for the preparation of compounds of Formula (I)
Scheme 13
Figure imgf000050_0002
The compound of Formula (I) may be prepared according to scheme 13 by use of a solvent such as methanol and a reducing agent such as sodium borohydride, and by mixing at room temperature for a few hours. A purification method such as silica gel chromatography is employed if needed.
Method N for the preparation of compounds of Formula (I)
Scheme 14
Figure imgf000051_0001
The compound of Formula (I) may be prepared according to scheme 14 by use of a solvent such as THF, optionally a base such as triethylamine and a salt such as lithium chloride and an electrophile such as an acetyl halide and by mixing at or above room temperature for several hours. A purification method such as silica gel
chromatography or trituration is employed if needed.
Method O for the preparation of compounds of Formula (I)
Scheme 15
Figure imgf000051_0002
The compound of Formula (I) may be prepared according to scheme 15 by use of a solvent such as THF, a nucleophile such as a thiol or an alcohol, a catalyst such as palladium and by mixing at or above room temperature for several hours. A purification method such as silica gel chromatography or trituration is employed if needed.
Preparation of intermediates
Intermediates of Formula 1 :
Figure imgf000051_0003
Intermediate 1 forms in an acidic solvent such as acetic acid, below room temperature. A silica filtration can be done if necessary. Inhibitory effect
The inventors have surprisingly found that compounds of Formula (I) have an inhibitory effect on the activity of one or more HDMEs. In this respect said one or more HDMEs may be any HDME, however preferably the one or more HDMEs are selected from the JmjC (Jumonji) family, more preferably said one or more HDME(s) are HDME of the human JmjC family. Yet more preferably the one or more HDME(s) are selected from the group consisting of GASC1 (JMJD2C), JMJD2A, JMJD2B, JMJD2D and JMJD2E, and even more preferably from the group consisting of human GASC1 (JMJD2C), human JMJD2A, human JMJD2B, human JMJD2D and human JMJD2E. Preferably said HDME is GASC1 and preferably said HDME is GASC1 comprising or even consisting of SEQ ID NO:1 .
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. Thus, preferably in an assay for demethylation of a histone substrate by said HDME, then preferred compounds of Formula (I) according to the invention are compounds capable of reducing or preferably inhibiting said demethylation by said HDME. Said histone substrate may be any histone, but preferably is histone H3 or a fragment thereof, and more preferably histone H3 methylated at lysine 9, even more preferably trimethylated histone H3, which is methylated at lysine 9. Said demethylation is preferably demethylation of histone H3, lysine 9.
Preferably, said inhibition is determined as the IC50 of said compound according to Formula (I) in respect of the said demethylation assay.
Preferred compounds of the present invention are compounds of Formula (I) which have an IC50 at or below 1 μΜ, more preferably less than 300 nM, for example less than 100 nM, such as less than 50 nM in respect of demethlation of any of said histone substrates by any of said HDME. Thus very preferred compounds of the present invention are compounds of Formula (I) which have an IC50 at or below 1 μΜ, more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM in respect of demethylation of histone H3 methylated at least on lysine 9 by GASC1 .
In a preferred embodiment IC5o is determined as described in Example 3, 4 and 5 herein below. Thus, very preferred compounds of the present invention are compounds of Formula (I) which have an IC50 at or below 1 μΜ, more preferably less than 500 nM, for example less than 100 nM, such as less than 50 nM when said IC50 is determined as described in Example 3, 4 and 5 herein below. Very preferred compounds according to the invention are compounds that lead to a decreased tumour size and/or decreased number of metastases when tested as described herein below in Example 7.
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. 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)
Figure imgf000067_0001
Standard Hi-Res method (7 min)
MET/CR/1416
High resolution method'
Column Waters Atlantis dC18 100 x
2.1 mm, 3μηι column
40 <C
Mobile phase A - 0.1 % Formic acid
(water)
B - 0.1 % Formic acid
(acetonitrile)
Flow rate 0.6 mL/min Injection 3μΙ
volume
Detector 215 nm (nominal)
Gradient Time (min) % Organic
0.00 5
5.00 100
5.40 100
5.42 5
7.00 5
Preparation of intermediates Preparation of 3-hydroxypyrido[1 ,2-a]indole esters
Scheme 16: Preparation of 3-hydroxypyrido[1 ,2-a]indole esters
Figure imgf000068_0001
Preparation of ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000068_0002
Ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared on an 50 mmol scale according to Aust. J. Chem. 1969, 22, 1525.
Preparation of methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000069_0001
Methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared by an analogous procedure to the ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate preparation using methyl pyridine-2-acetate on an 10.0 mmol scale. H NMR (500 MHz, CDCI3) δ 8.33-8.38 (m, 1 H), 8.24-8.30 (m, 2H), 7.33 (d, , 1 H), 7.23- 7.27 (m, 1 H), 7.09 (dd, 2.3 Hz, 1 H), 6.75-6.79 (m, 1 H), 4.92 (s, 1 H), 4.00 (s, 3H). LCMS: 93% UV215 at 1 .79 minutes with m/z 242 (M+1 )+ 100%.
Preparation of prop-2-en-1-yl hydroxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000069_0002
Prop-2-en-1 -yl hydroxypyrido[1 ,2-a]indole-10-carboxylate was prepared by a procedure adapted from Aust. J. Chem. 1969, 22, 1525.
To a solution of prop-2-en-1 -yl pyridin-2-yl-acetate (20.0 g, 1 12.87 mmol) in glacial acetic acid (80 ml) stirred under nitrogen and cooled in an ice bath, was added p- benzoquinone (12.2 g, 1 12.87 mmol) in portions over ninety minutes. Towards the end of the addition, the reaction mixture became partly solid. After stirring at 0 °C for an additional 30 minutes, the reaction was quenched with water (250 ml). The resultant solid was filtered, washed with water (20 ml), dried on the filter overnight, and then dried in high vacuum oven at 45 °C for 8 hours. The title compound was furnished as a yellow-green solid and was used for alkylation without further purification. H NMR (500 MHz, d4-methanol) δ 8.57 (d, 1 H), 8.22 (d, 1 H), 8.10 (d, 1 H), 7.40 (d, 1 H), 7.30 (dd, 1 H), 7.04 (dd, 1 H), 6.79-6.87 (m, 1 H), 6.10-6.23 (m, 1 H), 5.45 (dd, 1 H), 5.29 (dd, 1 H), 4.87-4.90 (m, 2H), 4.88 (d, 3H). LCMS: 95% UV215 at 1 .96 min, m/z 268 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-(trimethylstannyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000070_0001
To a solution of 2-(dimethylamino)ethyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2- a]indole-10-carboxylate (2.57 g) in anhydrous 1 ,4-dioxane (30 mL) were introduced tetrakis(triphenylphosphine)palladium(0) (0.69 g), lithium chloride (1 .52 g) and hexamethylditin (3.91 g).The reaction mixture was heated to 100 °C for 2 h. After cooling to room temperature the mixture was concentrated in vacuo and then purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient, containing 1 % by volume triethylamine) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.55 (d, 1 H), 8.44 (d, 1 H), 8.38-8.41 (m, 1 H), 7.95-8.05 (m, 1 H), 7.57-7.66 (m, 1 H), 7.34 (ddd, 1 H), 6.83 (dt, 1 H), 4.54 (t, 2H), 2.84 (t, 2H), 2.39 (s, 6H), 0.33-0.44 (m, 9H).
LCMS (3 min): 1 .86 min;m/z 443-449* (M+1 )+ 100%.
1-(pyrido[1 ,2-a]indol-3-yl)ethanone
Figure imgf000070_0002
Potassium 3-acetylpyrido[1 ,2-a]indole-10-carboxylate (300 mg) was dissolved in dioxane (10 ml_) and 1 .5 ml_ of 1 M HCI aqueous solution was added to the reaction solution (pH:2). The mixture was stirred at room temperature for 4h.The solvent was evaporated and the residue was dissolved in ethylacetate, washed with saturated NaHC03 solution and finally with brine. The organic layer was dried (MgS04), filtered and evaporated. The crude residue was purified on a silica gel column using dichloromethane as eluent to give the title product as light brown solid. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.61 (s, 1 H), 8.48 (d, 1 H), 7.94 (d, 1 H), 7.78 (d, 1 H), 6.95 (d, 1 H), 7.0 (t, 1 H), 6.7 (s, 1 H), 6.66 (t, 1 H).
ES-MS: m/z 210 (M+1 ) 100%
Preparation of prop-2-en-1 -yl pyridin-2-yl-acetate
Figure imgf000071_0001
To a suspension of 4-pyridylacetic acid hydrochloride (20.0 g, 1 15 mmol) in DMF (150 ml) was added allyl alcohol (33.46 g, 576 mmol), EDCI (30.92 g, 161 mmol), DMAP (2.81 g, 2.3 mmol) and DIPEA (29.8 g, 230 mmol) sequentially at 0 °C. The resultant yellow solution was stirred at 0 °C for one hour, and then allowed to warm up to room temperature for 48 hours. The solvent was removed in vacuo, and then the residue was dissolved in EtOAc (100ml). The solution was washed with water (200 ml), and 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 evaporated under reduced pressure to furnish the title compound as a brown oil. 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, 2H), 3.89 (s, 2H).
LCMS: 98% UV215 at 0.93 min, m/z 178 (M+1 )+ 100%.
Preparation of compounds having HDME inhibitory effect Alkyl and benzyl ethers
One-Step Analogues
Scheme 17: Formation of O-linked analogues (One-step)
Figure imgf000072_0001
Reagents and conditions: a. i. NaH, DMF, ii. RX, DMF or K-.2C03, RX, DMF, RT.
Procedure A: Sodium hydride (60% dispersion in mineral oil, 0.3 mmol) was added to a stirring solution of the hydroxyl starting material (0.1 mmol) in DMF (1 ml_) at room temperature. After 30 min electrophile (0.2 mmol) was added as a solution in DMF (1 ml_) and stirring was maintained overnight. If starting material remained the reaction was heated to 50 °C for 8h. The reaction was quenched with water and extracted with diethyl ether (3 x 1 ml_). The combined organics were washed with 1 M HCI (1 ml_), water (2 x 1 ml_), 1 M NaOH (2 x 1 ml_), water (1 ml_), brine (1 ml_) and excess solvent was removed under a stream of nitrogen. When required purification was achieved by either flash chromatography (10-33% EtOAc: heptanes) or via preparative HPLC.
Procedure B: Ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate (0.1 mmol), electrophile (0.2 mmol) and K2C03 (0.3 mmol) in DMF or acetone (2 ml_) were stirred overnight at room temperature. If starting material remained the reaction was heated to 50 QC for 8h. The reaction was quenched with water and extracted with diethyl ether (3 x 1 ml_). The combined organics were washed with 1 M HCI (1 ml_), water (2 x 1 ml_), 1 M NaOH (2 x 1 ml_), water (1 ml_), brine (1 ml_) and excess solvent was removed under a stream of nitrogen. When required, purification was achieved by either flash chromatography (10-33% EtOAc:heptanes) or via preparative HPLC. Preparation of ethyl 3-[2-(dimethylamino)ethoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000073_0001
Procedure A: Using 2-dimethylamino-1 -chloroethane. HCI.
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.25-8.42 (m, 3H), 7.33-7.37 (m, 1 H), 7.19-7.26 (m, 2H), 6.78 (t, 1 H) 4.47 (q, 2H), 4.23 (t, 2H), 2.85 (br. s., 2H), 2.42 (s, 6 H), 1 .50 (t, 3H).
LCMS: 100% UV 2i5 at 1 .55 min with m/z 327 (M+1 )+ 100%.
Preparation of ethyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000073_0002
Procedure A: Using 2-bromopropionitrile
Purification: Silica gel FCC (2:1 heptane/EtOAc)
Form: Brown wax H NMR (500 MHz, CDCI3) δ 8.33-8.43 (m, 3H), 7.53 (d, 1 H), 7.22-7.33 (m, 2 H), 6.82 (t, 1 H), 5.00 (q, 1 H), 4.48 (q, 2H), 1 .88 (d, 3H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.30 min with m/z 309 (M+1 )+ 100%. Preparation of ethyl 3-(2-ethoxyethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000074_0001
Procedure A: Using 2-ethoxybromoethane
Purification: Silica gel FCC (2:1 heptane/EtOAc)
Form: Green amorphous solid H NMR (500 MHz, CDCI3) δ 8.33-8.44 (m, 1 H), 8.21 -8.33 (m, 2H), 7.34 (br. s., 1 H), 7.20-7.26 (m, 2H), 6.76 (t, 1 H), 4.47 (q, 2H), 4.26 (br. s., 2H), 3.85-3.90 (m, 2H), 3.65 (q, 2H), 1 .50 (t, 3H), 1 .29 (t, 3H).
LCMS: 100% UV215 at 2.36 min with m/z 328 (M+1 )+ 100%.
Preparation of ethyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000074_0002
Procedure A: Using benzyl chloride
Purification: Mass directed prep-LCMS (on half sample)
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.21 -8.45 (m, 2H), 7.49-7.53 (m, 2H), 7.43 (t, 2H), 7.33- 7.40 (m, 2H), 7.20-7.31 (m, 2H), 6.77 (br. s., 1 H), 5.21 (br. s., 2H), 4.48 (q, 2H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.61 min with m/z 346 (M+1 )+ 100%. Preparation of ethyl 3-[2-piperidinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000075_0001
Procedure B (acetone): Using 1 -chloro-2-(1 -piperidinyl)ethane.HCI
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 1 1 .26 (br. s., 1 H), 8.44 (d, 1 H), 8.35 (d, 1 H), 8.31 (d, 1 H), 7.41 -7.43 (m, 1 H), 7.26-7.32 (m, 1 H), 7.12 (dd, 1 H), 6.81 (t, 1 H), 4.50-4.55 (m, 2H), 4.47 (q, 2H), 3.84 (d, 2H), 3.56-3.61 (m, 2H), 2.85-2.96 (m, 2H), 1 .90-2.08 (m, 6H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 1 .59 min with m/z 367 (M+1 )+ 100%.
Preparation of ethyl 3-[2-piperidinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000075_0002
Procedure B (acetone): using 1 -chloro-2-(morpholin-4-yl)ethane.HCI
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.40 (d, 1 H), 8.35 (d, 1 H), 8.31 (d, 1 H), 7.41 (d, 1 H), 7.26- 7.32 (m, 1 H), 7.12 (dd, 1 H), 6.81 (t, 1 H), 4.51 -4.57 (m, 2H), 4.47 (q, 2H), 3.95-4.12 (m, 4H), 3.79 (d, 2H), 3.58-3.66 (m, 2H), 3.15 (td, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 1 .51 min with m/z 369 (M+1 )+ 100%. Preparation of ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000076_0001
Procedure A: Using chloroacetonitrile on an 1 .0 mmol scale
Purification: Recrystallisation (EtOH)
Form: Yellow-green amorphous solid H NMR (500 MHz, CDCI3) δ 8.35-8.42 (m, 3H), 7.48 (d, 1 H), 7.30 (dd, 1 H), 7.25 (dd, 1 H), 6.80-6.84 (m, 1 H), 4.91 (s, 2H), 4.48 (q, 2H), 1 .51 (t, 3H)
LCMS: 100% UV215 at 2.15 min with m/z 295 (M+1 )+ 100%. Preparation of ethyl 3-[(2-methylprop-2-en-1-yl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000076_0002
Procedure B (DMF): Using 3-bromo-2-methylpropene
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.34-8.40 (m, 1 H), 8.27-8.34 (m, 2H), 7.33 (d, 1 H), 7.24- 7.27 (m, 2H), 7.22 (dd, 1 H), 6.74-6.80 (m, 1 H), 5.18 (s, 1 H), 5.05 (s, 1 H), 4.58 (s, 2H), 4.47 (q, 2H), 1 .90 (s, 3H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.56 min with m/z 310 (M+1 )+ 100%. Preparation of ethyl 3-(3-cyanopropoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000077_0001
Procedure B (DMF): Using 4-bromobutyronitrile
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.35-8.40 (m, 1 H), 8.28-8.35 (m, 2H), 7.31 (d, 1 H), 7.23 7.27 (m, 1 H), 7.17 (dd, 1 H), 6.78 (td, 1 H), 4.47 (q, 2H), 4.22 (t, 2H), 2.68 (t, 2H), 2.19 2.27 (m, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.23 min with m/z 323 (M+1 )+ 50%, 345 (M+Na)+ 100%
Preparation of ethyl 3-(1-phenylethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000077_0002
Procedure B (DMF): Using rac-1 -bromo-1 -phenylethane
Purification: Silica gel FCC (2:1 heptane/EtOAc)
Form: Yellow-green solid H NMR (500 MHz, CDCI3) δ 8.33 (d, 1 H), 8.23 (d, 1 H), 8.15 (d, 1 H), 7.45 (d, 2H), 7.36 (t, 2H), 7.24-7.30 (m, 1 H), 7.17-7.24 (m, 3H), 6.71 (dt, 1 H), 5.43 (q, 1 H), 4.45 (q, 2H), 1 .72 (d, 3H), 1 .48 (t, 3H).
LCMS: 100% UV215 at 2.63 min with m/z 360 (M+1 )+ 100%. Preparation of ethyl 3-[(6-chloropyridin-3-yl)methoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000078_0001
Procedure B (DMF): using 2-chloro-5-chloromethylpyridine
Purification: Mass directed prep-LCMS
Form: Yellow amorphous solid H NMR (250 MHz, CDCI3) δ 8.57-8.64 (m, 1 H), 8.28-8.42 (m, 3H), 7.91 (dd, 1 H), 7.45 (d, 1 H), 7.38 (d, 1 H), 7.20-7.33 (m, 2H), 6.76-6.85 (m, 1 H), 5.22 (s, 2H), 4.48 (q, 2H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.37 min with m/z 381 (M+1 )+ 100%.
Preparation of ethyl 3-[(3-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000078_0002
Procedure B (DMF): Using 3-methylbenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.37 (d, 1 H), 8.26-8.34 (m, 2H), 7.38 (d, 1 H), 7.24-7.35 (m, 5H), 7.15-7.20 (m, 1 H), 6.77-6.82 (m, 1 H), 5.17 (s, 2H), 4.48 (q, 2H), 2.40 (s, 3H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.75 min with m/z 360 (M+1 )+ 100%. Preparation of ethyl 3-[(3-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000079_0001
Procedure B (DMF): Using 3-cyanobenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.36-8.40 (m, 1 H), 8.30-8.36 (m, 2H), 7.83 (br. s., 1 H), 7.72-7.77 (m, 1 H), 7.63-7.68 (m, 1 H), 7.54 (t, 1 H), 7.37 (d, 1 H), 7.24-7.29 (m, 2H), 6.77-6.82 (m, 1 H), 5.23 (s, 2H), 4.48 (q, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.50 min with m/z 371 (M+1 )+ 30%, 393 (M+Na)+ 100%.
Preparation of ethyl 3-[(2-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000079_0002
Procedure B (DMF): using 2-cyanobenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow-green amorphous solid H NMR (500 MHz, CDCI3) δ 8.35-8.40 (m, 2H), 8.33 (d, 1 H), 7.79 (d, 1 H), 7.72-7.76 (m, 1 H), 7.67 (td, J = 1 H), 7.43-7.49 (m, 2H), 7.24-7.30 (m, 2H), 6.78-6.83 (m, 1 H), 5.41 (s, 2H), 4.48 (q, 2H), 1 .50 (t, 3H). LCMS: 100% UV215 at 2.46 min with m/z 371 (M+1 )+ 50%, 393 (M+Na)+ 100% Preparation of ethyl 3-[(4-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000080_0001
Procedure B (DMF): 4-cyanobenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.27-8.40 (m, 3H), 7.71 (m, 2H), 7.62 (m, 2H), 7.35 (d, 1 H), 7.23-7.27 (m, 2H), 6.75-6.81 (m, 1 H), 5.26 (s, 2H), 4.47 (q, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.48 min with m/z 371 (M+1 )+ 100%.
Preparation of ethyl 3-[(3-chlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000080_0002
Procedure B (DMF): Using 3-chlorobenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow-green amorphous solid H NMR (250 MHz, CDCI3) δ 8.26-8.42 (m, 3H), 7.49-7.55 (m, 1 H), 7.30-7.42 (m, 4H), 7.21 -7.30 (m, 2H), 6.78 (td, 1 H), 5.18 (s, 2H), 4.48 (q, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.71 min with m/z 380 (M+1 )+ 100%.
Preparation of ethyl 3-[(2,5-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000081_0001
Procedure B (DMF): Using 2,5-difluorobenzyl bromide
Purification: Mass directed prep-LCMS
Form: Yellow-green amorphous solid H NMR (250 MHz, CDCI3) δ 8.28-8.41 (m, 3H), 7.40 (d, J = 2.1 Hz, 1 H), 7.22-7.37 (m, 3H), 6.95-7.15 (m, 2H), 6.80 (td, 1 H), 5.25 (s, 2H), 4.48 (q, 2H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.62 min with m/z 382 (M+1 )+ 100%.
Preparation of ethyl 3-[(2,6-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000081_0002
Procedure B (DMF): Using 2,6-difluorobenzyl bromide
Purification: Mass directed prep-LC
Form: Yellow-green amorphous solid H NMR (250 MHz, CDCI3) δ 8.38 (dt, 1 H), 8.33 (d, 1 H), 8.31 (dt, 1 H), 7.17-7.40 (i 6H), 6.78 (td, 1 H), 5.14 (s, 2H), 4.48 (q, 2H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.63 min with m/z 382 (M+1 )+ 100%. Preparation of ethyl 3-[2-(3,4-difluorophenyl)-2-oxoethoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000082_0001
Procedure B (DMF): Using 3,4-difluorophenacyl bromide
Purification: Recrystallisation (Et20)
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.37 (d, 1 H), 8.29-8.35 (m, 2H), 7.94 (ddd, 1 H), 7.85- 7.91 (m, 1 H), 7.38 (d, 1 H), 7.28-7.34 (m, 2H), 7.19-7.25 (m, 1 H), 6.79 (td, 1 H), 5.31 (s, 2H), 4.5 (q, 2H), 1 .49 (t, 3H).
LCMS: 100% UV215 at 2.45 min with m/z 410 (M+1 )+ 100%.
Preparation of ethyl 3-[(1 ,3-dimethyl-1 H-pyrazol-5-yl)methoxy]pyrido[1 ,2-a]indole-
10-carboxylate
Figure imgf000082_0002
Procedure B (DMF): 5-chloromethyl-1 ,3-dimethylpyrazole
Purification: Mass directed prep-LCMS
Form: Yellow-green oil H NMR (500 MHz, CDCI3) δ 8.32-8.41 (m, 3H), 7.38 (d, 1 H), 7.26-7.31 (m, 1 H), 7.23 (dd, 1 H), 6.81 (td, 1 H), 6.22 (s, 1 H), 5.15 (s, 2H), 4.48 (q, 2H), 4.00 (s, 3H), 2.34 (s, 3H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.22 min with m/z 364 (M+1 )+ 100%.
Preparation of ethyl 3-[(2-methyl-1 ,3-thiazol-4-yl)methoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000083_0001
Procedure B (DMF): Using 4-chloromethyl-2-methylthiazole .HCI
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.34-8.40 (m, 2H), 8.32 (d, 1 H), 7.45 (d, 1 H), 7.30 (s, 1 H), 7.23-7.29 (m, 2H), 6.76-6.82 (m, 1 H), 5.35 (s, 2H), 4.48 (q, 2H), 2.84 (s, 3H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.29 min with m/z 367 (M+1 )+ 100%.
Preparation of ethyl 3-(3-methylbutoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000083_0002
Procedure B (DMF): Using 1 -bromo-3-methylbutane
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.36 (d, 1 H), 8.33 (d, 1 H), 8.28 (d, 1 H), 7.30 (d, 1 H), 7.25 (dd, 1 H), 7.19 (dd, 1 H), 6.78 (td, 1 H), 4.48 (q, 2H), 4.12 (t, 2H), 1 .84-1 .98 (m, 1 H), 1 .77 (q, 2H), 1 .51 (t, 3H), 1 .02 (d, 6H). LCMS: 100% UV215 at 2.75 min with m/z 326 (M+1 )+ 100%.
Preparation of ethyl 3-(4-cyanobutoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000084_0001
Procedure A: using 6-bromohexanenitrile
Purification: Trituration (hexane addition to Et20 solution)
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.33-8.42 (m, 3H), 7.76 (d, 1 H), 7.26-7.32 (m, 2H), 6.79 (t, 1 H), 4.48 (q, 2H), 3.65 (t, 2H), 3.54 (t, 2H), 1 .93-2.07 (m, 4H), 1 .22 (t, 3H).
LCMS: 100% UV215 at 2.29 min with m/z 337 (M+1 )+ 70%, 359 (M+Na)+ 100%.
Preparation of ethyl 3-[2-(dimethylamino)-2-oxoethoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000084_0002
Procedure A: Using 2-chloro-N,N-dimethylacetamide
Purification: Silica gel FCC (2:1 heptane/EtOAc)
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.33-8.39 (m, 2H), 8.31 (d, 1 H), 7.47 (d, 1 H), 7.23-7.26 (m, 1 H), 7.22 (dd, 1 H), 6.77 (td, 1 H), 4.84 (s, 2H), 4.47 (q, 2H), 3.16 (s, 3H), 2.99 (s, 3H), 1 .49 (t, 3H). LCMS: 100% UV215 at 1 .99 min with m/z 341 (M+1 )+ 100%.
Preparation of ethyl 3-[2-(2-hydroxyethoxy)ethoxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000085_0001
Procedure A: Using 2-(2-chloroethoxy)ethanol
Purification: Mass directed prep-LC
Form: Yellow-green oil H NMR (500 MHz, CDCI3) δ 8.34-8.39 (m, 1 H), 8.28-8.34 (m, 2H), 7.34 (d, 1 H), 7.23- 7.26 (m, 1 H), 7.21 (dd, 1 H), 6.77 (td, 1 H), 4.47 (q, 2H), 4.25-4.32 (m, 2H), 3.93-3.99 (m, 2H), 3.78-3.85 (m, 2H), 3.69-3.77 (m, 2H), 1 .50 (t, 3H). LCMS: 100% UV215 at 2.00 min with m/z 344 (M+1 )+ 50%, 366 (M+Na)+ 100%.
Preparation of methyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000085_0002
Procedure A: Using methyl iodide on a 0.4 mmol scale wrt the pyrido[1 ,2-a]indole Purification: 2M aq. NaOH and water wash a solution of crude product in diethyl ether. Dry organic phase over Na2S04, filter and evaporate in vacuo. Form: Yellow-brown oil H NMR (500 MHz, DMSO-d6) δ 9.08 (d, 1 H), 8.22 (d, 1 H), 8.12 (d, 1 H), 7.93 (d, 1 H), 7.42 (dd, 1 H), 7.16 (dd, 1 H), 6.97 (t, 1 H), 4.34 (q, 2H), 3.89 (s, 3H), 1 .39 (t, 3H).
LCMS: 95% UV215 at 2.24 min with m/z 270 (M+1 )+ 100%.
Preparation of ethyl 3-(2-oxopropoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000086_0001
To a solution of ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate (0.100 g, 0.392 mmol) in dry acetone (5 mL) were introduced chloroacetone (0.181 g, 1 .957 mmol), cesium carbonate (0.140 g, 0.430 mmol) and potassium iodide (0.007 g, 0.042 mmol). The reaction mixture was warmed to 50 °C for 1 hour. After cooling to room
temperature, the reaction mixture was evaporated in vacuo. The residue was re- dissolved in ethyl acetate (15 mL), washed with water (2 x 5 mL) and brine (5 mL) and dried over sodium sulfate. Filtration and evaporation of the filtrate furnished the title compound as a tan, amorphous solid. H NMR (500 MHz, CDCI3) δ 8.37 (d, 1 H), 8.34 (d, 1 H), 8.32 (d, 1 H), 7.26-7.28 (m, 2H), 7.21 (dd, 1 H), 6.79 (td, 1 H), 4.68 (s, 2H), 4.48 (q, 2H), 2.35 (s, 3H), 1 .50 (t, 3H).
LCMS: 98% UV215 at 2.09 min with m/z 312 (M+1 )+ 100%.
Three-step analogues
Scheme 18: Three step synthesis of 3-aminobenzylether analogues
Figure imgf000087_0001
Preparation of ethyl 3-(3-nitro-benzyloxy)-pyrido[1,2-a]indole-10-carboxylate
Figure imgf000087_0002
Procedure: generic procedure A using 3-nitrobenzyl bromide
Form: Orange-brown solid. H NMR (250 MHz, DMSO-d6) δ 8.99-9.09 (m, 1H), 8.36-8.42 (m, 1H), 8.18-8.26 (m, 2H),8.15(d, 1H),8.10(d, 1 H), 7.94-8.02 (m, 1H), 7.72 (t, 1H), 7.43 (ddd, 1H), 7.29 (dd, 1 H), 6.92-7.04 (m, 1 H), 5.39 (s, 2H), 4.34 (q, 2H), 1.39 (t, 3H).
LCMS: 100% UV215 at 2.55 min with m/z 391 (M+1)+ 70%, 413 (M+Na)+ 100%.
Preparation of ethyl 3-(3-amino-benzyloxy)-pyrido[1,2-a]indole-10-carboxylate
Figure imgf000087_0003
Iron (143 mg, 2.6 mmol) was added to ethyl 3-(3-nitro-benzyloxy)-pyrido[1 ,2-a]indole- 10-carboxylate (250 mg, 0.64 mmol) in ethanol (5 ml). Hydrochloric acid (0.1 M, 320 μΙ, 0.032 mmol) was added at 20 °C, then reaction heated in a sealed vessel (heating block temp 100 °C). The reaction mixture was chilled (ice bath) then filtered through a plug of celite (cold EtOH). Purification was achieved by FC (1 :1 EtOAc/hept. with 2% TEA) to provide title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.34-8.39 (m, 1 H), 8.31 (d, 1 H), 8.25-8.29 (m, 1 H), 7.34 (d, 1 H), 7.18-7.29 (m, 3H), 6.88 (d, 1 H), 6.82-6.85 (m, 1 H), 6.74 (td, 1 H), 6.67 (dd, 1 H), 5.1 1 (s, 2H), 4.48 (q, 2H), 3.73 (br. s., 2H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.09 min with m/z 361 (M+1 )+ 100%.
Preparation of ethyl 3-[(3-acetaminobenzyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000088_0001
To a solution of ethyl 3-aminobenzyloxy-benz[1 ,2-a]indole 10-carboxylate (25 mg, 0.07 mmol) and diisopropylethylamine (27 mg, 0.2 mmol) in THF (1 mL) was added acetyl chloride (8 mg, 0.1 mmol) in THF (1 mL) at 20 °C. After 90 minutes the reaction contents were poured into cold 1 M HCI (10 mL). The aqueous solution was extracted with EtOAc (20 mL) and the organic phase washed with 1 M HCI (10 mL) and water (5 mL) prior to drying (MgS04), filtration and removal of solvent in vacuo. Purification by trituration with acetonitrile and filtration furnished the title compound as an off-white solid. H NMR (500 MHz, CDCI3) δ 8.34 (d, 1 H), 8.24-8.31 (m, 2H), 7.68 (s, 1 H), 7.41 -7.51 (m, 2H), 7.35 (t, 1 H), 7.30-7.33 (m, 1 H), 7.18-7.25 (m, 2H), 6.74 (t, 1 H), 5.15 (s, 2H), 4.47 (q, 2H), 2.19 (s, 3H), 1 .49 (t, 3H). LCMS: 100% UV215 at 2.21 min with m/z 403 (M+1 )+ 80%, 425 (M+Na)+ 100%.
Preparation of ethyl 3-[(3-methylsulfonylaminobenzyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000089_0001
To a solution of ethyl 3-aminobenzyloxy-benz[1 ,2-a]indole 10-carboxylate (25 mg, 0.07 mmol) and diisopropylethylamine (27 mg, 0.2 mmol) in THF (1 mL) was added methanesulfonyl chloride (1 1 mg, 0.1 mmol) in THF (1 mL) at 20 °C. After 90 minutes, the reaction contents were poured into cold 1 M HCI (10 mL). The aqueous solution was extracted with EtOAc (20 mL) and the organic phase washed with 1 M HCI (10 mL) and water (5 mL) prior to drying (MgS04), filtration and removal of solvent in vacuo. The filtrate residue was purified by mass directed prep-LCMS to furnish the title compound as a pale yellow oil. H NMR (500 MHz, CDCI3) δ 8.35-8.40 (m, 1 H), 8.29-8.34 (m, 2H), 7.36-7.44 (m, 3H), 7.32-7.36 (m, 1 H), 7.23-7.26 (m, 1 H), 7.17-7.22 (m, 1 H), 6.79 (td, 1 H), 6.41 (br. s., 1 H), 4.47 (q, 2H), 3.01 (s, 3H), 1 .50 (t, 3H). LCMS: 100% UV215 at 2.24 min with m/z 439 (M+1 )+ 50%, 461 (M+Na)+ 100%.
Sulfonate esters
Methyl 3-{[(trif luoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000090_0001
Procedure C:
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%.
Preparation of ethyl 3-{[(trifluoromethyl)sulfonyl] oxy}pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000090_0002
Triflic anhydride (0.494 ml_, 3.0 mmol) was added to a stirring solution of ethyl 3- hydroxypyrido[1 ,2-a]indole-10-carboxylate (500 mg,) and pyridine (0.320 ml_) in 3:1 DCM:THF (40 ml_) at 0 °C under an atmosphere of nitrogen. After 10 min DMAP (36 mg) was added and the reaction allowed to warm to room temperature overnight (18h). The reaction was diluted with DCM (60 ml) and the organic was washed with saturated aqueous NaHC03 (20 ml_), 1 M HCI (2 x 20 ml_) and 1 M NaOH (2 x 20 ml_). The organic layer was then dried (Na2S04), filtered and excess solvent removed under reduced pressure. A portion of the crude material was subjected to FC (50 % ethyl acetate/heptanes) to provide title compound as a green solid. H NMR (500 MHz, CDCI3) δ 8.47 (d, 1 H), 8.40-8.46 (m, 2H), 7.83 (d, 1 H), 7.36-7.45 (m, 2H), 6.90 (td, 1 H), 4.49 (q, 2H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.61 min with m/z 388 (M+1 )+ 100%.
Preparation of ethyl 3-[(cyclopropylsulfonyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000091_0001
Procedure A: Using cyclopropanesulfonyl chloride
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.40-8.45 (m, 3H), 7.89 (d, 1 H), 7.33-7.38 (m, 1 H), 6.84- 6.89 (m, 1 H), 4.49 (q, 2H), 2.60-2.69 (m, 1 H), 1 .51 (t, 3H), 1 .51 (t, 3H), 1 .27-1 .34 (m, 2H), 1 .1 1 -1 .19 (m, 2H). LCMS: 100% UV215 at 2.24 min with m/z 360 (M+1 )+ 100%.
Preparation of ethyl 3-[(methylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000092_0001
Procedure A: Using methanesulfonyl chloride
Purification: Silica gel FCC (2:1 heptane:EtOAc)
Form: Yellow-brown solid H NMR (500 MHz, CDCI3) δ 8.40-8.48 (m, 3H), 7.90 (d, 1 H), 7.41 (dd, 1 H), 7.34-7.38 (m, 1 H), 6.84-6.90 (m, 1 H), 4.49 (q, 2H), 3.20 (s, 3H), 1 .51 (t, 3H). LCMS: 93% UV215 at 2.10 min with m/z 334 (M+1 )+ 100%.
Preparation of ethyl 3-{[(2,4-dimethyl-1 ,3-thiazol-5-yl)sulfonyl]oxy}pyrido[1 ,2- a]indole-10-carboxylate
Figure imgf000092_0002
Procedure A: Using 2,4-dimethylthiazole-5-sulfonyl chloride
Purification: Mass directed prep-LCMS
Form: yellow oil H NMR (500 MHz, CDCI3) δ 8.38-8.44 (m, 2H), 8.31 (d, 1 H), 7.81 (d, 1 H), 7.32-7.41 (m, 1 H), 7.04 (dd, 1 H), 6.87 (td, 1 H), 4.47 (q, 2H), 2.69 (s, 3H), 2.47 (s, 3H), 1 .49 (t, 3H).
LCMS: 88% UV215 at 2.38 min with m/z 431 (M+1 )+ 100%. 2-(Dimethylamino)ethyl 3-{[(trif luoromethyl)sulf onyl]oxy}pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000093_0001
Procedure C starting from 2-(dimethylamino)ethyl 3-hydroxypyrido[1 ,2-a]indole-10- carboxylate
(41 .6 g) Purification by silica gel column chromatography (eluent: dichloromethane containing 1 % by volume triethylamine) gave the title compound as a pale green solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.48 (d, 1 H), 8.45 (d, 1 H), 8.42 (d, 1 H), 7.82 (d, 1 H), 7.42 (dd, 1 H), 7.39 (ddd, 1 H), 6.90 (td, 1 H), 4.54 (t, 2H), 2.83 (t, 2H), 2.39 (s, 6H).
LCMS (3 min): 1 .64 min; m/z 431 (M+1 )+ 100%.
Carbamates and Carbonates
Preparation of ethyl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000093_0002
Procedure A: Using morpholinecarbamoyl chloride
Purification: Mass directed prep-LCMS
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.37-8.42 (m, 2H), 8.36 (d, 1 H), 7.72 (d, 1 H), 7.31 (ddd, 1 H), 7.25-7.29 (m, 1 H), 6.80 (td, 1 H), 4.49 (q, 2H), 3.78-3.84 (m, 4H), 3.77 (br. s., 2H), 3.63 (br. s., 2H), 1 .50 (t, 3 H).
LCMS: 100% UV215 at 2.08 min with m/z 369 (M+1 )+ 100%.
Preparation of ethyl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000094_0001
Procedure A: Using Ν,Ν-dimethylcarbamoyl chloride
Purification: Silica gel FCC (2:1 Heptane:EtOAc)
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.32-8.43 (m, 3H), 7.72 (d, 1 H), 7.25-7.32 (m, 2H), 6.78 (t, 1 H), 4.48 (q, 2H), 3.19 (s, 3H), 3.07 (s, 3H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 2.14 min with m/z 327 (M+1 )+ 100%.
Preparation of ethyl 3-[(pyrrolidin-1-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000094_0002
Procedure A: Using pyrrolidinecarbamoyl chloride
Purification: Hexane trituration from diethyl ether solution.
Form: Yellow amorphous solid H NMR (500 MHz, CDCI3) δ 8.38 (d, 1 H), 8.33 (d, 1 H), 8.31 (d, 1 H), 7.30 (d, 1 H), 7.22- 7.28 (m, 1 H), 7.17 (dd, 1 H), 6.78 (td, 1 H), 4.48 (q, 2H), 4.15 (t, 2H), 2.51 (t, 2H), 2.01 - 2.09 (m, 2H), 1 .93-2.01 (m, 2H), 1 .22 (t, 3H). LCMS: 100% UV215 at 2.27 min with m/z 353 (M+1 )+ 100%.
Preparation of prop-2-en-1 -yl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000095_0001
To solution of prop-2-en-1 -yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (268 mg, 1 .0 mmol) in THF (10 ml) was added NaH (90 mg, 2.0 mmol) portionwise at 0 °C. The reaction was stirred at room temperature for one hour, then dimethylcarbamyl chloride (175 μΙ, 1 .91 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature overnight. The reaction was then quenched by water (10 ml) at 0 °C and the resulting solution extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), dried over Na2S04, filtered and evaporated to dryness. The filtrate residue was purified by column chromatography (silica gel, eluent: 0.5-2% MeOH gradient in DCM) to furnish the title compound as yellow solid. H NMR (500 MHz, CDCI3) δ 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%. Preparation of prop-2-en-1-yl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-
10-carboxylate
Figure imgf000096_0001
To a solution of prop-2-en-1 -yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (100 mg, 0.374 mmol) in THF (5.0 ml) was added NaH (36 mg, 0.376 mmol) in portions at 0 °C. The reaction was stirred at room temperature for one hour and then morpholine-4- carbonyl chloride (88 μΙ, 0748 mmol) was added dropwise at 0 °C. The reaction was allowed to warm up to room temperature and left overnight. The solvent was removed in vacuo, and then the residue was purified by column chromatography (silica gel, eluent: 0.5-2% MeOH gradient in DCM). The title compound was isolated as a yellow amorphous solid. H NMR (500 MHz, CDCI3) δ 8.39 (dd, 2H), 8.35 (d, 1 H), 7.72 (d, 1 H), 7.31 (ddd, 1 H), 7.24-7.29 (m, 1 H), 6.80 (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), 3.72-3.84 (m, 6H), 3.58-3.68 (m, 2H). LCMS: 100% UV215 at 2.17 min, m/z 381 (M+1 )+ 100%.
Preparation of ethyl 3-[(ethoxycarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000096_0002
Procedure A: Using ethyl chloroformate
Purification: Silica gel FCC (2:1 Heptane:EtOAc)
Form: Yellow-brown solid H NMR (500 MHz, CDCI3) δ 8.36-8.43 (m, 2H), 8.34 (d, 1 H), 7.75 (d, 1 H), 7.28-7.35 (m, 2H), 6.78-6.82 (m, 1 H), 4.47 (q, 2H), 4.37 (q, 2H), 1 .50 (t, 3H), 1 .43 (t, 3H).
LCMS: 96% UV215 at 2.29 min with m/z 328 (M+1 )+ 100%.
Preparation of ethyl 3-(heteroaryloxy)pyridino[1 ,2-a]indole-1-carboxylate derivatives.
Scheme 19: Generic SNAr approach to heteroaryloxy derivatives of phenol 1
Figure imgf000097_0001
Procedure D:
To a solution of ethyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (0.100 g, 0.39 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) at 20 °C was introduced sodium hydride (0.018 g of a 50% dispersion in mineral oil, 0.39 mmol). After 2 minutes, the appropriate haloheterocycle was introduced and the reaction vessel (Ace #15 pressure tube) flushed with nitrogen and capped. The reaction warmed to a temperature at which product formation could be detected by LCMS, then held at this temperature until all starting materials were consumed. Workup and purification described for each compound.
Preparation of ethyl 3-(pyrazin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000098_0001
By Procedure D:
Haloheteroaromatic: 2-chloropyrazine
Reaction conditions: 60 °C for 3h.
Workup & Purification: On cooling to 20 °C, a precipitate was deposited from the reaction solution. This solid was collected by vacuum filtration and washed on the filter with N,N-dimethylformamide (2 x 0.2 mL). The precipitate was suspended in water (5 mL), re-filtered and washed on the filter with water (1 mL). Air drying on the filter furnished the title compound as a lemon yellow solid. H NMR (250 MHz, CDCI3) δ 8.51 (s, 1 H), 8.46 (d, 1 H), 8.42 (d, 1 H), 8.35 (d, 1 H), 8.30 (d, 1 H), 8.10-8.12 (m, 1 H), 7.73 (d, 1 H), 7.28-7.35 (m, 2H), 6.81 (t, 1 H), 4.49 (q, 2H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.19 min, m/z 334 (M+1 )+ 100%.
Preparation of ethyl 3-(pyridin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000098_0002
By Procedure D:Haloheteroaromatic: 2-bromopyridine
Reaction conditions: 120 °C for 12h
Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (20 mL). This solution was washed with water (2 x 20 mL) and brine (1 x 10 mL), dried over MgS04 and filtered. The filtrate was evaporated onto silica gel (1 .0 g). Purification of the dry loaded compound by silica gel flash column chromatography (heptane/ethyl acetate gradient of increasing polarity) furnished the title compound as a yellow powder. H NMR (500 MHz, CDCI3) δ 8.43 (d, 1 H), 8.41 (d, 1 H), 8.34 (d, 1 H), 8.21 (dd, 1 H), 7.70-7.73 (m, 2H), 7.33 (dd, 1 H), 7.30 (ddd, 1 H), 7.02 (dd, 1 H), 6.97 (d, 1 H), 6.79 (td, 1 H), 4.49 (q, 2H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.28 min, m/z 333 (M+1 )+ 100%.
Preparation of ethyl 3-[(2-methoxypyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000099_0001
By Procedure D:
Haloheteroaromatic: 4-chloro-2-methoxypyrimidine
Reaction conditions: 60 °C for 3h.
Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (3 x 5 mL) and brine (1 x 5 mL), dried over MgS04 and filtered under vacuum. The filtrate was evaporated onto silica gel (0.6 g). Purification of the dry loaded compound by silica gel flash column chromatography (heptane/ethyl acetate gradient of increasing polarity) furnished the title compound as a yellow powder. H NMR: (250 MHz, CDCI3) δ 8.33-8.46 (m, 4H), 7.70 (d, J = 2.2 Hz, 1 H), 7.30-7.36 (m, 2H), 6.81 (t, J = 8.3 Hz, 1 H), 6.52 (d, J = 5.8 Hz, 1 H), 4.49 (q, J = 6.9 Hz, 2H), 3.89 (s, 3H), 1 .51 (t, J = 7.1 Hz, 3H). LCMS: 100% UV215 at 2.23 min, m/z 364 (M+1 )+ 100%.
Preparation of ethyl 3-[(6-methylpyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000100_0001
By Procedure D:
Haloheteroaromatic: 4-chloro-6-methylpyrimidine (2 equivalents used)
Reaction conditions: 50 °C for 12h.
Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (3 x 10 mL) and brine (1 x 3 mL), dried over MgS04 and filtered. The filtrate was evaporated in vacuo and acetonitrile (1 mL) introduced to the residue. The resulting slurry was sonicated for several minutes and the precipitate isolated by vacuum filtration. Air drying on the filter furnished the title compound as a pale brown solid. H NMR (500 MHz, CDCI3) δ 8.70 (s, 1 H), 8.47 (d, 1 H), 8.43 (d, 1 H), 8.35 (d, 1 H), 7.70 (d, 1 H), 7.30-7.34 (m, 2H), 6.82 (t, 1 H), 6.77 (s, 1 H), 4.50 (q, 2H), 2.52 (s, 3H), 1 .51 (t, 3H).
LCMS: 100% UV215 at 2.15 min, m/z 348 (M+1 )+ 100%.
Preparation of ethyl 3-{[2-(dimethylamino)pyrimidin-4-yl]oxy}pyrido[1 ,2-a]indole-
10-carboxylate
Figure imgf000101_0001
By Procedure D:
Haloheteroaromatic: 2,4-dichloropyrimidine
Reaction conditions: 60 °C for 20 mins for SNAr reaction with phenolic pyrido[1 ,2- a]indole. Dimethylamine (1 .0 mL of a 2M solution in THF, 2.0 mmol, 5.1 equiv) was then introduced and heating continued at 60 °C for a further 30 minutes.
Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (20 mL). This solution was washed with water (2 x 20 mL) and brine (1 x 5 mL), dried over MgS04 and filtered under vacuum. The filtrate was evaporated onto silica gel (1 .0 g). Purification of the dry loaded compound by silica gel flash column chromatography (heptane/ethyl acetate gradient of increasing polarity) furnished the title compound as a yellow powder. H NMR (500 MHz, CDCI3) δ 8.42 (d, 1 H), 8.41 (d, 1 H), 8.35 (d, 1 H), 8.19 (d, 1 H), 7.70 (d, 1 H), 7.35 (dd, 1 H), 7.32 (ddd, 1 H), 6.82 (td, 1 H), 6.00 (d, 1 H), 4.50 (q, 2H), 3.07 (br. s, 6H), 1 .51 (t, 6H).
LCMS: 100% UV215 at 1 .94 min, m/z 377 (M+1 )+ 100%.
Preparation of ethyl 3-[(3-cyanopyrazin-2-yl)oxy]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000101_0002
By Procedure D:
Haloheteroaromatic: 2-chloro-3-cyanopyrazine
Reaction conditions: 20 °C for 10 minutes. Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (2 x 15 mL) and brine (1 x 5 mL), dried over MgS04 and filtered under vacuum. The filtrate was evaporated in vacuo, acetonitrile (0.5 mL) introduced to the residue and the slurry slowly stirred for 10 minutes. The solid was collected by vacuum filtration and air dried on the filter to furnish the title compound as a yellow-brown solid. H NMR (500 MHz, CDCI3) δ 8.49 (d, 1 H), 8.42-8.44 (m, 2H), 8.36 (d, 1 H), 8.28 (d, 1 H), 7.76 (d, 1 H), 7.32-7.36 (m, 2H), 6.84 (td, 1 H), 4.50 (q, 2H), 1 .51 (t, 3H). LCMS: 100% UV215 at 2.25 min, m/z 359 (M+1 )+ 80% and m/z 381 (M+Na)+ 100%
Preparation of ethyl 3-{[5-(methoxycarbonyl)pyrazin-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate (R = Me) and 5-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3- yl]oxy}pyrazine-2-carboxylic acid (R = H)
Figure imgf000102_0001
By Procedure D:
Haloheteroaromatic: methyl 5-chloropyrazine-2-carboxylate
Reaction conditions: 20 °C for 5 minutes.
Workup & Purification: A copious precipitate was deposited from the reaction mixture after 5 minutes at 20 °C. Acetonitrile (3 mL) and water (0.1 ml) were introduced to quench any remaining hydride and make the slurry mobile enough to filter. The precipitate was collected by vacuum filtration and washed on the filter with acetonitrile (0.5 mL). The sticky solid was suspended in acetonitrile (2.0 mL) and re-filtered. LCMS determined the precipitate to be a mixture of the methyl ester and carboxylic acid. Suspension of the precipitate in rapidly stirred ethyl acetate (20 mL) for 20 minutes and filtration gave a yellow filtrate. The precipitate was re-suspended in ethyl acetate (20 mL) for 20 minutes and the slurry re-filtered. Both the first and second slurry filtrates were combined and evaporated to furnish the methyl ester as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.84 (d, 1 H), 8.58 (d, 1 H), 8.49 (d, 1 H), 8.43 (d, 1 H), 8.36 (d, 1 H), 7.76 (d, 1 H), 7.32-7.35 (m, 2H), 6.83 (td, 1 H), 4.50 (q, 2H), 4.03 (s, 3H), 1 .51 (t, 3H).
LCMS: 96% UV215 at 2.19 min, m/z 392 (M+1 )+ ester 100%.
The carboxylic acid containing precipitate was slurried in water (0.5 mL) to dissolve a polar impurity and the solid collected by vacuum filtration. Air drying on the filter furnished the carboxylic acid as a yellow solid. H NMR (500 MHz, d6-DMSO) δ 9.07 (d, 1 H), 8.59 (s, 1 H), 8.34 (s, 1 H), 8.31 (s, 1 H), 8.28 (s, 1 H), 8.27 (s, 1 H), 7.50 (t, 1 H), 7.39 (d, 1 H), 6.99 (t, 1 H), 4.38 (q, 2H), 1 .41 (t, 3H).
LCMS: 100% UV215 at 1 .98 min, m/z 378 (M+1 )+ 100%.
Preparation of ethyl 3-(pyrimidin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000103_0001
By Procedure D:
Haloheteroaromatic: 2-chloropyrimidine
Reaction conditions: 60 °C for 80 minutes Workup & Purification: The reaction mixture was evaporated to dryness in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (1 x 15 mL) and the suspended precipitate in the organic phase isolated by vacuum filtration and washed on the filter with ethyl acetate (5 ml). Air drying on the filter furnished the title compound as a yellow solid. H NMR (500 MHz, d6-DMSO) δ 9.07 (d, 1 H), 8.66 (d, 1 H), 8.32 (d, 1 H), 8.27 (d, 1 H), 8.26 (d, 1 H), 7.51 (ddd, 1 H), 7.38 (dd, 1 H), 7.29 (t, 1 H), 7.00 (td, 1 H), 4.38 (q, 2H), 1 .41 (t, 3H).
LCMS: 97% UV215 at 2.06 min, m/z 334 (M+1 )+ 100%.
C3 Esters Preparation of ethyl 3-(acetyloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000104_0001
Procedure A: Using acetyl chloride
Purification: Silica gel FCC (2:1 heptane:EtOAc)
Form: Yellow oil H NMR (500 MHz, CDCI3) δ 8.38-8.44 (m, 2H), 8.33-8.38 (m, 1 H), 7.69 (d, 1 H), 7.29- 7.34 (m, 1 H), 7.25 (dd, 1 H), 6.81 (dt, 1 H), 4.48 (q, 2H), 2.39 (s, 3H), 1 .50 (t, 3H).
LCMS: 98% UV215 at 2.16 min with m/z 298 (M+1 )+ 100%
C3 Halo
2-(Dimethylamino)ethyl 3-bromopyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000105_0001
To a solution of 2-(dimethylamino)ethyl 3-(trimethylstannyl)pyrido[1 ,2-a]indole-10- carboxylate (500 mg) in dichloromethane at 5 °C was introduced bromine (1 .12 mL of a 1 M solution in dichloromethane). After 2 h at this temperature, the reaction mixture was diluted with dichloromethane and washed with 10% aqueous sodium thiosulfate. The combined sodium thiosulfate extracts were washed with dichloromethane, all the dichloromethane extracts were combined and washed with 10% aqueous sodium thiosulfate and brine. After drying over sodium sulfate, the dichloromethane extract was filtered and evaporated in vacuo. The residue was re-dissolved in methanol and percolated through an acid functionalised silica cartridge (Isolute SCX-2 cartridge, (5 g), eluent: methanol wash and 2M ammonia in methanol to release from the cartridge) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.42 (d, 1 H), 8.39 (d, 1 H), 8.30 (d, 1 H), 8.05 (d, 1 H), 7.60 (dd, 1 H), 7.35 (ddd, 1 H), 6.84 (td, 1 H), 4.53 (t, 2H), 2.82 (t, 2H), 2.39 (s, 6H).
LCMS (7 min): 3.04 min; m/z 361/363 (M+1 )+ 100%.
C3 C-linked
2-(Dimethylamino)ethyl 3-cyanopyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000105_0002
To a solution of de-oxygenated A/JV-dimethylformamide (4.5 mL) and water (0.04 mL) was introduced 2-(dimethylamino)ethyl 3-bromopyrido[1 ,2-a]indole-10-carboxylate (0.100 g), zinc(ll) cyanide (33 mg), 1 ,1 '-bis(diphenylphosphino)ferrocene (18 mg) and bis(dibenzylideneacetone)palladium(0) (12 mg). The reaction mixture was heated to 120 °C under an atmosphere of nitrogen for 24 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic extract was dried (sodium sulfate), filtered and the filtrate evaporated in vacuo. Purification by silica gel column chromatography (eluent:
dichloromethane containing a 0-0.75% gradient of methanol) gave the title compound as a brown solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.47 - 8.54 (m, 3H), 8.24 (s, 1 H), 7.72 (dd, 1 H), 7.49 (ddd, 1 H), 6.98 (td, 1 H), 4.55 (t, 2H) 2.83 (t, 2H), 2.39 (s, 6H). LCMS (7 min): 2.85 min; m/z 308 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-(1 -methyl-1 W-imidazol-2-yl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000106_0001
To a solution of 2-(dimethylamino)ethyl 3-(trimethylstannyl)pyrido[1 ,2-a]indole-10- carboxylate (200 mg) in anhydrous deoxygenated 1 ,4-dioxane (3.3 mL) under an atmosphere of nitrogen was introduced 2-bromo-1 -methylimidazole (80 mg), tetrakis(triphenylphosphine)palladium(0) (52 mg), copper(l) iodide (26 mg). The reaction mixture was heated to 150 °C for 30 min (microwave heating). After cooling, the reaction mixture was evaporated in vacuo, and the residue dissolved in dichloromethane. The solution was filtered through a pad of Celite® and the filtrate evaporated in vacuo. Purification by preparative LC (acetonitrile/water/ammonium hydroxide) gave the title compound as a yellow oil. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.54 (d, 1 H), 8.46 (m, 2H), 8.31 (s, 1 H), 7.71 (dd, 1 H), 7.38 (ddd, 1 H), 7.18 (s, 1 H), 7.04 (s, 1 H), 6.86 (td, 1 H), 4.56 (t, 2H), 3.85 (s, 3H), 2.85 (t, 2H), 2.40 (s, 6H).
LCMS (7 min): 2.14 min; m/z 363 (M+1 )+ 100%.
C3 Alkyl
2-(Dimethylamino)ethyl 3-ethenylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000107_0001
To a solution of 2-(dimethylamino)ethyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2- a]indole-10-carboxylate (1 .00 g) in anhydrous 1 ,4-dioxane (10 ml_) were introduced tetrakis(triphenylphosphine)palladium(0) (0.16 g), lithium chloride (99 mg) and tributyl(vinyl)tin (0.88 g). The reaction mixture was heated to 100 °C for 12 h. After cooling to room temperature the mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient, containing 1 % by volume triethylamine) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.49 (d, 1 H), 8.43 (d, 1 H), 8.36 (d, 1 H), 7.86 (s, 1 H), 7.66 (dd, 1 H), 7.33 (ddd, 1 H), 6.92 (dd, 1 H), 6.84 (td, 1 H), 5.86 (d, 1 H), 5.30 (d, 1 H), 4.54 (t, 2H), 2.84 (t, 2H), 2.39 (s, 6H).
LCMS (3 min): 1 .57 min; m/z 309 (M+1 )+ 100%.
Scheme 20: Elaboration of 2-(dimethylamino)ethyl 3-ethenylpyrido[1 ,2-a]indole-10- carboxylate to furnish C3-analogues.
Figure imgf000108_0001
2-(Dimethylamino)ethyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000108_0002
To a solution of 2-(dimethylamino)ethyl 3-ethenylpyrido[1 ,2-a]indole-10-carboxylate (550 mg) in 9:1 acetone / water (10 ml_) was added aqueous osmium tetroxide (0.57 ml_ of a 4% aqueous solution) over 2 min. The solution was cooled to 5 °C and 4- methylmorpholine-/V-oxide (418 mg) was added over 30 min. After warming to room temperature over 4 h, saturated aqueous sodium metabisulfite was introduced and stirring was continued for a further 5 min. The reaction mixture was diluted with ethyl acetate and the aqueous phase separated and washed with further ethyl acetate. The combined ethyl acetate extracts were dried (sodium sulfate), filtered through a Celite® plug and the filtrate concentrated in vacuo to give the title compound as a yellow foam. This material was used without further purification, but could be further purified by preparative- LC to furnish the title compound as a formate salt. H NMR of mono-formate salt (500 MHz, cW-methanol) δ ppm 8.85 (d, 1 H), 8.45 (s, 1 H), 8.31 (d, 1 H), 8.25 (d, 1 H), 8.14 (s, 1 H), 7.53 (d, 1 H), 7.45 (t, 1 H), 6.96 (t, 1 H), 4.92 (dd, 1 H), 4.72-4.75 (m, 2H), 3.72-3.78 (m, 2H), 3.56 (br. t, 2H), 2.93 (s, 6H). LCMS (7 min): 2.34 min; m/z 343 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-f ormylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000109_0001
To 2-(dimethylamino)ethyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate (1 .19 g) in 1 :1 1 ,4-dioxane / water (40 ml_) at room temperature was added sodium periodate (0.97 g). After 50 min, the reaction mixture was partially evaporated in vacuo and the residual aqueous slurry extracted with ethyl acetate, and the combined extracts were dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo and the crude was and purification by silica gel column chromatography (eluent: heptane / ethyl acetate gradient followed by ethyl acetate containing 5-15% tetrahydrofuran, all eluent mixtures contained 1 % by volume triethylamine) gave the title compound as an orange- yellow solid. H NMR (500 MHz,CHLOROFORM-d) δ ppm 10.12 (s, 1 H), 8.61 (d, 1 H), 8.49 (d, 1 H), 8.47 (d, 1 H), 8.44 (s, 1 H), 7.99 (d, 1 H), 7.47 (ddd, 1 H), 6.96 (td, 1 H), 4.55 (t, 2H), 2.84 (t, 2H), 2.40 (s, 6H).
LCMS (3 min): 1 .28 min; m/z 31 1 (M+1 )+ 100%. 2-(Dimethylamino)ethyl 3-(2,2,2-trifluoro-1-hydroxyethyl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000109_0002
To a solution of 2-(dimethylamino)ethyl 3-formylpyrido[1 ,2-a]indole-10-carboxylate (160 mg) in anhydrous tetrahydrofuran (1 .0 ml_) at +5 °C under an atmosphere of nitrogen was introduced trimethyl(trifluoromethyl)silane (298 mg in 1 .0 ml_ anhydrous tetrahydrofuran). After 10 min, tetra-n-butylammonium fluoride (0.52 mL of a 0.1 M solution in tetrahydrofuran) was added dropwise. The reaction was stirred for 60 min, before water (2 mL), tetra-n-butylammonium fluoride (1 .0 mL of a 0.1 M solution in tetrahydrofuran) and ethyl acetate (100 mL) were introduced. The solution was washed with water and brine, dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient followed by ethyl acetate containing 5-10% tetrahydrofuran, all eluent mixtures contained 1 % by volume triethylamine) to give the title compound as a yellow wax which was used without further purification.
LCMS (3 min): 1 .49 min; m/z 381 (M+1 )+ 100%.
Additional purification by preparative-LC furnished the title compound as a mono-formic acid salt. H NMR (500 MHz, 3:1 d3-acetonitrile/D20) δ ppm 8.77 (d,), 8.33 (s, 1 H), 8.21 -8.26 (m, 3H), 7.60 (d, 1 H), 7.51 (dd, 1 H), 6.99 (td, 1 H), 5.30 (q, 1 H), 4.65-4.67 (m, 2H), 3.57 (m, 2H), 2.90 (s, 6H). LCMS (7 min): 100% UV215 at 2.91 min with m/z 381 (M+1 )+ 100%.
C3 Keto
Scheme 21 : Preparation of C-linked ethyl esters via Stille coupling
Figure imgf000110_0001
Preparation of ethyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000111_0001
Procedure E:
To a solution of ethyl 3-trifluoromethanesulfonyloxy-pyrido[1 ,2-a]indole-10-carboxylate (0.010 g, 0.026 mmol) in anhydrous 1 ,4-dioxane (1 .0 ml_) was introduced
ethoxyvinyltributylstannane (0.01 1 g, 0.031 mmol), lithium chloride (0.050 g, 1 .18 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.017 mmol). After bubbling the solution with nitrogen for 2 minutes, the reaction tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 150 °C for 72 hours. The cooled reaction mixture was filtered through a cotton-wool plugged pipette and the filtrate adsorbed onto silica gel (0.5 g) in vacuo. The dry-loaded substrate was purified by flash column chromatography (silica gel, eluent: hexane containing a 0-50% gradient of ethyl acetate) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) 5 8.61 (d, 1 H), 8.59 (s, 1 H), 8.45 (d, 1 H), 8.41 (d, 1 H), 8.06 (dd1 H), 7.44 (dd, 1 H), 6.92 (t, 1 H), 4.50 (q, 2H), 2.74 (s, 3H), 1 .52 (t, 3H).
LCMS: 93% UV215 at 2.16 min with m/z 282 (M+1 )+ 100%.
Methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000111_0002
The tiltle compound was prepared by Procedure E (at 140 °C for 3 days) from methyl 3- {[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate (100 mg). After work up, 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%. Scheme 22: Elaboration of 2-(dimethylamino)ethyl 3-(trimethylstannyl)pyrido[1 ,2- a]indole-10-carboxylate to furnish 3-keto analogues and derivatives
Figure imgf000112_0001
2-(Dimethylamino)ethyl 3-(cyclopropylcarbonyl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000112_0002
Procedure F:
To a slurry of bis(dibenzylideneacetone)palladium(0) (3 mg) in anhydrous
dichloromethane (0.5 ml_) under an atmosphere of nitrogen was introduced tri-te/t- butylphosphine (2 mg) and diisopropylethylamine (36 mg). The reaction was cooled to 5 °C and a solution of cyclopropanecarbonyl chloride (18 mg in 0.1 ml_ dry
dichloromethane) was introduced. After 15 min, 2-(dimethylamino)ethyl 3- (trimethylstannyl)pyrido[1 ,2-a]indole-10-carboxylate solution (50 mg in 0.5 ml_ anhydrous dichloromethane) was added over 5 min. After 12 h at 5 °C, the reaction mixture was warmed to room temperature for a further 96 h. After this time the mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient containing 1 % by volume triethylamine), followed by preparative- LC to give the formate salt of the title compound as a yellow oil. H NMR (500 MHz, cW-Methanol) δ ppm 9.12-9.13 (m, 1 H), 8.95-8.96 (m, 1 H), 8.44- 8.56 (br. s, 1 H), 8.42 (br. d, 1 H), 8.35-8.37 (m, 1 H), 8.19 (br. d, 1 H), 7.61 (br. t, 1 H), 7.09 (br. t, 1 H), 4.71 (br. t, 2H), 3.38-3.43 (br. s, 2H), 3.04-3.09 (m, 1 H), 2.81 (s, 6H), 1 .25-1 .47 (m, 4H).
LCMS (7 min): 3.00 min; m/z 351 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-(3-methoxypropanoyl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000113_0001
The title compound was prepared by Procedure F (48 h at room temperature) using a solution of 3-methoxypropionoyl chloride (69 mg in 0.1 ml_ dry dichloromethane).
Concentrated in vacuo and purified by silica gel column chromatography (eluent:
heptane / ethyl acetate gradient containing 1 % by volume triethylamine) followed by reverse phase chromatography (0.5 g C18-ec reverse phase cartridge; eluent: 95:5 to 20:80 water / acetonitrile gradient, all eluent mixtures contain 0.1 % by volume acetic acid) to give the mono acetate salt of the title compound as a yellow solid. H NMR (250 MHz, 2:1 cW-methanol/D20) δ ppm 8.85 (d, 1 H), 8.56 (s, 1 H), 8.20 (d, 1 H), 8.10 (d, 1 H), 7.98 (dd, 1 H), 7.60 (ddd, 1 H), 7.07 (td, 1 H), 4.63 (t, 2H), 3.90 (t, 2H), 3.41 (s, 3H), 3.40 (t, 2H), 2.71 (s, 6H), 1 .90 (s, 3H).
LCMS (7 min): 2.81 min; m/z 369 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-acryloylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000114_0001
The title compound was prepared by Procedure F (48 h at room temperature) using a solution of 3-chloropropionoyl chloride (285 mg in 1 .0 mL dry dichloromethane).
Filtration of the reaction mixture gave the title compound as a yellow solid which was used without further purification.
LCMS (3 min): 1 .41 min; m/z 337 (M+1 )+ 100%. 2-(Dimethylamino)ethyl 3-[3-(dimethylamino)propanoyl]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000114_0002
To a solution of 2-(dimethylamino)ethyl 3-acryloylpyrido[1 ,2-a]indole-10-carboxylate (60 mg) in 1 ,4-dioxane (10 mL) and water (2 mL) at room temperature was introduced dimethylamine (2.7 mL of a 2M solution in tetrahydrofuran). After 16 h, reverse phase silica gel (Fluka C18, 0.4 g) was introduced to the reaction mixture and the resulting slurry concentrated in vacuo. Purification by reverse phase chromatography (0.5 g C18-ec reverse phase cartridge; eluent: 100:0 to 1 :1 water / acetonitrile gradient, all eluent mixtures contain 0.1 % by volume acetic acid) gave the mono acetate salt of the title compound. H NMR (250 MHz, D20) δ ppm 8.17 (1 H, d, 1 H), 7.76 (s, 1 H), 7.61 (d, 1 H), 7.54 (dd, 1 H), 7.41 (d, 1 H), 7.34 (dd, 1 H), 6.78 (td, 1 H), 4.46-4.50 (m, 2H), 3.46-3.54 (m, 4H), 2.95 (s, 6H), 2.88 (s, 6H), 2.79-2.91 (m, 2H), 1 .80 (s, 3H). LCMS (7 min): 2.09 min; m/z 382 (M+1 )+ 50%, 191 .6 ([M+2]/2)+ 100%. 2-(Dimethylamino)ethyl 3-(3-cyanopropanoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000115_0001
To a solution of 2-(dimethylamino)ethyl 3-acryloylpyrido[1 ,2-a]indole-10-carboxylate (100 mg) in 4:1 1 ,4-dioxane / water (10 ml_) was introduced acetic acid (53 mg) and sodium cyanide (48 mg). The reaction was stirred for 4 h at room temperature. The reaction mixture was concentrated in vacuo and then purified by reverse phase chromatography (1 .0 g C18-ec reverse phase cartridge; eluent: 100:0 to 0:100 water / acetonitrile gradient, all eluent mixtures contain 0.2% by volume acetic acid) to give the mono acetate salt of the title compound as an orange-brown foam. H NMR (500 MHz, D20) δ ppm 7.46 (br. d, 1 H), 7.24 (br. d, 1 H), 7.09 (br. t, 1 H), 6.92 (br. d, 1 H), 6.74-6.86 (br. m, 2H), 6.44-6.54 (br. m, 1 H), 4.34 (br. s, 2H), 3.44-3.54 (br. m, 2H), 2.96 (s, 6H), 2.79-2.95 (br. m, 2H), 2.57-2.67 (br. m, 2H), 1 .88 (s, 3H). LCMS (7 min): 2.67 min; m/z 364 (M+1 )+ 100%.
Compounds prepared via Friedel-Crafts acylation of 2-(dimethylamino)ethyl 3- (trimethylstannyl)pyrido[1,2-a]indole- 10-carboxylate.
2-(Dimethylamino)ethyl 3-(4-chlorobutanoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000115_0002
To a solution of aluminium trichloride (45 mg) and 3-chloropropionoyl chloride (48 mg) in anhydrous dichloromethane (1 .0 mL) at -30 °C under an atmosphere of nitrogen was introduced a solution of 2-(dimethylamino)ethyl 3-(trimethylstannyl)pyrido[1 ,2-a]indole- 10-carboxylate (100 mg) in anhydrous dichloromethane dropwise over 10 min. After 60 min, the reaction mixture was warmed to room temperature and then stirred for a further 12 h. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate added and the resulting thick suspension filtered and the precipitate washed on the filter with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (eluent: heptane / ethyl acetate gradient containing 1 % by volume triethylamine) to give the title compound which was used without further purification. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.63-8.65 (m, 2H), 8.48 (d, 1 H), 8.45 (d, 1 H), 8.13 (dd, 1 H), 7.46 (ddd, 1 H), 6.95 (td, 1 H), 4.55 (t, 2H), 3.75 (t, 2H), 3.34 (t, 2H), 2.84 (t, 2H), 2.40 (s, 6H), 2.32 (quintet, 2H).
LCMS (3 min): 1 .62 min; m/z 387/389 (M+1 )+ 100%/50%.
2-(Dimethylamino)ethyl 3-(4-A/,A/-dimethylamino)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000116_0001
To a pressure tube containing a solution of 2-(dimethylamino)ethyl 3-(4- chlorobutanoyl)pyrido[1 ,2-a]indole-10-carboxylate (20 mg) in 1 ,4-dioxane (5 mL) was introduced sodium iodide (160 mg). After 5 min, dimethylamine (1 .5 mL of a 2M solution in tetrahydrofuran) was added, the tube was sealed and the reaction was heated to 65 °C for 48 h. The reaction mixture was cooled to room temperature, filtered. The filtrate was concentrated in vacuo and purified by reverse phase chromatography (1 .0 g C18-ec reverse phase cartridge; eluent: 100:0 to 60:40 water / acetonitrile gradient, all eluent mixtures contain 0.3% by volume acetic acid) to give the di-acetate salt of the title compound as a yellow-brown solid. H NMR (500 MHz, D20) δ ppm 8.22 (d, 1 H), 7.71 (s, 1 H), 7.69 (d, 1 H), 7.54 (d, 1 H), 7.45 (d, 1 H), 7.39 (dd, 1 H), 6.82 (t, 1 H), 4.58 (br. t, 2H), 3.64 (br. t, 2H), 3.26-3.29 (m, 2H), 3.05 (br. t, 2H), 3.00 (s, 6H), 2.98 (s, 6H), 2.05-2.12 (m, 2H), 1 .87 (s, 6H). LCMS (7 min): 2.26 min; m/z 396 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-[(1 -methyl-1 H-imidazol-2-yl)carbonyl]pyrido[1 ,2- a]indole-10-carboxylate
Figure imgf000117_0001
To a solution of 10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3-carboxylic acid (80 mg) in dichloromethane (2.4 ml_) was introduced A/JV-dimethylformamide (1 drop) and oxalyl chloride (36 μΙ_). After 2 h at room temperature, 1 -methyl-1 /-/-imidazole (0.3 ml_) and triethylamine (0.6 ml_) were introduced. After 16 h, water was added and the mixturewas extracted with dichloromethane. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and evaporated in vacuo. Purification of the filtrate by preparative LC (acetonitrile/water/ammonium hydroxide) gave the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.26 (s, 1 H), 8.68 (d, 1 H), 8.48 (m, 3H), 7.42 - 7.49 (m, 1 H), 7.29 (d, 1 H), 7.16 (s, 1 H), 6.93 (td, 1 H), 4.56 (t, 2H), 4.14 (s, 3H), 2.87 (br. s, 2H), 2.41 (s, 6H). LCMS (7 min): 2.78 min; m/z 391 (M+1 )+ 50%, 196 ([M+2]/2)+ 100%.
[10-(Methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl](oxo)acetic acid
Figure imgf000118_0001
A mixture of methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate (200 mg) and selenium dioxide (166 mg) was dissolved in anhydrous pyridine (0.48 ml_) under an atmosphere of nitrogen and heated to 100 °C for 40 min. After cooling to room temperature, aqueous sodium hydroxide (10 ml_ of 1 M sodium hydroxide) was introduced and the resulting solution washed with ethyl acetate. The aqueous extract was adjusted to pH 5 with aqueous hydrochloric acid (1 M) then extracted with ethyl acetate. Evaporation of the combined extracts in vacuo gave the title compound as a yellow solid which was used without further purification. H NMR (500 MHz, c 6-DMSO) δ ppm 9.49 (d, 1 H), 9.01 (s, 1 H), 8.35 (m, 2H), 8.01 (dd, 1 H), 7.72 (ddd, 1 H), 7.17 (td, 1 H), 3.92 (s, 3H).
LCMS (7 min): 3.35 min; m/z 298 (M+1 )+ 100%.
Methyl 3-[(dimethylamino)(oxo)acetyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000118_0002
To a solution of [10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl](oxo)acetic acid (90 mg) in dichloromethane (2.4 ml_) at room temperature was introduced N,N- dimethylformamide (1 drop) and oxalyl chloride (44 μΙ_). After 20 min, dimethylamine (4.0 ml_ of a 2M solution in tetrahydrofuran) was added dropwise and stirring continued for a further 20 min. The reaction mixture was quenched by addition of water, extracted with dichloromethane and the combined dichloromethane extracts dried (sodium sulfate)sulphate, filtered and purified by silica gel chromatography (Isolute Flash Si II, 5 g cartridge; eluent: heptane / ethyl acetate gradient) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.66 (dt, 1 H), 8.6 (d, 1 H), 8.49 (dt, 1 H), 8.45 (d, 1 H), 8.06 (dd, 1 H), 7.50 (ddd, 1 H), 6.98 (td, 1 H), 4.03 (s, 3H), 3.19 (s, 3H), 3.03 (s, 3H).
LCMS (7 min): 3.96 min; m/z 325 (M+1 )+ 100%.
Scheme 23: Synthesis of 3-acetyl 10- esters and amides
Figure imgf000119_0001
Potassium 3-acetylpyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000119_0002
Procedure G:
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 imgf000120_0001
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.
[2-({3-acetylpyrido[1 ,2-a]indol-10-yl]carbonyloxy)ethyl][2- (dimethylamino)ethyl]dimethylazanium acetate
Figure imgf000120_0002
Procedure H:
To a solution of potassium 3-acetylpyrido[1 ,2-a]indole-10-carboxylate (65 mg) in N,N- dimethylformamide (2.0 ml_) was introduced potassium carbonate (509 mg), (2- chloroethyl)dimethylamine hydrochloride (128 mg) and sodium iodide (218 mg). The reaction mixture was warmed to 50 °C for 16 h. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with additional ethyl acetate and then passed through reverse phase silica (0.5 g C18-ec reverse phase cartridge, eluting with deionised water and 3:1 water / acetonitrile). The water / acetonitrile fractions containing product were evaporated purified by reverse phase chromatography (1 .0 g C18-ec cartridge; eluent: water / acetonitrile gradient containing 1 % acetic acid) to give the title compound as a yellow oil.
1 H NMR (500 MHz, D20) δ ppm 8.35 (d, 1 H), 7.90-7.92 (m, 2H), 7.64 (d, 1 H), 7.59 (d, 1 H), 7.54 (dd, 1 H), 6.96 (t, 1 H), 4.79-4.83 (m, 2H), 3.95-3.99 (m, 2H), 3.80-3.82 (m, 2H), 3.42-3.45 (m, 2H), 3.31 (s, 6H), 2.60 (s, 6H), 2.57 (s, 3H), 1 .91 (s, 6H). LCMS (7 min): 2.42 min; m/z 396 (M+) 100%.
C3 Esters, Amides, and Thioamides
Scheme 24: Synthesis of C3 ester and amide derivatives
Figure imgf000121_0001
Procedure I:
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%.
3,10-Dimethyl pyrido[1 ,2-a]indole-3,10-dicarboxylate
Figure imgf000122_0001
To a stirred solution of 10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid (50 mg) in dry A/JV-dimethylformamide (2.0 mL), was added potassium carbonate (51 mg), followed by methyl iodide (23.1 μΙ_). The reaction mixture was stirred at room temperature for 4.5 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate (3 x 20 mL) and the combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column
chromatography (10% ethyl acetate / heptanes) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.41 (d, 1 H), 9.02 (s, 1 H), 8.32 (d, 1 H), 8.29 (d, 1 H), 8.08 (dd, 1 H), 7.61 - 7.68 (m, 1 H), 7.1 1 (t, 1 H), 3.92 (s, 3H), 3.91 (s, 3H).
LCMS (7 min): 4.60 min; m/z 284 (M+1 )+ 100%.
Methyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000123_0001
Procedure J:
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 dimethylamine (0.186 μΙ_ of a 2.0M solution in tetrahydrofuran), followed by A/JV-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 (20-60% ethyl acetate / heptanes) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.25 (d, 1 H), 8.51 (s, 1 H), 8.29 (d, 1 H), 8.24 (d, 1 H), 7.58 (ddd, 1 H), 7.56 (dd, 1 H), 7.06 (td, 1 H), 3.90 (s, 3H), 3.03 (br. s., 6H).
LCMS (7 min): 3.77 min; m/z 297 (M+1 )+ 100%.
Methyl 3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000123_0002
Procedure J: using methylamine
Purification: Column chromatography (10-60% ethyl acetate / heptanes) and Prep- HPLC (acetonitrile/water).
Form: Yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.18 (d, 1 H), 8.86 (s, 1 H), 8.43 - 8.50 (m, 1 H), 8.30 (d, 1 H), 8.23 (d, 1 H), 7.98 (d, 1 H), 7.60 (dd, 1 H), 7.10 (t, 1 H), 3.91 (s, 3H), 2.86 (d, 3H). LCMS (7 min): 3.59 min; m/z 283 (M+1 )+ 100%.
Methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000124_0001
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 imgf000124_0002
Procedure G from methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate (0.147 g) (50 °C 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).
2-(Dimethylamino)ethyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000125_0001
Procedure H from potassium 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate (77 mg) gave after work-up and purification by column chromatography (0- 10% methanol / dichloromethane) the title compound as a green solid. H NMR (500 MHz, DMSO-c 6) δ ppm 9.18 (d, 1 H), 8.89 (s, 1 H), 8.53 (br. s., 1 H), 8.32 (d, 1 H), 8.27 (d, 1 H), 8.01 (dd, 1 H), 7.61 (ddd, 1 H), 7.10 (td, 1 H), 4.41 (t, 2H), 3.48 - 3.54 (m, 4H), 3.30 (s, 3H), 2.72 (t, 2H), 2.27 (s, 6H).
LCMS (7 min): 2.65 min; m/z 384 (M+1 )+ 100%.
10-{[2-(Dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3-carboxylic acid
Figure imgf000125_0002
Procedure I starting from 2-(dimethylamino)ethyl 3-
{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate (1 .0 g). The residue after removal of Ν,Ν-dimethylformamide in ι/acuo was suspended in 1 M aq. sodium hydroxide and extracted with ether. The aqueous phase was acidified to pH 1 by the addition of 1 M hydrochloric acid and extracted with ethyl acetate followed by dichloromethane. The aqueous phase was further extracted with 1 :1
chloroform:isopropanol. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to give the title compound as the HCI salt as a green solid. H NMR (500 MHz, DMSO-c/6) δ ppm 12.73 (br. s., 1 H), 9.94 (br. s., 1 H), 9.42 (d, 1 H), 9.02 (s, 1 H), 8.35 (m, 2H), 8.09 (dd, 1 H), 7.64 - 7.72 (m, 1 H), 7.09 - 7.19 (m, 1 H), 4.61 - 4.76 (m, 2H), 3.62 (t, 2H), 2.89 (s, 6H). LCMS (3 min): 1 .32 min; m/z 327 (M+1 )+ 100%.
10-[2-(Dimethylamino)ethyl 3-[2-methysulf anyl)ethyl]pyrido[1 ,2-a]indole-3,10- dicarboxylate
Figure imgf000126_0001
Procedure J starting from 10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3- carboxylic acid (50 mg) using 1 -chloro-2-(methylsulfanyl)ethane (13.7 μΙ_). Purified by column chromatography (0-5% methanol/dichloromethane) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c 6) δ ppm 9.40 (d, 1 H), 9.02 (s, 1 H), 8.35 (d, 1 H), 8.33 (d, 1 H), 8.08 (dd, 1 H), 7.62 - 7.68 (m, 1 H), 7.08 - 7.14 (m, 1 H), 4.51 (t, 2H), 4.42 (t, 2H), 2.91 (t, 2H), 2.71 (t, 2H), 2.26 (s, 6H), 2.18 (s, 3H). LCMS (7 min): 3.1 1 min; m/z 401 (M+1 )+ 100%.
Scheme 25: Synthesis of C(3) amides and thioamides
Figure imgf000127_0001
Figure imgf000127_0002
Methyl 3-[methoxy(methyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000127_0003
Procedure K:
A solution of 10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid (100 mg) in dichloromethane (2.4 mL) containing a catalytic amount of A/JV-dimethylformamide was treated with oxalyl chloride (53 μΙ_) dropwise. The solution was stirred at room temperature for 2 h. The reaction mixture was cooled in an ice bath and Ν,Ο- dimethylhydroxylamine hydrochloride (362 mg) was added followed by triethylamine (0.62 mL). The reaction mixture was left to warm to room temperature and stirred for 30 min The reaction mixture was quenched with water. The organic phase was washed with water, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel (ethyl acetate / heptane gradient) gave the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.56 (d, 1 H), 8.46 (d, 1 H), 8.41 (s, 1 H), 8.38 (d, 1 H), 7.93 (dd, 1 H), 7.41 (ddd, 1 H), 6.90 (td, 1 H), 4.03 (s, 3 H), 3.59 (s, 3 H), 3.45 (s, 3H).
LCMS (7 min): 3.94 min; m/z 313 (M+1 )+.
Methyl 3-[methoxycarbamoyl]pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000128_0001
Procedure K using O-methylhydroxylamine hydrochloride. After quenching, the aqueous phase was adjusted to pH 5 with 1 M hydrochloric acid (1 mL) and the biphasic mixture filtered to collect the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 1 1 .77 (s, 1 H), 9.23 (d, 1 H), 8.81 (s, 1 H), 8.31 (d, 1 H), 8.25 (d, 1 H), 7.87 (dd, 1 H), 7.62 (ddd, 1 H), 7.10 (td, 1 H), 3.91 (s, 3 H), 3.76 (s, 3 H).
LCMS (7 min): 3.51 min; m/z 299 (M+1 )+.
2-(Dimethylamino)ethyl 3-{[2-(dimethylamino)ethyl](methyl)carbamoyl}pyrido[1 ,2- a]indole-10-carboxylate
Figure imgf000129_0001
Procedure K from 10-{[2-(Dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3- carboxylic acid using a solution of Λ/,Λ/,/V-trimethylethane-l ,2-diamine in
dichloromethane. Purified by column chromatography on silica gel (dichloromethane containing 0.5% triethylamine and a 0-10% gradient of methanol) to give the title compound as a yellow oil. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.49 (d, 1 H), 8.45 (d, 1 H), 8.40 (d, 1 H), 8.10 (s, 1 H), 7.57 (dd, 1 H), 7.39 (ddd, 1 H), 6.87 (td, 1 H), 4.54 (t, 2H), 3.70 (br. s, 1 H), 3.50 (br. s, 1 H), 3.13 (br. s, 3H), 2.83 (t, 2H), 2.64 (br. s, 1 H), 2.51 (br. s, 1 H), 2.39 (s, 6H), 2.33 (br. s, 3H), 2.10 (br. s, 3H).
LCMS (7 min): 2.12 min; m/z 41 1 (M+1 )+.
Methyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000129_0002
Procedure K using a solution of A/JV-dimethylethylenediamine in dichloromethane.
Work-up and 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 imgf000130_0001
Procedure G 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-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000130_0002
Procedure L:
To a mixture of methyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate (122 mg) and dry toluene (2.5 ml_) was added Lawesson's reagent (183 mg) and the reaction was heated at Ι ΟΟ 'Ό for 15 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (dichloromethane containing a 0-10% methanol gradient) to give the title compound as an orange solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.47 (d, 1 H), 8.42 (d, 1 H), 8.33 (d, 1 H), 8.07 (d, 1 H), 7.41 (dd, 1 H), 7.37 (ddd, 1 H), 6.86 (td, 1 H), 4.01 (s, 3H), 3.68 (s, 3H), 3.26 (s, 3H). LCMS (7 min): 4.54 min; m/z 313 (M+1 )+.
Methyl 3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000131_0001
Procedure K using methylamine (2M in tetrahydrofuran, 2.0 ml_). Purified by column chromatography on silica gel (methanol / dichloromethane gradient dichloromethane containing a 0-10% methanol gradient) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.18 (d, 1 H), 8.86 (s, 1 H), 8.49 (d, 1 H), 8.30 (d, 1 H), 8.23 (d, 1 H), 7.98 (dd, 1 H), 7.60 (dd, 1 H), 7.10 (t, 1 H), 3.90 (s, 3H), 2.86 (d, 3H).
LCMS (3 min): 1 .86 min; m/z 283 (M+1 )+.
Methyl 3-(methylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000131_0002
Procedure L from methyl 3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate (37 mg) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.70 (d, 1 H), 8.59 (d, 1 H), 8.40 (d, 1 H), 8.30 (d, 1 H), 7.91 (br. s, 1 H), 7.70 (dd, 1 H), 7.41 (ddd, 1 H), 6.89 (td, 1 H), 4.02 (s, 3H), 3.47 (d, 3H).
LCMS (7 min): 4.46 min; m/z 299 (M+1 ) 2-(Dimethylamino)ethyl3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000132_0001
Procedure K from 10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3- carboxylic acid (150 mg) using dimethylamine (2M in tetrahydrofuran, 1 mL). Purified by column chromatography on silica gel (dichloromethane containing a 0-10% methanol gradient) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.49 (d, 1 H), 8.44 (d, 1 H), 8.40 (d, 1 H), 8.10 (s, 1 H), 7.56 (dd, 1 H), 7.38 (ddd, 1 H), 6.86 (td, 1 H), 4.54 (t, 2H), 3.13 (br. s, 6H), 2.83 (t, 2H), 2.39 (s, 6H).
LCMS (3 min): 1 .25 min; m/z 354 (M+1 )+.
2-(Dimethylamino)ethyl 3-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000132_0002
Procedure L from 2-(dimethylamino)ethyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10- carboxylate (70 mg) to give the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.47 (d, 1 H), 8.43 (d, 1 H), 8.35 (d, 1 H), 8.06 (s, 1 H), 7.41 (dd, 1 H), 7.37 (ddd, 1 H), 6.85 (td, 1 H), 4.55 (t, 2H), 3.68 (s, 3H), 3.26 (s, 3H), 2.86 (t, 2H), 2.41 (s, 6H).
LCMS (7 min): 2.80 min; m/z 370 (M+1 )+.
2-(Dimethylamino)ethyl 3-(hydroxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000133_0001
Procedure K from 10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3- carboxylic acid (80 mg) using hydroxylamine hydrochloride. Purification by preparative LC (acetonitrile/water) gave the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.53 - 8.60 (m, 1 H), 8.37 - 8.52 (m, 3H), 7.66 - 7.73 (m, 1 H), 7.45 (dd, 1 H), 6.93 (t, 1 H), 4.57 - 4.63 (m, 2H), 2.82 - 2.93 (m, 2H), 2.37 - 2.50 (m, 6H).
LCMS (7 min): 2.23 min; m/z 342 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-(methoxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000133_0002
Procedure K from 10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3- carboxylic acid (80 mg) using O-methylhydroxylamine hydrochloride. Purification of the filtrate residue by silica gel column chromatography (eluent: dichloromethane containing 0-6% by volume methanol) gave the title compound as a yellow-green solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.81 (br. s., 1 H), 8.61 (d, 1 H), 8.55 (s, 1 H), 8.46 (d, 1 H), 8.42 (d, 1 H), 7.68 - 7.76 (m, 1 H), 7.41 - 7.47 (m, 1 H), 6.93 (td, 1 H), 4.55 (t, 2H), 3.97 (s, 3H), 2.84 (t, 2H), 2.40 (s, 6H).
LCMS (7 min): 2.53 min; m/z 356 (M+1 )+ 100%. 1 -0-1 (R)-2-[pyrrolidin-1-yl]ethyl analogues
Figure imgf000134_0001
Scheme 26: O-alkylation and elaboration of 1 -0-1 (R)-2-[pyrrolidin-1 -yl]ethyl analogues
Figure imgf000134_0002
Preparation of ethyl 3-{[1-methoxy-1-oxo-3-(pyrrolidin-1-yl)propan-2- yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate (Step a)
Figure imgf000134_0003
To a solution of ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate (5.00 g) in dry N,N- dimethylformamide (80 ml_) was introduced sodium hydride (0.94 g of a 50% dispersion in mineral oil). After 5 minutes at room temperature, evolution of gas had ceased and the reaction mixture was cooled to 0 °C under an atmosphere of nitrogen. A solution of methyl 2-bromo-3-(pyrrolidin-1 -yl)propanoate(1 ) (16.18 g) in dry N,N- dimethylformamide (15 ml_) was introduced dropwise over 10 minutes at 0 °C. The reaction mixture was warmed to room temperature and held at this temperature for 1 hour. Evaporation of the reaction mixture in vacuo (15 mbar at 55 °C) gave a brown oily residue which was partitioned between diethyl ether (400 ml_) and water (2 x 200 ml washes). The aqueous washes were combined and extracted with diethyl ether (100 ml_). The diethyl ether extracts were combined, washed with brine (100 ml_) and dried over sodium sulfate. After filtration, silica gel (10 g) was introduced to the filtrate and the resulting slurry evaporated in vacuo. The dry loaded substrate was purified by flash column chromatography (silica gel), eluting with a heptane/ethyl acetate gradient of increasing polarity (all solvent mixtures contained 0.5% by volume triethylamine). All product containing fractions were pooled and evaporated in vacuo to furnish the title compound as a brown wax. H NMR (500 MHz, CDCI3) δ 8.37 (d, 1 H), 8.29-8.31 (m, 2H), 7.39 (d, 1 H), 7.25 (ddd, 1 H), 7.21 (dd, 1 H), 6.77 (td, 1 H), 4.97 (dd, 1 H), 4.47 (q, 2H), 3.76 (s, 3H), 3.14 (dd, 1 H), 3.1 1 (dd, 1 H), 2.66-2.74 (m, 4H), 1 .78-1 .81 (m, 4H), 1 .49 (t, 3H).
LCMS: 98% UV215 at 1 .51 min with m/z 41 1 (M+1 )+ 100%.
(1 prepared as: J. Org. Chem. 2006, 71 , 6444 (SI).
Preparation of 2-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}-3-(pyrrolidin-1- yl)propanoic acid (Step b)
Figure imgf000135_0001
To a solution of methyl 4-(pyrrolidin-1 -yl)-3-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3- yl]oxy}butanoate from Step a (1 .000 g) in tetrahydrofuran (50 ml_) at 0 °C was introduced lithium hydroxide (0.51 1 g of LiOH.H20 in 20 ml_ water) dropwise over 20 minutes. The reaction was warmed to room temperature for two hours. Evaporation of the tetrahydrofuran in vacuo furnished an aqueous solution which was adjusted to pH 7 with 0.1 M HCI. The aqueous solution was applied to a reverse phase column (10 g of Fluka C18 reverse phase silica) and after slow elution of the aqueous reaction solution, a further 10 ml_ of de-ionised water was passed through the column to ensure all salt (LiCI) had been removed. Elution of the carboxylic acid from the column was achieved by passing 1 :1 acetonitrile:water (50 ml_) through the column (collecting 10 ml_ per fraction). The desired carboxylic acid was observed to precipitate from the second fraction and was collected by filtration. After drying in a vacuum oven (40 °C, 10 mmHg) for 14 hours, the title compound was isolated as fine yellow crystals. H NMR (500 MHz, d4-MeOH) δ 8.67 (d, J = 7.0 Hz, 1 H), 8.25 (d, 1 H), 8.18 (d, 1 H), 7.61 (d, 1 H), 7.34 (ddd, 1 H), 7.28 (dd, 1 H), 6.87 (td, 1 H), 4.92-4.94 (m, 1 H), 4.42 (q, 2H), 3.78 (dd, 1 H), 3.72 (dd, 1 H), 3.41 -3.63 (br. s, 4H), 2.05-2.18 (br. m, 4H), 1 .48 (t, 3H).
LCMS: 100% UV215 at 1 .53 min with m/z 397 (M+1 )+ 100%.
Preparation of ethyl 3-{[1 -hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2- a]indole-10-carboxylate (Step e)
Figure imgf000136_0001
To a solution of methyl 4-(pyrrolidin-1 -yl)-3-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3- yl]oxy}butanoate from Step a (1 .000 g) in dry methanol (50 ml_) at room temperature was introduced sodium borohydride (18 x 0.15 g portions) over 6 hours. Water (4 ml_) was slowly introduced to the reaction mixture, and the resulting solution evaporated in vacuo to furnish a milky aqueous residue. The aqueous residue was diluted with water (20 ml_), extracted with ethyl acetate (3 x 100 ml_), the organic extracts combined, washed with water (50 ml_) and brine (50 ml_) and dried over sodium sulfate.
Evaporation in vacuo furnished the title compound as a viscous yellow syrup. LCMS: 92% UV215 at 1 .45 min with m/z 383 (M+1 )+ 100%.
15.0 mg of the crude product was dissolved in dichloromethane, silica gel (0.2 g) introduced and the slurry evaporated in vacuo. The dry-loaded material was purified by flash column chromatography (silica gel), eluting with dichloromethane containing a 0- 8% by volume gradient of 1 .5M ammonia in methanol. The title compound was furnished as a viscous yellow oil. H NMR (500 MHz, CDCI3) δ 8.36 (d, 1 H), 8.29-8.32 (m, 2H), 7.42 (d, 1 H), 7.24 (ddd, 1 H), 7.20 (dd, 1 H), 6.77 (td, 1 H), 4.54-4.59 (m, 1 H), 4.47 (2H, q, 2H), 4.06 (ddd, 1 H), 3.95 (dd, 1 H), 3.10 (dd, 1 H), 3.00 (ddd, 1 H), 2.67-2.76 (m, 4H), 1 .77-1 .85 (m, 4H), 1 .50 (t, 3H).
LCMS: 100% UV215 at 1 .45 min with m/z 383 (M+1 )+ 100%.
Preparation of ethyl 3-{[1-(methanesulfonyloxy)-3-(pyrrolidin-1 -yl)propan-2- yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate (Step f)
Figure imgf000137_0001
To a solution of ethyl 3-{[1 -(pyrrolidin-1 -yl)-4-hydroxybutan-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate from Step e (0.300 g) in dry dichloromethane (10 ml_) at 0 °C was introduced diisopropylethylamine (0.152 g) and methanesulfonyl chloride (0.1 17 g). After 2h at 0 °C the reaction mixture was evaporated in vacuo to furnish the title compound containing residual diisopropylethylamine hydrochloride and
methanesulfonyl chloride. The crude product was used without purification.
LCMS: 93% UV215 at 1 .63 min with m/z 461 (M+1 )+ 100%. Preparation of ethyl 3-{[1-cyano-3-(pyrrolidin-1-yl)propan-2-yl]oxy}pyrido[1 ,2- a]indole-10-carboxylate (Step g)
Figure imgf000138_0001
To a solution of ethyl 3-{[1 -(pyrrolidin-1 -yl)-4-(methylsulfonyloxy)butan-2- yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate from Step f (0.1 OOg) in dry N,N- dimethylformamide (5.0 ml_) at room temperature was introduced sodium cyanide (0.01 1 g). The reaction mixture was warmed to 75 °C for 2 hours. After evaporation of the reaction mixture in vacuo (15 mbar at 60 °C), the residue was partitioned between ethyl acetate (20 ml) and water (20 ml_). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel (0.5 g) in vacuo. Purification of the dry-loaded substrate by flash column chromatography (silica gel, eluent:
heptane:ethyl acetate gradient of increasing polarity [all solvent mixtures contain 1 % by volume triethylamine]) furnished the title compound as a yellow solid.
LCMS: 97% UV215 at 1 .60 min with m/z 392 (M+1 )+ 100%. H NMR (500 MHz, d6-DMSO) δ 9.04 (d, 1 H), 8.22 (d, 1 H), 8.14 (d, 1 H), 8.07 (d, 1 H), 7.44 (ddd, 1 H), 7.23 (dd1 H), 6.98 (td1 H), 4.91 (quint., 1 H), 4.35 (q, 2H), 3.09 (dd, 1 H), 2.98 (dd, 1 H), 2.86 (dd, 1 H), 2.78 (dd, 1 H), 2.54-2.60 (m, 4H), 1 .66-1 .71 (m, 4H), 1 .40 (t, 3H).
C3 O-linked methyl esters Preparation of methyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000139_0001
Procedure A: using methyl iodide on a 0.083 mmol scale wrt the pyrido[1 ,2-a]indole Purification: 2M aq. NaOH and water wash a solution of crude product in diethyl ether. Dry organic phase over Na2S04, filter and evaporate in vacuo. No further purification required.
Form: Brown amorphous solid H NMR (500 MHz, CDCI3) δ 8.33-8.38 (m, 1 H), 8.24-8.30 (m, 2H), 7.33 (d, 1 H), 7.23- 7.27 (m, 1 H), 7.09 (dd, 1 H), 6.75-6.79 (m, 1 H), 4.92 (s, 1 H), 4.00 (s, 3H).
LCMS: 93% UV215 at 1 .79 min with m/z 242 (M+1 )+ 100%.
Preparation of methyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000139_0002
Procedure A: Using bromoacetonitrile on a 0.213 mmol scale wrt the pyrido[1 ,2- a]indole starting material.
Purification: 2M aq. NaOH and water wash a solution of crude product in diethyl ether. Dry organic phase over Na2S04, filter and evaporate in vacuo. No further purification required.
Form: Yellow-brown amorphous solid H NMR (500 MHz, CDCI3) δ 8.33-8.40 (m, 3H), 7.46 (d, 1 H), 7.30 (ddd, 1 H), 7.24 (dd, 1 H), 6.79-6.85 (m, 1 H), 4.90 (s, 2H), 4.01 (s, 3H).
LCMS: 100% UV215 at 2.05 min with m/z 281 (M+1 )+ 100%. Preparation of methyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000140_0001
Procedure A: Using 2-bromopropionitrile on a 0.213 mmol scale wrt pyrido[1 ,2-a]indole. Purification: Silica gel FCC (1 :1 EtOAc: Heptane)
Form: Yellow-green amorphous solid H NMR (500 MHz, CDCI3) δ 8.36-8.40 (m, 2H), 8.35 (s, 1 H), 7.52 (d, 1 H), 7.30 (ddd, 1 H), 7.26 (dd, 1 H), 5.00 (d, J = 6.7 Hz, 1 H), 4.01 (s, 3H), 1 .88 (d, 3H).
LCMS: 100% UV215 at 2.15 min with m/z 295 (M+1 )+ 100%.
Preparation of methyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000140_0002
Procedure A: Using benzyl chloride on a 0.213 mmol scale wrt pyrido[1 ,2-a]indole. Purification: Silica gel FCC (1 :1 EtOAc: Heptane)
Form: Yellow-green solid H NMR (500 MHz, CDCI3) δ 8.34-8.39 (m, 1 H), 8.27-8.32 (m, 2H), 7.48-7.53 (m, 2H), 7.40-7.45 (m, 2H), 7.34-7.40 (m, 3H), 7.28 (dd, 1 H), 7.24 (ddd, 1 H), 6.76 (td, 1 H), 5.20 (s, 2H), 4.00 (s, 3H).
LCMS: 94% UV215 at 2.49 min with m/z 332 (M+1 )+ 100%.
C3 N-linked ethyl esters Scheme 27: N-linked ethyl esters via Buchwald coupling
Figure imgf000141_0001
Buchwald coupling conditions: (i) R1 R2NH, Pd2(dba)3, NaOtBu, (±)-BINAP, toluene, 100 <€; or (ii) H2NBOC, Pd2(dba)3, Cs2C03, Xantphos, 80 °C.
Preparation of ethyl 3-(morpholin-4-yl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000141_0002
Procedure M:
To a dry flask was added aryl triflate (25 mg), NaOtBu (9 mg), (±) BINAP (1 .6 mg), morpholine (7.0 mg.) and dry toluene (2 mL). Nitrogen was then bubbled through this solution for 10 min prior to addition of Pd2(dba)3 (0.6 mg, 0.0006 mmol, 1 mol%), after which degassing was continued for a further 5 minutes prior to sealing the vessel and heating to 100 ^ for 48h. The solvent was removed in vacuo and purification was achieved by preparative mass-directed HPLC. The title compound was isolated as a brown oil. H NMR (500 MHz, CDCI3) δ 8.35-8.43 (m, 2H), 8.30-8.35 (m, 1 H), 7.22-7.37 (m, 3H), 6.76-6.83 (m, 1 H), 4.47 (q, 2H), 3.99 (br. s., 4H), 3.30 (br. s, 4H), 1 .50 (t, 3H). LCMS: 100% UV215 at 2.12 min with m/z 325 (M+1 )+ 100%. Preparation of ethyl 3-(4-t-butyloxycarbonylpiperazyl)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000142_0001
By Procedure M :
Purification: Mass directed prep-LCMS
Form: yellow oil H NMR (500 MHz, CDCI3) δ 8.26-8.46 (m, 3H), 7.27 (s, 2H), 6.72-6.89(m, 2H), 4.43- 4.52 (m, 2H), 3.58-3.79 (m, 4H), 3.12-3.34 (m, 4H), 1 .51 (s, 9H), 1 .25-1 .28 (m, 3 H).
LCMS: 100% UV215 at 1 .73 min with m/z 424 (M+1 )+ 100%. Preparation of ethyl 3-[(tert-butoxycarbonyl)amino]pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000142_0002
In a dry flask was combined t-butyl carbamate (19 mg), cesium carbonate (61 mg), 9, 9-dimethyl-4,5- bis(diphenylphosphino) xanthene (Xantphos, 18 mg). The aryl triflate (44mg, 0.1 1 mmol) was added to this flask as a solution in dry THF (4 x 0.5 ml_ washes). The mixture was degassed for 10 min (N2), then tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3, 2.6 mg) was added. The mixture was stirred at 80 °C overnight. Upon cooling, the reaction was diluted with hexane (10 ml_), filtered
(washing with diethyl ether) and concentrated to give crude product, which was purified by flash column chromatography (silica, 20% EtOAc/heptane) to give the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.48 (br. s, 1 H), 8.45 (d, 1 H), 8.33-8.38 (m, 1 H), 8.27 (d, 1 H), 7.24-7.29 (m, 1 H), 7.07 (dd, 1 H), 6.72-6.79 (m, 1 H), 4.47 (q, 2H), 1 .57 (s, 9H), 1 .50 (t, 3H). LCMS: 100% UV215 at 2.39 min with m/z 355 (M+1 )+ 100%.
C3 S-linked methyl esters
Scheme 28: Procedures for synthesis of C3 S-substituted analogues
Figure imgf000143_0001
Methyl 3-(acetylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000143_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-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000144_0001
A mixture of methyl 3-(acetylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate (50 mg) in ethanol (3.0 mL) at 0 °C, was treated with methyl iodide (12.4 μΐ) and NaOH (aq) (200 μ\- of a 1 M solution). The reaction mixture was stirred at 0 'Ό for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-10% ethyl acetate / heptanes) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-d6) δ ppm 9.17 (d, 1 H), 8.29 (d, 1 H), 8.24 (d, 1 H), 8.15 (d, 1 H), 7.50 (ddd, 1 H), 7.44 (dd, 1 H), 7.01 (td, 1 H), 3.89 (s, 3H), 2.61 (s, 3H). LCMS (7 min): 4.76 min; m/z 272 (M+1 )+ 100%.
Methyl 3-(methanesulfinyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000145_0001
To a solution of methyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate (18.8 mg) in dichloromethane (2.0 mL) at 0 °C, was added m-chloroperoxybenzoic acid (17 mg, of a 70-77% wt in water) over 16 min. After 3.5 h at 0°C, the reaction mixture was quenched by the addition of 1 M aq. sodium hydroxide (2 mL) and stirred for 5 min. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with 1 M aq. sodium hydroxide, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified by column chromatography (20-100% ethyl acetate / heptanes) to give the title compound as a yellow solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.30 (d, 1 H), 8.75 (d, 1 H), 8.38 (d, 1 H), 8.31 (d, 1 H), 7.80 (dd, 1 H), 7.61 (ddd, 1 H), 7.10 (td, 1 H), 3.91 (s, 3H), 2.83 (s, 3H).
LCMS (7 min): 3.59 min; m/z 288 (M+1 )+ 80%.
Methyl 3-(methanesulfonyl)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000145_0002
To a stirred solution of methyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate (24 mg) in dichloromethane (2.0 mL), at 0 'Ό, was added m-chloroperoxybenzoic acid (39 mg, of a 70-77% wt in water) over 50 min. The reaction was then stirred at 0 ^ to 10 <Ό for 8 h and then sealed and stored in the fridge overnight. The reaction mixture was cooled on ice and treated with 1 M aq. sodium hydroxide (5 mL)and then extracted with dichloromethane. The combined organics were washed with 1 M aq. sodium hydroxide, 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. H NMR (500 MHz, DMSO-c/6) δ ppm 9.42 (d, 1 H), 9.02 (d, 1 H), 8.41 (d, 1 H), 8.34 (d, 1 H), 8.00 (dd, 1 H), 7.69 (ddd, 1 H), 7.16 (td, 1 H), 3.93 (s, 3H), 3.27 (s, 3H).
LCMS (7 min): 3.88 min; m/z 304 (M+1 )+ 80%.
C10 esters via transesterification
Scheme 29: Transesterification procedure
Figure imgf000146_0001
STEP 1 : Transesterification
Preparation of propan-2-yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000146_0002
A solution of methyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (25 mg) in isopropanol (2.0 mL) was treated with Sc(OTf)3 (5.1 mg) and heated thermally for 44 hours. After which time isopropanol (2 mL) and Sc(OTf)3 (5.1 mg) was added and the reaction mixture heated in the microwave (120 °C, 1 h 20 mins). The reaction mixture was concentrated in-vacuo and purified by column chromatography (10-20% ethyl acetate / heptane) to furnish the title compound as a yellow oil. H NMR (500 MHz, CDCI3) δ 8.33 (br. s, 2H), 7.10 (br. s, 2H), 6.73 (br. s, 1 H), 5.20- 5.57 (m, 1 H), 1 .47 (d, 6H) not all protons accounted for due to a very broad spectrum.
LCMS: 89% UV215 at 2.00 min, m/z 270 (M+1 )+ 100%.
Preparation of butyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000147_0001
A solution of methyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (25 mg) in 1 -butanol (2.0 ml_) was treated with Sc(OTf)3 (5.1 mg) and heated under reflux for 18 h. Once complete by LCMS, the reaction mixture was allowed to reach room temperature, concentrated in-vacuo and purified by column chromatography (10-20% ethyl acetate / heptane) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.33 (br. s, 2H), 7.29-7.66 (m, 1 H), 7.1 1 (br. s, 2H), 6.73 (br. s, 1 H), 4.76-5.69 (m, 1 H), 4.44 (d, 2H), 1 .78-1 .93 (m, 2H), 1 .48-1 .69 (m, 2H), 1 .03 (t, 3H). LCMS: 98% UV215 at 2.13 min, m/z 284 (M+1 )+ 100%.
Preparation of propyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000147_0002
A solution of methyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (25 mg) in n- propanol (2.0 mL) was treated with Sc(OTf)3 (5.1 mg) and heated under microwave irradiation (120 °C, 30 mins) and (130 °C, 50 mins). Once complete by LCMS, the reaction mixture was concentrated in-vacuo and purified by column chromatography (10-20% ethyl acetate / heptane) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.32 (br. s, 2H), 7.34 (br. s, 1 H), 7.10 (br. s, 2H), 6.75 (br. s, 1 H), 5.05 (br. s, 1 H), 4.39 (br. s, 2H), 1 .90 (sxt, 2H), 1 .12 (t, 3H).
LCMS: 97% UV215 at 2.00 min, m/z 270 (M+1 )+ 100%.
Preparation of pentyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000148_0001
A solution of methyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (25 mg) in 1 -pentanol (2.0 mL) was treated with Sc(OTf)3 (5.1 mg) and heated under microwave irradiation (140 °C, 1 h). Once complete by LCMS, the reaction mixture was concentrated in- vacuo and purified by column chromatography (10-20% ethyl acetate / heptane) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.38 (br. s, 5H), 7.15 (br. s, 2H), 4.45 (br. s, 2H), 1 .82- 1 .93 (m, 2H), 1 .68 (br. s, 1 H), 1 .47-1 .56 (m, 2H), 1 .38-1 .47 (m, 2H), 0.95 (t, 3H).
LCMS: 100% UV215 at 2.27 min, m/z 298 (M+1 )+ 100%.
2-(Dimethylamino)ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000148_0002
To dimethylaminoethanol (125 mL) was added sodium (5.0 g) over 30 min followed by methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate (20.0 g) . The reaction was heated to 1 10 °C. After 36 h, the reaction mixture was cooled to room temperature and evaporated to dryness to furnish the sodium salt of the product as a green foam which was used without purification. H NMR (500 MHz, DMSO-c 6) δ ppm 8.31 (d, 1 H), 8.04 (d, 1 H), 7.62 (d, 1 H), 7.04 (dd, 1 H), 6.65 (t, 1 H), 6.51 (d, 1 H), 6.46 (dd, 1 H), 4.30 (t, 2H), 3.44 (t, 2H), 2.24 (s, 6H).
LCMS (3 min): 1 .25 min; m/z 299 (M+1 )+ 100%. STEP 2: O-alkylation with bromoacetonitrile or chloroacetonitrile
Preparation of propan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000149_0001
To a stirred solution of propan-2-yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (16.1 mg) in dry DMF (1 .0 mL), was added sodium hydride (7.18 mg of a 60% dispersion in mineral oil). The resulting suspension was stirred at room temperature for 1 h. Bromoacetonitrile (8.34 μΙ_) in dry DMF (1 .0 mL) was then added and the resulting solution was stirred at room temperature for 26 hours. Once complete by LCMS, the reaction mixture was quenched with a saturated solution of NH4CI (aq) (10 mL) and extracted with ether (3 x 25 mL). The combined organic extracts were washed with 2M KOH (aq) (20 mL), water (3 x 20 mL), brine (20 mL), dried (MgS04) and concentrated in-vacuo to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.34-8.42 (m, 3H), 7.48 (d, 1 H), 7.28-7.31 (m, 1 H), 7.25 (dd, 1 H), 6.81 (t, 1 H), 5.39 (sept., 1 H), 4.90 (s, 2H), 1 .48 (d, 6H).
LCMS: 86% UV215 at 2.22 min, m/z 309 (M+1 )+ 100%. Preparation of Butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000150_0001
To a stirred solution of butyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (17.4 mg) in dry DMF (1 .0 mL), was added sodium hydride (7.36 mg of a 60% dispersion in mineral oil). The resulting suspension was stirred at room temperature for 1 h.
Chloroacetonitrile (7.8 μί,) in dry DMF (1 .0 mL) was then added and the resulting solution was stirred at room temperature for 20 hours. Once complete by LCMS, the reaction mixture was quenched with a saturated solution of NH4CI (aq) (10 mL) and extracted with ether (3 x 25 mL). The combined organic extracts were washed with water (3 x 20 mL), brine (30 mL), dried (MgS04) and concentrated in-vacuo to furnish the title compound as a yellow residue. H NMR (500 MHz, CDCI3) δ 8.32-8.45 (m, 3H), 7.48 (d, 1 H), 7.28-7.33 (m, 1 H), 7.25 (dd, 1 H), 6.79-6.85 (m, 1 H), 4.90 (s, 2H), 4.44 (t, 2H), 1 .80-1 .92 (m, 2H), 1 .52-1 .63 (m, 2H), 1 .03 (t, 3H).
LCMS: 94% UV215 at 2.39 min, m/z 323 (M+1 )+ 100%.
Preparation of propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000150_0002
To a stirred solution of propyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (24.2 mg) in dry DMF (1 .0 mL), was added sodium hydride (10.8 mg of a 60% dispersion in mineral oil). The resulting suspension was stirred at room temperature for 1 h.
Bromoacetonitrile (12.5 μΙ_) in dry DMF (1 .0 mL) was then added and the resulting solution was stirred at room temperature for 26 hours. Once complete by LCMS, the reaction mixture was quenched with a saturated solution of NH4CI (aq) (10 mL) and extracted with ether (3 x 30 mL). The combined organic extracts were washed with 2M KOH (aq) (30 mL), water (3 x 30 mL), brine (30 mL), dried (MgS04) and concentrated in-vacuo to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.19-8.39 (m, 3H), 7.40 (d, 1 H), 7.22 (dd, 1 H), 7.17 (dd, 1 H), 6.74 (td, 1 H), 4.82 (s, 2H), 4.32 (t, 2H), 1 .83 (sxt, 2H), 1 .04 (t, 3H).
LCMS: 95% UV215 at 2.26 min, m/z 309 (M+1 )+ 100%.
Preparation of pentyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000151_0001
To a stirred solution of pentyl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (25.9 mg) in dry DMF (1 .0 mL), was added sodium hydride (10.5 mg of a 60% dispersion in mineral oil). The resulting suspension was stirred at room temperature for 45 mins.
Bromoacetonitrile (12.15 μί,) in dry DMF (1 .0 mL) was then added and the resulting solution was stirred at room temperature for 18 hours. Once complete by LCMS, the reaction mixture was quenched with a saturated solution of NH4CI (aq) (20 mL) and extracted with ether (3 x 30 mL). The combined organic extracts were washed with 2M KOH (aq) (30 mL), water (3 x 30 mL), brine (40 mL), dried (MgS04) and concentrated in-vacuo to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.33-8.43 (m, 3H), 7.48 (d, 1 H), 7.30 (ddd, 1 H), 7.25 (dd, 1 H), 6.82 (td, 1 H), 4.91 (s, 2H), 4.42 (t, 2H), 1 .84-1 .92 (m, 2H), 1 .40-1 .55 (m, 4H), 0.96 (t, 3H). LCMS: 94% UV215 at 2.52 min, m/z 337 (M+1 )+ 100%.
C10 esters via esterification of carboxylic acids Scheme 30: Preparation and O-alkylation of 3-cyanomethoxy-pyrido[1 ,2-a]indole-10- carboxylic acid.
Figure imgf000152_0001
Preparation of prop-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000152_0002
To a solution of prop-2-en-1 -yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (5.0 g) in DMF (100 ml) was added NaH (1 .34 g) portionwise at 0 °C. After the reaction was stirred at 0 °C for 30 minutes, bromoacetonitrile (3.366 g) in DMF (10 ml) was added dropwise at 0 °C to the solution, and then the reaction was allowed to warm up to room temperature and stirred at room temperature for one hour. The reaction was quenched with water (10 ml) and saturated aqueous NH4CI (10 ml), and then the solvent was removed to one third of original volume in vacuo. Addition of water (250 ml_) to the residue resulted in formation of a yellow precipitate. This precipitate was filtered, washed with water (30 ml_), and then dried in a vacuum oven for 6 hours. The title compound was furnished as a yellow solid. The crude product was used without further purification for the next step. In order to isolate sample for analysis and biological testing, 1 .00 g of the crude product was purified by flash column chromatography (silica gel, eluent: heptanes containing a 10%-40% gradient of ethyl acetate). The title compound was isolated as a 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%.
Preparation of 3-Cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid
Figure imgf000153_0001
To a solution of prop-2-en-1 -yl 3-hydroxy-pyrido[1 ,2-a]indole-10-carboxylate (1 .50 g) in THF (25 ml) was added Pd(PPh3)4 (283 mg) at 0 °C, followed by morpholine (2.14ml) under an atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 15 min, and then was allowed to warm to room temperature for two hours (over which time the solution had precipitated a yellow solid). The solid was isolated by filtration, and filtrate was concentrated under reduced pressure. The filtrate residue was suspended in EtOAc (7ml), stirred at room temperature for 30 min, and the resulting slurry filtered to isolate the solid. The combined precipitates were dried in a vacuum oven to furnish the title compound as a yellow powder. This material was of sufficient purity to progress to the next step without additional purification. H NMR (500 MHz, d4-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%. Synthesis of esters:
Procedure N:
To a solution of 3-cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid (0.188 mmol) in DMF (2 ml) was added Cs2C03 (0.376 mmol) and corresponding halide (0.376 mmol) at room temperature. The reaction was stirred at room temperature for 18 hours, then the solvent was removed in vacuo and the residue partitioned between EtOAc (6 ml) and water (2 ml). The organic layer was washed with brine (2 ml), dried over Na2S04, filtered and evaporated under reduced pressure to furnish the crude product.
Purification by flash column chromatography (silica gel, eluent: DCM containing 0-5% MeOH) surrendered the title compounds.
Preparation of benzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000154_0001
The title compound was synthesized using benzyl bromide according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.30-8.44 (m, 3H), 7.54 (d, 2H), 7.46 (d, 1 H), 7.40-7.45 (m, 2H), 7.33-7.39 (m, 1 H), 7.26-7.32 (m, 1 H), 7.21 (dd, 1 H), 6.78-6.86 (m, 1 H), 5.49 (s, 2H), 4.89 (s, 2H).
LCMS: 100% UV215 at 2.38 min, m/z 357 (M+1 )+ 80%, 379 (M+Na)+ 100% Preparation of 3-methylbut-2-en-1-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000155_0001
The title compound was synthesized using 3,3-dimethylallyl bromide according to Procedure N and isolated as yellow solid. H NMR (500 MHz, CDCI3) δ 8.32-8.40 (m, 3H), 7.45 (d, 1 H), 7.26-7.31 (m, 2H), 7.23 (dd, 1 H), 6.80 (td, 1 H), 5.60 (tt, 1 H), 4.93 (d, 2H), 4.90 (s, 2H), 1 .83 (d, 6H).
LCMS: 95% UV215 at 2.42 min, m/z 334 (M+1 )+ 100%.
Preparation of prop-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000155_0002
The title compound was synthesized using propargyl bromide according to Procedure Nand isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.32-8.44 (m, 3H), 7.46 (d, 1 H), 7.33 (ddd, 1 H), 7.25 (dd, 1 H), 6.85 (td, 1 H), 5.03 (d, 2H), 4.91 (s, 2H), 2.55 (t, 1 H).
LCMS: 100% UV215 at 2.1 1 min, m/z 305 (M+1 )+ 100%.
Preparation of 4-methyl benzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000156_0001
The title compound was synthesized using 4-methylbenzyl bromide according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.26-8.43 (m, 3H), 7.38-7.52 (m, 3H), 7.24-7.33 (m, 3H), 7.21 (dd, 1 H), 6.80 (td, 1 H), 5.47 (s, 2H), 4.90 (s, 2H), 2.42 (s, 3H).
LCMS: 99% UV215 at 2.47 min, m/z 371 (M+1 )+ 70%, 393 (M+Na)+ 100%.
Preparation of 3-methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000156_0002
The title compound was synthesized using 3-methylbenzyl bromide according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.27-8.41 (m, 3H), 7.42 (d, 1 H), 7.23-7.37 (m, 4H), 7.15- 7.22 (m, 2H), 6.79 (td, 1 H), 5.45 (s, 2H), 4.88 (s, 2H), 2.40 (s, 3H).
LCMS: 100% UV215 at 2.48 min, m/z 371 (M+1 )+ 80%, 393 (M+Na)+ 100%.
Preparation of 4-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000157_0001
The title compound was synthesized using 4-chlorobenzyl bromide according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.27-8.42 (m, 3H), 7.47 (dd, 3H), 7.35-7.42 (m, 2H), 7.28- 7.34 (m, 1 H), 7.22 (dd, 1 H), 6.77-6.88 (m, 1 H), 5.44 (s, 2H), 4.90 (s, 2H).
LCMS: 100% UV215 at 2.50 min, m/z 391 & 393 (M+1 )+ 100%.
Preparation of 2-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000157_0002
The title compound was synthesized using 2-chlorobenzyl bromide according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.30-8.41 (m, 3H), 7.59 (dd, 1 H), 7.41 -7.47 (m, 2H), 7.27- 7.32 (m, 3H), 7.21 (dd, 1 H), 6.80 (td, 1 H), 5.60 (s, 2H), 4.88 (s, 2H).
LCMS: 94% UV215 at 2.50 min, m/z 413 & 415 (M+1 )+ 100%.
Preparation of 3-cyanopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000158_0001
The title compound was synthesized using 4-bromobutyronitrile according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.38 (d, 1 H), 8.35 (d, 1 H), 8.29 (d, 1 H), 7.48 (d, 1 H), 7.34 (ddd, 1 H), 7.26 (dd, 1 H), 6.86 (td, 1 H), 4.91 (s, 2H), 4.56 (t, 2H), 2.61 (t, 2H), 2.20-2.30 (m, 2H). LCMS: 97% UV215 at 2.01 min, m/z 334 (M+1 )+ 65%, 356 (M+Na)+ 100%.
Preparation of cyanomethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000158_0002
The title compound was synthesized using bromoacetonitrile according to Procedure N and isolated as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.39-8.44 (m, 1 H), 8.34 (d, 1 H), 8.28 (d, 1 H), 7.49 (d, 1 H), 7.37-7.44 (m, 1 H), 7.27 (s, 1 H), 6.92 (t, 1 H), 5.08 (s, 2H), 4.92 (s, 2H).
LCMS: 100% UV215 at 2.01 min, m/z 306 (M+1 )+ 90%, 328 (M+Na)+ 100%.
Preparation of 2-(dimethylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000159_0001
Prepared according to Procedure N using 2-dimethylaminoethyl chloride hydrochloride (54 mg). Reaction mixture stirred at room temperature for 23 h and treated with potassium iodide (62 mg, 0.38 mmol) and stirred for a further 24 h. Purified by silica gel column chromatography (10-80% ethyl acetate / heptane then 2% MeOH /CH2CI2) to give the title compound as a green wax. H NMR (500 MHz, CDCI3) δ 8.39 (td, 3H), 7.47 (d, 1 H), 7.31 (ddd, 1 H), 7.25 (dd, 1 H), 6.83 (td, 1 H), 4.90 (s, 2H), 4.54 (t, 2H), 2.83 (t, 2H), 2.39 (s, 6H).
LCMS: 100% UV215 at 1 .45 min, m/z 338 (M+1 )+ 100%.
3-(Dimethylamino)propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000159_0002
Prepared according to Procedure N using 3-chloro-1 -(/V,/V-dimethylamino)propane. Purification of the residue by silica gel chromatography (eluent: dichloromethane containing a 0-5% gradient of methanol) gave the title compound as a yellow solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 (d, 1 H), 8.36 (m, 2H), 7.48 (d, 1 H), 7.30 (ddd, 1 H), 7.24 (dd, 1 H), 6.82 (td, 1 H), 4.90 (s, 2H), 4.48 (t, 2H), 2.56 (t, 2H), 2.33 (s, 6H), 2.08 (quintet, 2H). LCMS (7 min): 2.93 min; m/z 352 (M+1 )+ 100%.
2-[(ieri-Butoxycarbonyl)(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2- a]indole-10-carboxylate
Figure imgf000160_0001
Prepared according to Procedure N using te/t-butyl (2-chloroethyl)methylcarbamate. Purification by silica gel chromatography (Eluent: dichloromethane containing a 0-1 % methanol gradient) gave the title compound as a pale brown oil. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 (s, 3H), 7.48 (br. s., 1 H), 7.29 - 7.36 (m, 1 H), 7.25 (d, 1 H), 6.79 - 6.88 (m, 1 H), 4.90 (s, 2H), 4.54 (t, 2H) 3.66 - 3.79 (m, 2H), 2.94 - 3.03 (m, 3H), 1 .35 - 1 .48 (m, 9H).
LCMS (3 min): 2.21 min; m/z 446 (M+Na)+ 100%.
Preparation of 2-methylprop-2-en-1-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000160_0002
Procedure N, using 3-bromo-2-methylpropene (37.9 μΙ_) and purified by silica gel column chromatography (100% CH2CI2) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.32-8.48 (m, 3H), 7.48 (d, 1 H), 7.31 (dd, 1 H), 7.25 (dd, 1 H), 6.84 (t, 1 H), 5.15 (s, 1 H), 5.02 (s, 1 H), 4.91 (s, 2H), 4.88 (s, 2H), 1 .92 (s, 3H).
LCMS: 100% UV215 at 2.33 min, m/z 321 (M+1 )+ 100%.
Preparation of 2-hydroxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000161_0001
Procedure N, using 2-chloroethanol (25.2 μΙ_). Reaction mixture stirred at room temperature for 23 h and treated with potassium iodide (62 mg, 0.38 mmol) and stirred for a further 24 h. Purification by silica gel column chromatography (10-60% ethyl acetate / heptane) furnished the title compound as a green solid. H NMR (500 MHz, DMSO-d6) δ 9.05 (d, 1 H), 8.25 (dd, 2H), 8.16 (d, 1 H), 7.47 (dd, 1 H), 7.29 (dd, 1 H), 7.02 (t, 1 H), 5.27 (s, 2H), 4.96 (t, 1 H), 4.32 (t, 2H), 3.78 (q, 2H).
LCMS: 88% UV215 at 1 .81 min, m/z 31 1 (M+1 )+ 90%, 333 (M+Na)+ 100%.
Preparation of 2-methoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000161_0002
Procedure N using 2-bromoethyl methyl ether (35.3 μΙ_) and purified by silica gel column chromatography (100% CH2CI2) to furnish the title compound as a green solid. H NMR (500 MHz, CDCI3) δ 8.33-8.42 (m, 3H), 7.46 (d, 1 H), 7.31 (dd, 1 H), 7.24 (dd, 1 H), 6.80-6.85 (m, 1 H), 4.90 (s, 2H), 4.56-4.60 (m, 2H), 3.81 -3.86 (m, 2H), 3.49 (s, 3H).
LCMS: 100% UV215 at 2.04 min, m/z 325 (M+1 )+ 70%, 347 (M+Na)+ 100%.
Preparation of 2-ethoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000162_0001
Procedure N, using 2-bromoethyl ethyl ether (42.4 μΙ_) and purified by silica gel column chromatography (100% CH2CI2) to furnish the title compound as a yellow solid. H NMR (500 MHz, CDCI3) δ 8.31 -8.47 (m, 3H), 7.47 (d, 1 H), 7.30 (dd, 1 H), 7.24 (dd, 1 H), 6.83 (t, 1 H), 4.91 (s, 2H), 4.54-4.60 (m, 2H), 3.84-3.90 (m, 2H), 3.65 (q, 2H), 1 .29 (t, 3H). LCMS: 99% UV215 at 2.14 min, m/z 339 (M+1 )+ 60%, 361 (M+Na)+ 100%.
Scheme 31 : Esterification via 3-cyanomethoxy-pyrido[1 ,2-a]indole-10-carbonyl chloride.
Figure imgf000162_0002
Preparation of tert-butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000163_0001
To a suspension of 3-cyanomethoxy-pyrido[1 ,2-a]indole-10-carboxylic acid (50 mg, 0.188 mmol) in DCM (3 ml) was added oxalyl chloride (95 μΙ, 1 .127 mmol) at 0 °C, followed by a drop of DMF. After the reaction was stirred at 0 °C for 15 minutes, the yellow suspension had become a clear blue-green solution to which was introduced potassium tert-butoxide (1 .65 ml_ of a 1 .0 M solution in tetrahydrofuran 1 .65 mmol) dropwise. After stirring for 30 minutes at 0 °C, the reaction was allowed to warm up to room temperature for 30 minutes. The reaction mixture was adsorbed onto silica gel (2.0 g), and evaporated under reduced pressure. The dry-loaded product was placed onto a silica gel (5.0 g) column and eluted with DCM to furnish the title compound as a yellow solid. H NMR (500 MHz, d4-methanol) δ 8.73 (d, 1 H), 8.20-8.31 (m, 2H), 7.79 (d, 1 H), 7.31 - 7.37 (m, 1 H), 7.23 (dd, 1 H), 6.84-6.90 (m, 1 H), 5.10 (s, 2H), 1 .67-1 .73 (m, 9H). LCMS: 92% UV215 at 2.35 min, m/z 323 (M+1 )+ 100%.
2-(Methylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate
Figure imgf000163_0002
To a solution of 2-[(tert-butoxycarbonyl)(methyl)amino]ethyl 3- (cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate (50 mg) in 2:1 1 ,2- dichloroethane:acetonitrile was introduced trifluoroacetic acid (0.077 ml_). After warming to 60 °C for 90 min, the reaction was cooled and concentrated in vacuo. The residue was slurried in diethyl ether (2 ml_) and the precipitate isolated by filtration to give the trifluoroacetate salt of the title compound as a green solid. H NMR (500 MHz, DMSO-c/6) δ ppm 9.09 (d, 1 H), 8.57 (br. s, 2H), 8.28 (d, 1 H), 8.24 (d, 1 H), 8.18 (d, 1 H), 7.52 (dd, 1 H), 7.31 (dd, 1 H), 7.07 (t, 1 H), 5.28 (s, 2H), 4.58 (t, 2H), 2.67 (t, 2H), 2.51 (s, 3H). LCMS (3 min): 1 .30 min; m/z 324 (M+1 )+ 100%.
2-[(2-Amino-2-oxoethyl)(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2- a]indole-10-carboxylate
Figure imgf000164_0001
To a solution of 2-(methylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate (40 mg) in A/JV-dimethylformamide (2 ml_) was introduced 2- bromoacetamide (15 mg) and cesium carbonate (83 mg). After 15 h at 60 °C, the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate extract was washed with brine, dried (magnesium sulfate), filtered and the filtrate evaporated in vacuo. Purification of the residue by silica gel chromatography (5 g Isolute Flash Si II cartridge; eluent: dichloromethane containing a 0-1 % methanol gradient) gave the title compound as a yellow waxy solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 - 8.42 (m, 2H), 8.36 (d, 1 H), 7.50 (d, 1 H), 7.31 - 7.37 (m, 1 H), 7.25 (d, 1 H), 7.13 (br. s, 1 H), 6.86 (t, 1 H), 5.21 (br. s, 1 H), 4.91 (s, 2H), 4.56 (t, 2H), 3.16 (s, 2H), 2.96 (t, 2H), 2.47 (s, 3H).
LCMS (7 min): 2.70 min; m/z 381 (M+1 )+ 100%. 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl 3-acetylpyrido[1 ,2-a]indole-10- carboxylate
Figure imgf000165_0001
To a solution of 3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid (125 mg) in anhydrous THF (5 mL) was added triethylamine (0.25 mL) and MsCI (68 mg). The mixture was stirred at -40QC for 10 min. under nitrogen atmosphere. 2-((2- (dimethylamino)ethyl)(methyl)amino) ethanol (412 mg) was added to the reaction mixture and the mixture was stirred for further 30 min. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel using DCM- MeOH (9:1 ) to DCM-MeOH-NH4OH (8:1 .5:0.5) as eluent.
The fractions containing product were combined and evaporated and the residue was dissolved in water (20 mL) and extracted with ethylacetate (2X 30 mL), dried (MgS04), filtered and evaporated to give the title compound as yellow solid. H NMR (300 MHz, MeOH-d4) δ ppm 9.1 (d, 1 H), 8.91 (s, 1 H), 8.38 (dd, 2H), 8.16 (d, 1 H), 7.62 (t, 1 H), 7.1 (t, 1 H), 4.60 (t, 2H), 3.02 (t, 2H), 2.86-2.78 (m, 7H), 2.18 (s, 6H), 2.35 (s, 3H).
ES-MS: m/z 382(M+1 ) 100%
C10 amides and thioamides
3-(Cyanomethoxy)-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000166_0001
A stirred solution containing 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid (0.095 g) and 1 H-benzotriazol-1 -ol hydrate (1 :1 ) (0.06 g) in dry Λ/JV-dimethylformamide (5.0 ml_), was treated with /V-[3-(dimethylamino)propyl]-/V-ethylcarbodiimide (138 μΙ_), A/JV-dimethylethylenediamine (39 μΙ_) and A/-ethyl-/V-(propan-2-yl)propan-2-amine (205 μΙ_) dropwise. The reaction mixture was stirred at room temperature under nitrogen for 70 h. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate (aq), water, brine, dried
(magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-13% methanol / dichloromethane) to give the title compound as a dark green crystalline solid. H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (dt, 1 H), 8.30 (d, 1 H), 8.05 (d, 1 H), 7.50 (d, 1 H), 7.25 (dd, 1 H), 7.18 (ddd, 1 H), 6.72 (td, 2H), 4.91 (s, 2H), 3.62 - 3.68 (m, 2H), 2.63 (t, 2H), 2.36 (s, 6H).
LCMS (7 min): 2.79 min; m/z 337 (M+1 )+ 100%.
3-Λ/,10-A/-bis[2-(Dimethylamino)ethyl]pyrido[1 ,2-a]indole-3,10-dicarboxamide
Figure imgf000166_0002
A solution of potassium 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10- carboxylate (100 mg) in dichloromethane (5 ml_) containing a catalytic amount of N,N- dimethylformamide (1 drop) was treated with a solution of oxalyl chloride (40 μΙ_) in dichloromethane (3 ml_). The solution was stirred at room temperature for 60 min. A solution of A/JV-dimethylethylenediamine (60 μΙ_) in dichloromethane (2 ml_) was added dropwise and stirring continued at room temperature for 5 min. The reaction mixture was washed with 1 M aq sodium hydrogen carbonate solution. The aqueous phase was extracted with isopropanol / chloroform (1 :1 ).The organic phases were combined, dried (sodium sulfate), filtered and the solvent was removed in vacuo to give brown solid. The residue was purified by column chromatography on silica gel (dichloromethane containing 1 % triethylamine and methanol [0-10%] gradient) and the product was dissolved in methanol and filtered through an acid scavenger cartridge (isolute PE-AX). Final purification by prep-HPLC (0.1 % formic acid in water/acetonitrile) gave the di- formate salt of the title compound as a yellow semi solid H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.71 (d, 1 H), 8.61 (d, 1 H), 8.58 (t, 1 H), 8.46 (d, 1 H), 8.14 (d, 1 H), 8.04 (dd, 1 H), 7.32 (ddd, 1 H), 7.21 (t, 1 H), 6.83 (td, 1 H), 3.86 (q, 2H), 3.83 (q, 2H), 3.09 - 3.14 (m, 2H), 2.98 (t, 2H), 2.71 (s, 6H), 2.59 (s, 6H).
LCMS (7 min): 1 .92 min; m/z 396 (M+1 )+.
3-acetyl-N-(2-(dimethylamino)ethyl)-pyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000167_0001
Procedure O:
A mixture containing 3-acetylpyrido[1 ,2-a]indole-10-carboxylic acid (219 mg) and triethylamine (0.55g) in 30 ml of anhydrous THF was cooled to -45 °C under positive nitrogen pressure. Methanesulfonyl chloride (300mgl) was added and the mixture stirred at -45 'Ό for 15 minutes. N, N, dimethylethylenediamine (648mg) was added and the reaction mixture was allowed to warm at room temperature. Solvent removed by rotary evaporation and the residue was dissolved in MeOH containing few drops of ammonium hydroxide. Purified by silica gel column chromatography (eluent: MeOH in DCM) to give the title compound as yellow solid powder. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.56 (t, 2H), 8.30 (d, 1 H), 8.18 - 8.08 (m, 2H), 7.35 (ddd, 1 H), 7.05 (br s, 1 H), 6.85 (ddd, 1 H), 3.82 - 3.70 (m, 2H), 2.90 - 2.80 (m, 2H), 2.72 (s, 3H), 2.52 (s, 6H). ES-MS: m/z 324(M+1 ) 100%.
3-acetyl-N-(2-(dimethylamino)ethyl)-N-methylpyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000168_0001
Prepared by Procedure O using N1 ,N1 ,N2-trimethylethane-1 ,2-diamine (302.3mg). The Title compound obtained as yellow semi solid. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.60 (s, 1 H), 8.53 (d, 1 H), 8.01 (d, 1 H), 7.81 (d, 1 H) 7.27 (t, 1 H), 6.76 (t, 2H), 3.75-3.71 (m, 2H), 3.16 (s, 3H), 2.74 (s, 3H), 2.64-2.60 (m, 2H), 2.23 (br s, 6H).
ES-MS: m/z 338 (M+1 ) 100%. 3-(cyanomethoxy)-N-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide
Figure imgf000168_0002
Triethylamine (739 mg) was added followed by methane sulfonyl chloride (537 mg) to a mixture of 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylic acid (765 mg) in 39 ml THF under nitrogen at -40 'Ό. In a separate flask n-BuLi (12ml of 1 .6M in hexanes) was added to a solution of methanesulfonamide (1 .81 g) in 25 ml of THF at -40 °C. Allowed to stir for 8 minutes, before added to the reaction mixture. DMF (25 ml) was added and the mixture was allowed to stir for 12 hours at rt. The mixture quenched with acetic acid and the volatiles removed by the rotary evaporation. Purified by flash chromatography (eluent: MeOH in dichloromethane) to give a green solid. H NMR (300 MHz, ACETONE-d6) δ ppm 8.78 (d, 1 H), 8.20 (d, 1 H), 8.07 (d, 1 H), 7.89 (m, 1 H), 7.31 (t, 1 H), 7.18 (d, 1 H), 6.87 (t, 1 H), 5.12 (s, 2H); 3.28 (s, 3H).
ES-MS: m/z 342 (M-1 )" m/z 344 (M+1 )+ m/z 366 (M+Na)+
3-Acetyl-N-(2-(dimethylamino)ethyl)pyrido[1 ,2-a]indol-10-carbothioamide
Figure imgf000169_0001
To a suspension of 3-acetyl-N-(2-(dimethylamino)ethyl)pyrido[1 ,2-a]indol-10- carboxamide (310 mg) in toluene (20 mL), Lawesson's reagent (0.5 eq) was added and the mixture was refluxed under nitrogen atmosphere. After 45 and 60 minutes 0.25 equivalents of Lawesson's reagent was added to the reaction mixture and continue to reflux for an additional 30 minutes. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel using DCM-MeOH-NH4OH (95:5:1 ) to 10 % MeOH/DCM as eluents to get the title product as yellow solid. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.90 (d, 1 H), 8.50 (dd, 2H), 8.30 (br s, 1 H), 8.20 (dd, 1 H), 8.05 (dd, 1 H), 7.40 - 7.30 (m, 1 H), 6.90 - 6.85 (m, 1 H), 4.10 - 4.00 (m, 2H), 2.85 - 2.75 (m, 2H), 2.70 (s, 3H), 2.40 (s, 6H).
MS (ES+): 340 (M+H+), calcd m/z (for C19H21 N3OS) 339.
C10 keto
1-(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-chloroethanone
Figure imgf000170_0001
Triethylamine (87 mg) was added to a solution of 1 -(pyrido[1 ,2-a]indol-3-yl)ethanone (60 mg, 0.28 mmol) and chloroacetyl chloride in anhydrous THF (15 ml_) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated in vacc and the crude product was purified on a silica gel column using ethyl acetate as eluent to give the title product as green solid. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.70 (d, 1 H), 8.70 (m, 1 H), 8.64 (s, 1 H), 8.15 (d, 1 H), 8.13 (d, 1 H), 7.6 (t, 1 H), 6.94 (t, 1 H), 4.79 (s, 2H), 2.75 (s, 3H).
ES-MS: m/z 286(M+1 ) C16H12CIN02
1-(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-((2-methoxyethyl)(methyl)amino)ethanone
Figure imgf000170_0002
A mixture of 1 -(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-chloroethanone (250 mg), 2- methoxy-N-methylethanamine (780 mg), in 1 ,4-dioxane (5 ml_) was stirred at room temperature for 18 h. The solvent was evaporated and solid was dissolved in DCM (10 ml_). The precipitate formed was collected by filtration, washed repeatedly with DCM and acetonitrile to give the title product. H NMR (300 MHz, MeOH-d4) δ ppm 9.25 (d, 1 H), 9.0 (s, 1 H), 8.67 (d, 1 H), 8.20 (dd, 2H), 7.8 (t, 1 H), 7.3 (t, 1 H), 5.0 (s, 2H), 3.86-3.84 (m, 2H), 3.58-3.56 (m, 2H), 3.39 (s, 1 H), 3.16 (s, 3H), 2.78 (s, 3H). ES-MS: m/z 339(M+1 ) C2oH22N203
1 -(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-(dimethylamino)ethanone
Figure imgf000171_0001
A mixture of 1 -(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-chloroethanone (150 mg), 40% aqueous solution of NN-dimethylamine (0.6ml), and Nal (391 mg) in 1 ,4-dioxane (2 ml_) was stirred at room temperature for 18 h. The solvent was evaporated and solid was dissolved in diethylether (10 ml_). The precipitate formed was collected by filtration, washed repeatedly with DCM and acetonitrile to give the title product as yellow solid. H NMR (300 MHz, MeOH-d4) δ ppm 9.25 (d, 1 H), 8.95 (s, 1 H), 8.62 (d, 1 H), 8.19 (dd, 2H), 7.8 (t, 1 H), 7.22 (t, 1 H), 4.9 (s, 2H), 3.09 (s, 6H), 2.78 (s, 3H).
ES-MS: m/z 295(M+1 ) C18H18N202
1-(3-acetylpyrido[1 ,2-a]indol-10-yl)-5-chloropentan-1 -one
Figure imgf000171_0002
Procedure P:
To a solution of 1 -(pyrido[1 ,2-a]indol-3-yl)ethanone (60 mg) in dry THF (15 ml_) was added lithium chloride (121 mg) followed by 5-chlorovaleryl chloride (133 mg). The mixture was heated to reflux overnight. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel using 20% ethyl acetate/hexane to 40% ethyl acetate/hexane to give the title product. Used without characterisation and further purification. 1-(3-acetylpyrido[1 ,2-a]indol-10-yl)-5-(dimethylamino)penthan-1-one
Figure imgf000172_0001
To a solution of 1 -(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-chloroenthan-1 -one (35 mg) in
1 ,4-dioxane (1 mL) was added dimethylamine 40wt % solution in water (2 mL) followed by sodium iodide (32 mg). The mixture was heated at 100 °C in a sealed tube overnight. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel using DCM:MeOH:NH4OH (9:5:1 ) to give the title product as yellow solid. H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.70 - 8.50 (m, 3H), 8.25 (dd, 1 H), 8.10 (d, 1 H), 7.50 (dd, 1 H), 7.00 (t, 1 H), 3.20 (t, 2H), 2.75 (s, 3H), 2.45 - 2.30 (m, 2H), 2.30 (s, 6H), 1 .98 -1 .80 (m, 2H), 1 .75 - 1 .60 (m, 2H).
MS (ES+): 337 (M+H+), calcd m/z (for C21 H24N202) 336.
1 ,1 '-(Pyrido[1 ,2-a]indol-3,10-diyl)diethanone
Figure imgf000172_0002
Procedure P using acetyl chloride gave the title product as green solid.
H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.7-8.6 (m, 3H), 8.2 (d, 1 H), 8.1 (d, 1 H), 7.5 (dd, 1 H), 6.9 (t, 1 H), 2.81 (s, 3H), 2.75 (s, 3H).
ES-MS: m/z 252(M+1 ) C16H13N02
1-(3-(1-(hydroxyimino)ethyl)pyrido[1 ,2-a]indol-10-yl)-2-((2-methoxyethyl)
(methyl)amino)ethanone
Figure imgf000173_0001
NH2OH. HCI (16.3 mg) was dissolved in anhydrous MeOH (2 ml) and DIPEA (30 mg) was added to this solution. The mixture was stirred for 10 min. at room temperature and then, 1 -(3-acetylpyrido[1 ,2-a]indol-10-yl)-2-((methoxyethyl)(methyl)amino)ethanone (20 mg) was added. The mixture was stirred at room temperature for overnight under nitrogen. The solvent was evaporated and the crude product mixture was purified on a silica gel column using DCM-MeOH (9.5:05) as eluent. The fractions containing product were combined and re-purified on silica gel Prep. TLC using MeOH-DCM-NH30H (95:5:1 ) eluents to give the title product as yellow solid. H-NMR (300 MHz, Methanol-d4): δ 8.88 (dd, H), 8.44 (dd, 1 H), 8.29 (brs, 1 H), 8.02 (d, 1 H), 7.82 (d, 1 H), 7.48 (dd, 1 H), 6.96 (dd, 1 H), 4.1 1 (s, 2H), 3.57 (t, 2H), 3.25 (s, 3H), 2.88 (t, 2H), 2.53 (s, 3H), 2.28 (s, 3H).
MS (ES+): 354 (M+H+), calcd m/z (for C20 23 3O3) 353.41 .
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 imgf000174_0001
Assay protocol and conditions:
The uHTS run was carried out on the EVOscreen™ Mark III system 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.
The table below shows an overview of the reaction and plate set up.
Assay steps and Control wells (nl) Compound (nl) Final cone, on reagents microplate
Negative Positive IC50 DMSO Sample control control control wells
1 ) Compound in
Figure imgf000176_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. 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 imgf000177_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 imgf000178_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 tremperature: 90 ^
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 imgf000179_0001
ethyl 3-
4 (cyanomethoxy)pyrido[l,2- +++ a]indole-10-carboxylate
Figure imgf000180_0001
ethyl 3-(2-
5 oxopropoxy)pyrido[l,2- ++ a]indole-10-carboxylate
o
ethyl 3-[2-
6 piperidinylethoxy]pyrido[l, +++
2-a]indole-10-carboxylate
Figure imgf000180_0002
ethyl 3-[2- (dimethylamino)-2-
7 ++ oxoethoxy]pyrido[l,2- o
a] indole-10-carboxylate
o \
ethyl 3-(3-
8 cyanopropoxy)pyrido[l,2- +++ a] indole-10-carboxylate
ethyl 3-
9 (benzyloxy)pyrido[l,2- +++ a] indole-10-carboxylate
Figure imgf000181_0001
ethyl 3-{[(3,5-dimethyl-l,2- oxazol-4-
16 +++
yl)sulfonyl]oxy}pyrido[l,2- a]indole-10-carboxylate
3-methoxy-N,N-
17 dimethylpyrido[l,2- +
a]indole-10-carboxamide
Figure imgf000182_0001
Example 4
GASC1 AlphaLISA assay for IC50 value determination at conditions with high carrier protein and detergent concentration
Assay principle:
Quantification of product 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 imgf000184_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. Table 2: GASC1 AlphaLISA assay - high carrier protein and detergent concentrations
Figure imgf000185_0001
Figure imgf000186_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
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
, Γ' 2-(dimethylamino)ethyl 3- (dimethylcarbamoyl)pyrido
47 +++
[l,2-a]indole-10- carboxylate
10-[2-
(dimethylamino)ethyl] 3- [2-
48 +++
(methylsulfanyl)ethyl]
pyrido[l,2-a]indole-3,10- dicarboxylate
2-(dimethylamino)ethyl 3-
49 bromopyrido[l,2-a]indole- +++
10-carboxylate
2-(dimethylamino)ethyl 3- (1,2-
50 +++ dihydroxyethyl)pyrido[l,2- a]indole-10-carboxylate
l-{3-acetylpyrido[l,2- a]indol-10-yl}-2-[(2-
51 +++ methoxyethyl)(methyl)ami
no]ethan-l-one
1 methyl 3-acetylpyrido[l,2-
52 ++ a]indole-10-carboxylate
1
2-{[2-
(dimethylamino)ethyl](met
53 hyl)amino}ethyl 3- +++
0¾ acetylpyrido[l,2-a]indole- 10-carboxylate 3-acetyl-N-[2-
(dimethylamino)ethyl]-N-
54 +++
methylpyrido[l,2-a]indole- 10-carboxamide
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:
Figure imgf000193_0001
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 imgf000194_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
6-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, halo, trifluoromethyl, -NH2, methylamino, dimethylamino, sulfamoyi, dimethylsulfamoyi, methylsulfonyl, methylsulfonyloxo, methylsulfinyl, methylsulfanyl, cyano, -(C=0)R', a phenyl group, and a monocyclic or bicyclic heterocyclic group, where
FT represents hydroxy, Ci-4-alkyl, halo-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, halo, cyano, acetamino, methylsulfonylamino, and a monocyclic or bicyclic heterocyclic group;
• -OH or -(C=0)R",
where R" represents hydrogen, hydroxy, C1-4-alkyl, cyclopropyl, halo-Ci.4-alkyl,
Ci_4-alkoxy, -COOH, -NH2, methylamino, dimethylamino, methylsulfonyl, or a monocyclic or bicyclic heterocyclic group; or where R" represents Ci-4-alkyl, Ci-4-alkoxy, oxy, carbamoyl, amine or a monocyclic or bicyclic heterocyclic group, which is substituted with one or more substituents selected from the group consisting of hydroxy, methyl, ethyl, -0-Ci-6- alkyl, hydroxymethyl, hydroxymethyl, methoxyethyl, acetyl, cyano,
ethoxycarbonyl, dimethylamino, N-[3-(dimethylamino)propyl]- N'ethylcarbamimidoyl, methylsulfinyl, methylsulfanyl, methylsulfonyl,
methoxyethoxyethyl, (dimethylamino)ethyl and methylsulfanylethyl, which -O-C1- 6-alkyl may optionally be substituted with hydroxy, methoxy or dimethylamino;
• -(C=S)R"\
where R'" represents -NH2, methylamino or dimethylamino;
• -C(CH3)=N-R"",
where R"" represents hydroxy or methoxy;
• sulfamoyi, dimethylsulfamoyl, sulfinyl or sulfonyl,
which sulfamoyi, sulfonyl or sulfonyl may optionally be substituted with one or more substituents selected from the group consisting of Ci-4-alkyl, halo-Ci-4-alkyl, methoxy-C1-4-alkyl, dimethylamino, (dimethylamino)methyl, (dimethylamino)ethyl, C3-6-cycloalkyl, C2-4-alkenyl and a monocyclic or bicyclic heterocyclic group; · fluoro, chloro, bromo or cyano; or • a monocyclic or bicyclic heterocyclic group, where the monocyclic or bicyclic 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; and
X2 represents
• Ci-18-alkyl, C2-i8-alkenyl, or C2-i8-alkynyl,
which Ci-18-alkyl, C2-i8-alkenyl, C2-i8-alkynyl may optionally be substituted with one or more substituents selected from the group consisting of C3-6-cycloalkyl, hydroxy, halo, trifluoromethyl, Ci-e-alkoxy, hydroxy-Ci-6-alkoxy, d-e-alkyl -Ci-6- alkoxy, trifluoromethyl-Ci-6-alkoxy, oxo-Ci-6-alkyl, -NH2, dimethylamino, cyano, phenyl, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group, which phenyl, 5-membered monocyclic heterocyclic group, or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of Ci_6-alkyl or halo; or
• -0-Xa, -(C=0)-0-Xb, -(C=0)-Xc, -NXd Xd2, -(CO)-NXe Xe2, or -(C=0)-NH-S02-Xf, where Xa, Xb, Xc, Xd , Xd2, Xe , Xe or Xf independently of each other represent hydrogen, Ci-i8-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-6-cycloalkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group
which Ci-i8-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3-6-cycloalkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of C3-6-cycloalkyl, hydroxy, halo, trifluoromethyl, Ci-4-alkyl, Ci-e-alkoxy, Ci-6-alkoxycarbonyl, Ci-4- alkylamino, hydroxy-Ci-6-alkoxy, Ci-6-alkyl-Ci-6-alkoxy, trifluoro- Ci-e-alkoxy, trifluoromethyl-0-Ci-6-alkyl, oxo-Ci.6-alkyl, -NH2, methylamino, dimethylamino, (methoxyethyl)(methyl) amino,
[(dimethylamino)ethyl](methyl)amino, cyano, -0-Ci-6-alkyl-phenyl, phenyl, a 5-membered monocyclic heterocyclic group, or a 6-membered monocyclic heterocyclic group, which phenyl, 5-membered monocyclic heterocyclic group, or 6-membered monocyclic heterocyclic group may optionally be substituted with one or more substituents selected from the group consisting of Ci-6-alkyl,
Figure imgf000197_0001
or halo; or where Xe and Xe2 independently of each other represent hydrogen, hydroxy, d. 18-alkyl, C2-i8-alkenyl, C2-i8-alkynyl, C3.6-cycloalkyl, -0-Ci-6-alkyl, phenyl, a 5- membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group, which -0-Ci-6-alkyl may optionally be substituted with hydroxy, methoxy, or dimethylamino; with the proviso that Xe and Xe2 cannot both represent hydrogen; and
with the proviso that Xb cannot represent hydrogen; or · -(C=0)-0-CH2-CH2-NXi Xi2, -S-Xk, -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn,
where Xj , Xj2, Xk, Xm, Xn independently of each other represent methyl, ethyl, propyl, amino, methylamino or dimethylamino,
which methyl, ethyl or propyl may optionally be substituted with one or more substituents selected from the group consisting of methoxycarbonyl, dimethylamino, carbamoyl, phenyl, cyanophenyl, and a 5- or 6-membered monocyclic heterocyclic group;
and
X3 represents hydrogen, C1-4-alkyl, C2.4-alkenyl, C2.4-alkynyl; or
• -O-X9, -S-Xh or -NXi Xi2, where X9, Xh, Xi , and Xi2 independently of each other represent hydrogen, -(CH2)n-CH3, or -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4; and X4 and X5 independently of each other represent
• hydrogen, C1-4-alkyl, halo-Ci_4-alkyl, C3-6-cycloalkyl, halo, nitro, -NH2, or cyano; with the proviso that the compound is not ethyl 3-[(3-chlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-amino-2-oxoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-chloro-6-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}acetic acid,
ethyl 3-[(2,6-dichlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-ethoxy-2-oxoethoxy)]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-chloro-5-trifluoromethyl-pyridine-2-yl)oxy] pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(3-trifluoromethyl-benzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 2-hydroxy-3-phenylmethoxypyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate, and
ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate.
2. The compound according to claim 1 , 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 ,
• -OH, or -(C=0)R", where R" is as defined in claim 1 and optionally substituted as indicated in claim 1 ,
• -(C=S)R"\ where FT is as defined in claim 1 ,
• -C(CH3)=N-R"", where R"" is as defined in claim 1 ,
· sulfamoyi, dimethylsulfamoyi, sulfinyl or sulfonyl, which sulfonyl may be substituted as indicated in claim 1 ,
• fluoro, chloro, bromo or cyano, or
• a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
3. The compound according to claim 1 , wherein A represents a bond, and B represents
• Ci-6-alkyl, C2-4-alkenyl or C2-4-alkynyl, which C1-6-alkyl, C2-4-alkenyl or C2-4-alkynyl may optionally be substituted as indicated in claim 1 ,
• -OH or -(C=0)R", where R" is as defined in claim 1 and where R" optionally is substituted as indicated in claim 1 ,
• sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may be substituted as indicated in claim 1 ,
• bromo or cyano, or
• a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
4. The compound according to claim 1 , wherein A represents O and B represents
• d-e-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 ,
· -(C=0)R", where R" is as defined as indicated in claim 1 ,
• sulfamoyl, dimethylsulfamoyl or sulfonyl, which sulfonyl may be substituted as indicated in claim 1 , or
• a monocyclic or bicyclic heterocyclic group, which monocyclic or bicyclic heterocyclic group may optionally be substituted as indicated in claim 1 .
5. The compound according to claim 1 , wherein A represents S and B represents
• 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 as indicated in claim 1 .
6. The compound according to claim 1 , 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 .
7. The compound according to claim 1 , wherein A represents a bond, O, S or NH and B represents C1-6-alkyl, C2.4-alkenyl or C2.4-alkynyl which d_6-alkyl, C2.4-alkenyl or C2.4- alkynyl may optionally be substituted as indicated in claim 1 .
8. The compound according to claim 1 , wherein A represents a bond, O or NH and B represents -(C=0)R", where R" is as defined in claim 1 and where R" optionally is substituted as indicated in claim 1 .
9. The compound according to claim 1 , wherein A represents a bond and B represents -(C=S)R"\ where FT is as defined in claim 1 .
10. The compound according to claim 1 , wherein A represents a bond and B represents -C(CH3)=N-R"", where R"" is as defined in claim 1 .
1 1 . The compound according to claim 1 , wherein A represents a bond, O or NH and B represents sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyl, sulfonyl or sulfonyl may be substituted as indicated in claim 1 .
12. The compound according to claim 1 , wherein A represents a bond and B represents fluoro, chloro, bromo or cyano.
13. The compound according to claim 1 , 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 .
14. The compound according to any of claims 1 -13, 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 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.
15. The compound according to claim 14, 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.
16. The compound according to claim 14, wherein the compound comprises at least one monocyclic heterocyclic group, which is a 5-membered monocyclic heterocyclic group comprising 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S.
17. The compound according to any of claims 16, 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, 1 ,2,5-oxadiazolyl and tetrazolyl.
18. The compound according to claim 14, wherein the compound comprises at least one monocyclic heterocyclic group, which is a 6-membered monocyclic heterocyclic group comprising 1 , 2, 3 or 4 heteroatoms each independently selected among N, O, and S.
19. The compound according to claim 18, 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.
20. The compound according to claim 14, 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.
21 . The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6- membered carbocyclic group.
22. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 6-membered heterocyclic group and a 6- membered carbocyclic group.
23. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered carbocyclic group and a 6- membered heterocyclic group.
24. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered heterocyclic group and a 6- membered heterocyclic group.
25. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered heterocyclic groups.
26. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of a 5-membered group and a 6-membered group sharing a heteroatom.
27. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 5-membered groups sharing a heteroatom.
28. The compound according to claim 20, wherein the bicyclic heterocyclic group is a bicyclic heterocyclic group consisting of two 6-membered groups sharing a heteroatom.
29. The compound according to claim 1 , wherein A represents a bond and B represents d-e-alkyl, which Ci_6-alkyl is substituted one time with dimethylamino.
30. The compound according to claim 29, 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 dimethylamino.
31 . The compound according to claim 30, wherein B represents methyl, ethyl, propyl or isopropyl, which methyl, ethyl, propyl or isopropyl is substituted one time with dimethylamino.
32. The compound according to claim 1 , wherein B represents Ci.6-alkyl, which Ci-6- alkyl is substituted one or more substituents selected from the group consisting of hydroxy, fluoro, trifluoromethyl, cyano, dimethylamino and methylsulfinyl.
33. The compound according to claim 1 , wherein B represents C2-4-alkenyl, which C2-4- alkenyl may optionally be substituted with methylsulfinyl.
34. The compound according to claim 1 , wherein B represents unsubstituted methyl or unsubstituted ethyl.
35. The compound according to claim 1 , wherein A represents a bond and B represents methyl, which methyl 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 with one or more substituents selected from the group consisting C1-2-alkyl, halo, halo-Ci_2-alkyl, Ci.4-alkoxy, Ci-4- alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
36. The compound according to claim 35, wherein R' represents hydroxy.
37. The compound according to claim 1 , wherein B represents hydroxy.
38. The compound according to claim 1 , wherein A represents a bond and B represents -(C=0)R", where R" represents hydroxy, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, 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.
39. The compound according to claim 38, wherein R" represents methyl, ethyl, trifluoromethyl or trifluoroethyl.
40. The compound according to claim 1 , wherein A represents a bond and B represents -(C=0)R", where R" represents hydrogen, methoxy, -COOH,
dimethylamino, cyclopropyl or morpholinyl.
41 . The compound according to claim 1 , wherein A represents a bond and B represents -(C=0)R", where R" represents Ci-4-alkyl, which is substituted with one or more substituents selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxymethyl, methoxyethyl, acetyl, cyano, ethoxycarbonyl, dimethylamino, N-[3-(dimethylamino)propyl]-N'ethylcarbamimidoyl, methylsulfinyl, methylsulfanyl, methylsulfonyl, methoxyethoxyethyl, dimethylaminoethyl and methylsulfanylethyl.
42. The compound according to claim 1 , wherein A represents a bond and B represents -(C=0)R", where R" represents Ci-4-alkoxy, which is substituted with one or more substituents selected from the group consisting of methoxy, dimethylamino, methylsulfinyl and methylsulfanyl.
43. The compound according to claim 1 , wherein A represents a bond and B represents -(C=0)R", where R" represents oxy group, which is substituted with one substituent selected from the group consisting of N-[3-(dimethylamino)propyl]- N'ethylcarbamimidoyl, methoxyethoxyethyl, dimethylaminoethyl and
methylsulfanylethyl.
44. The compound according to claim 1 , wherein A represents a bond and B
represents -(C=0)R", where R" represents amine, which is subsistuted one or more times with a substituent which is independently selected from the group consisting of hydroxy, methyl, methoxy, hydroxyethyl, methoxyethyl, acetyl, (dimethylamino)ethyl and methylsulfonyl.
45. The compound according to claim 1 , wherein A represents a bond and B
represents -(C=S)R"', where R'" represents methylamino or dimethylamino.
46. The compound according to claim 1 , wherein A represents a bond and B
represents -C(CH3)=N-R"", where R"" represents hydroxy or methoxy.
47. The compound according to claim 1 , wherein A represents a bond and B
represents sulfamoyi, dimethylsulfamoyl, sulfinyl or sulfonyl, which sulfamoyi, sulfonyl or sulfonyl may optionally be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxyethyl, dimethylaminoethyl, cyclopropyl, ethenyl, 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, halo, halo-Ci_2-alkyl, Ci-4-alkoxy, Ci-4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
48. The compound according to claim 47, wherein B represents sulfamoyi, which may optionally be substituted with methyl or which may optionally be substituted with methyl and methoxyethyl.
49. The compound according to claim 47, wherein A represents a bond and B represents sulfinyl or sulfonyl, which sulfonyl or sulfinyl is substituted with one substituent selected from the group consisting of methyl, methoxyethyl,
dimethylaminoethyl and ethenyl.
50. The compound according to claim 1 , wherein A represents a bond and B
represents bromo or cyano.
51 . The compound according to claim 1 , 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 Ci-2-alkyl, halo, halo-Ci_2-alkyl, Ci-4-alkoxy, Ci-4- alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
52. The compound according to claim 51 , 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, 1 ,2,5-oxadiazolyl, and tetrazolyl.
53. The compound according to claim 52, wherein the 5-membered monocyclic heterocyclic group is selected from the group consisting of pyrrolidinyl, pyrazolyl, imidazolyl, 3H-pyrazolyl, oxolanyl, 1 ,2-oxazolyl, 1 ,3-oxazolyl, 1 ,2-thiazolyl, 1 ,3-thiazolyl and tetrazolyl.
54. The compound according to claim 51 , 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.
55. The compound according to claim 54, wherein the 6-membered monocyclic heterocyclic group is selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, and morpholinyl.
56. The compound according to claim 54, wherein the 6-membered monocyclic heterocyclic group represents piperazinyl substituted with butyloxycarbonyl or morpholinyl.
57. The compound according to claim 1 , wherein A represents O and B represents d. 6-alkyl, C2-4-alkenyl, or C2-4-alkynyl, where the Ci_6-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.
58. The compound according to claim 57, wherein the Ci_6-alkyl is methyl.
59. The compound according to claim 57, 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.
60. The compound according to claim 57, 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.
61 . The compound according to any of claims 57-60, wherein B is selected from the group consisting of methyl, isopropyl, isobutyl, isopentyl, 1 - butenyl, 2-butenyl, 1 -, butynyl and 2-butynyl.
62. The compound according to claim 1 , wherein A represents O and B represents d. 6-alkyl, which Ci_6-alkyl is substituted one time with cyano.
63. The compound according to claim 62, wherein B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
64. The compound according to claim 62, wherein B is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl.
65. The compound according to any of claims 62-64, wherein B is substituted with cyclopropyl in addition to the cyano substituent.
66. The compound according to any of claims 62-64, 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.
67. The compound according to any of claims 62-64, wherein B represents
cyanomethyl.
68. The compound according to claim 1 , wherein A represents O and B represents Ci- 6-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.
69. The compound according to claim 68, wherein B represents propyl or butyl substituted with hydroxy.
70. The compound according to claim 68, 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, 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.
71 . The compound according to claim 68, 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.
72. The compound according to claim 68, 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.
73. The compound according to claim 1 , 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.
74. The compound of claim 73, 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.
75. The compound according to claim 73, wherein B represents ethyl or 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 hydroxy or an alkoxy group, preferably a methoxy group.
76. The compound according to claim 73, 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.
77. The compound according to claim 73, wherein B preferably represents butyl substituted with dimethylamino and hydroxy.
78. The compound according to claim 1 , wherein A represents O and B represents d. 6-alkyl, which Ci_6-alkyl is substituted with -(C=0)R', where R' represents C1-4-alkyl, halo-Ci-4-alkyl, hydroxy, -NH2, methylamino or dimethylamino.
79. The compound according to claim 78, 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.
80. The compound according to claim 78, wherein B represents isopropyl, which isopropyl is substituted one time with -(C=0)R', where R' represents hydroxy, -NH2, or dimethylamino.
81 . The compound according to claim 78, wherein B represents methyl, ethyl, propyl or isopropyl and R' represents methyl, trifluoromethyl, hydroxy, -NH2, methylamino or dimethylamino.
82. The compound according to claim 78, wherein B represents methyl or isopropyl and R' represents hydroxy, methyl, trifluoromethyl or dimethylamino.
83. The compound according to claim 1 , wherein A represents O and B represents methyl, which methyl has been substituted one time with -(C=0)R', where R' represents phenyl, which phenyl has been substituted one or two times with halo.
84. The compound according to claim 83, wherein phenyl is substituted two times with fluoro so as to form a difluorophenyl group.
85. The compound according to claim 1 , wherein A represents O and B represents Ci- 6-alkyl, which Ci_6-alkyl is substituted with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl, methylsulfanyl and methylsulfonyl.
86. The compound according to claim 85, 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, methylsulfanyl and methylsulfonyl.
87. The compound according to claim 85, wherein B represents ethyl or isopropyl, which isopropyl is substituted one time with a substituent selected from the group consisting of sulfamoyl, dimethylsulfamoyl, methylsulfanyl and methylsulfonyl.
88. The compound according to claim 1 , wherein A represents O and B represents d. 6-alkyl, which C1-6-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, halo, 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, halo, halo-Ci_2-alkyl, Ci-4-alkoxy, Ci-4- alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
89. The compound according to claim 88, 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.
90. The compound according to claim 1 , wherein A represents O and B represents - (C=0)R", where R" represents C1-4-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.
91 . The compound according to claim 90, wherein R" represents methyl, ethyl, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, dimethylamino, or a 5- or 6- membered monocyclic heterocyclic group.
92. The compound according to claim 90, wherein R" is selected from the group consisting of methyl, ethoxy, dimethylamino, pyrrolidinyl and morpholinyl.
93. The compound according to claim 1 , wherein A represents O and B represents sulfamoyl, dimethylsulfamoyl, sulfinyl or sulfonyl, which 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 C1-2-alkyl, halo, halo- Ci_2-alkyl, Ci.4-alkoxy, Ci.4-alkoxycarbonyl, COOH, cyano, -NH2, methylamino and dimethylamino.
94. The compound according to claim 93, wherein B represents sulfamoyl,
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, preferably two methyl groups.
95. The compound according to claim 1 , 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.
96. The compound according to claim 95, 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.
97. The compound according to claim 95, 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.
98. The compound according to claim 95, 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.
99. The compound according to claim 95, wherein the 6-membered monocyclic heterocyclic groups may be selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl.
100. The compound according to claim 99, wherein pyridinyl, pyrimidinyl, and pyrazinyl is substituted with one substituent selected from the group consisting of methyl, methoxy, methoxycarbonyl, -COOH, cyano and dimethylamino.
101 . The compound according to claim 1 , wherein B represent methyl or ethyl, which may optionally be substituted with one substituent selected from the group consisting of hydroxy, methoxy, fluoro and chloro.
102. The compound according to claim 1 , 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).
103. The compound according to claim 1 , 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.
104. The compound according to claim 103, wherein R" represents methyl, ethyl, propyl, tertiary butyl, methoxy, ethoxy, propoxy, butoxy, dimethylamino, or a 5- or 6- membered monocyclic heterocyclic group.
105. The compound according to claim 103, wherein R" represents methyl, butoxy or dimethylamino.
106. The compound according to claim 1 , wherein 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, 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.
107. The compound according to claim 106, wherein R' represents methylsulfonyl.
108. The compound according to any of the preceding claims, wherein X2 represents Ci-18-alkyl, C2-i8-alkenyl, or C2-i8-alkynyl, which Ci_18-alkyl, C2-i8-alkenyl, or C2-i8-alkynyl may optionally be substituted as indicated in claim 1 , or X2 represents -0-Xa, -(C=0)-0- Xb, -(C=0)-Xc or -NXdXe, where Xa, Xb, Xc, Xd, and Xe is as defined in claim 1 , or X2 represents -(C=0)-0-CH2-CH2-NXi Xj2, -S-X\ -(C=S)-N(CH3)-Xm or -(C=S)-N-Xn, where Xj\ Xj2, Xk, Xm, Xn and is as defined in claim 1 .
109. The compound according to claim 108, wherein X2 represents -0-Xa, -(C=0)-0- Xb, -(C=0)-Xc or -NXdXe, where Xa, Xb, Xc, Xd, and Xe is as defined in claim 1 .
1 10. The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb is as defined in claim 1 .
1 1 1 . The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb represents a linear or branched Ci-i8-alkyl, more preferred a linear or branched Ci_6- alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl or tertiary pentyl, even more preferred a linear or branched C3.6-alkyl, which C3.6-alkyl may optionally be substituted with one substituent selected from the group consisting hydroxy, chloro, methoxy, ethoxy, trifluoromethoxy, oxo-methyl, NH2, methylamino, dimethylamino, cyano, phenyl, methylphenyl, chlorophenyl, or a 5- or a 6-membered monocyclic heterocyclic group.
1 12. The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb, represents a linear or branched C2-i8-alkenyl, more preferred a linear or branched C2-8-alkenyl, even more preferred a linear or branched C3-6-alkenyl, which C3-6-alkenyl may optionally be substituted with hydroxy.
1 13. The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb, represents a linear or branched C2.i8-alkynyl, more preferred a linear or branched C2-8-alkynyl, even more preferred a linear or branched C3.8-alkynyl, which C3.6-alkynyl may optionally be substituted with hydroxy.
1 14. The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb, represents C3.6-cycloalkyl, more preferred cyclopropyl or cyclobutyl.
1 15. The compound according to claim 108, wherein X2 represents -(C=0)-0-Xb, where Xb, represents a 5-membered monocyclic heterocyclic group, more preferred piperazinyl or tetrahydrofuranyl.
1 16. The compound according to claim 108, wherein X2 represents -(C=0)-Xc, where Xc represents hydrogen.
1 17. The compound according to claim 108, wherein X2 represents -(C=0)-Xc, where Xc represents Ci.6-alkyl, which d-e-alkyl may be substituted with one or more substituents selected from the group consisting of chloro, hydroxy, dimethylamino, (methoxyethyl)(methyl) amino, and [(dimethylamino)ethyl](methyl)amino.
1 18. The compound according to claim 108, wherein X2 represents -(C=0)-Xc, where Xc represents a 5- or 6-membered monocyclic heterocyclic group.
1 19. The compound according to claim 1 18, wherein X2 represents -(C=0)-Xc, where Xc represents a 5- or 6-membered monocyclic heterocyclic group selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl and optionally substituted with one or more substituents selected from the group consisting of Ci-6- alkyl,-(C=0)-0-C1 -6-alkyl and halo.
120. The compound according to claim 108, wherein X2 represents -(C=0)-NXe Xe2, where Xe and Xe2 independently of each other represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, methoxy, dimethylamino, phenyl and a 5- or 6-membered monocyclic heterocyclic group.
121 . The compound according to claim 120, wherein X2 represents -(C=0)-NXe Xe2, where Xe and Xe2 independently of each other represent hydrogen, methyl or ethyl, which methyl or ethyl is substituted with phenyl or a 5- or 6-membered monocyclic heterocyclic group, preferably pyridinyl.
122. The compound according to claim 108, wherein X2 represents -(C=0)-NH-S02-Xf, where Xf represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl or phenyl, which methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl or phenyl may optionally be substituted withCi_4-alkyl, Ci-4-alkoxy or Ci-6-alkylamino.
123. The compound according to claim 108, wherein X2 represents -(C=0)-NH-S02-Xf, where Xf represents methyl or ethyl, which methyl or ethyl is substituted with -O- methyl-phenyl, -O-ethyl-phenyl, phenyl, methylphenyl or a 5- or 6-membered monocyclic heterocyclic group, preferably pyridinyl.
124. The compound according to claim 108, wherein X2 represents -(C=0)-NH-S02-Xf, where Xf represents phenyl, which may be substituted with methyl.
125. The compound according to claim 108, wherein X2 represents -(C=0)-0-CH2-
CH2-NXi Xj2, where NXj and Xj2 independently of each other each represents methyl or ethyl, which methyl or ethyl may be substituted with one or two substituents selected from the group consisting of methoxycarbonyl, dimethylamino, carbamoyl, phenyl, cyanophenyl, and a 5- or 6-membered monocyclic heterocyclic group, preferably pyridinyl or indolyl.
126. The compound according to claim 108, wherein X2 represents-S-Xk, where Xk represents methyl, ethyl or propyl, which methyl, ethyl or propyl may optionally be substituted with dimethylamino.
127. The compound according to claim 108, wherein X2 represents -(C=S)-N(CH3)-Xm, where Xm represents methyl, ethyl or propyl, which methyl, ethyl or propyl may optionally be substituted with dimethylamino.
128. The compound according to claim 108, wherein X2 represents -(C=S)-N-Xn, where Xn represents amino, methylamino or dimethylamino, preferably amino.
129. The compound according to any of the preceding claims, wherein X3 represents hydrogen, d_4-alkyl, C2_4-alkenyl, C2_4-alkynyl, or -O-X9, -S-Xh or -NXi Xi2, where X9, Xh, X'1 , and X'2, are as defined in claim 1 .
130. The compound according to claim 129, wherein X3 represents hydrogen, Ci-4- alkyl, more preferred hydrogen or methyl.
131 . The compound according to claim 129, wherein X3 represents hydrogen.
132. The compound according to claim 129, wherein X3 represents -O-X9, where X9 represents -(CH2)n-CH3, or -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4.
133. The compound according to claim 129, wherein X3 represents -O-X9 ,
where X9 represents -(CH2)n-COOH, where n is 0, 1 , 2, 3 or 4, in which the -(CH2)n may be linear or branched.
134. The compound according to any of the preceding claims, wherein X4 and X5 represents independently of each other hydrogen, C1-4-alkyl, halo-Ci_4-alkyl, C3-6- cycloalkyl, halo, nitro, -NH2, or cyano.
135. The compound according to claim 134, wherein X4 and X5 independently of each other is selected from the group consisting of hydrogen, Ci-4-alkyl, and C3-6-cycloalkyl.
136. The compound according to claim 134, wherein X4 and X5 both represents hydrogen.
137. The compound according to claim 134, wherein X4 represents hydrogen and X5 is selected from the group consisting of Ci-4-alkyl, and C3-6-cycloalkyl.
138. The compound according to claim 134, wherein X5 represents hydrogen and X4 is selected from the group consisting of Ci-4-alkyl, and C3-6-cycloalkyl.
139. The compound according to any of the preceding claims, wherein the compound is selected from the group consisting of:
methyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate,
[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]acetic acid,
propyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate, butyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 2-methyl-3-[(methylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate,
cyclopropyl 3-(sulfamoyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
benzyl 3-[(dimethylamino)methyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-[cyano(cyclopropyl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -cyanobutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -cyano-2-methylpropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-(1 -cyanopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-[1 -(dimethylamino)propan-2-yl]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)propyl]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(acetyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(2-oxopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-morpholinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-piperidinylethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(2-hydroxyethoxy)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(2-ethoxyethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(acetylamino)pyrido[1 ,2-a]indole-10-carboxylate,
3-methyl-phenylmethyl 3-[(dimethylcarbamoyl)amino]pyrido[1 ,2-a]indole-10- carboxylate,
(2Z)-pent-2-en-1 -yl 3-[(methylsulfonyl)amino]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(4-t-butyloxycarbonylpiperazyl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(morpholin-4-yl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -cyanoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(1 -cyanopropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(1 -cyanobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[2-(dimethylamino)-2-oxoethoxy]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[4-(dimethylamino)-4-oxobutan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(4-amino-4-oxobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, 3- {[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid, propyl 3-{[1 -(methylsulfonyl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, butyl 3-{[2-(methylsulfonyl)propan-1 -yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, propyl 3-[(1 -sulfamoylpropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[1 -(dimethylsulfamoyl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[4-amino-1 -(dimethylamino)-4-oxobutan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
4- (dimethylamino)-3-{[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid, methyl 3-{[1 -cyano-3-(dimethylamino)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
ethyl 3-{[1 -(dimethylamino)-4-hydroxybutan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[1 -(dimethylamino)-4-oxopentan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, propyl 3-{[1 -(dimethylamino)-4-oxo-5,5,5-trifluoropentan-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate,
propyl 3-[(4-amino-4-oxobutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
3-{[10-(butoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}butanoic acid,
pentyl 3-[(1 -cyanopropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(4-hydroxybutan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(4-oxopentan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-[(5,5,5-trifluoro-4-oxopentan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(3-cyanopropoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(ethoxycarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(benzyloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-cyanobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2,6-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2,5-difluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(6-chloropyridin-3-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-methylprop-2-en-1 -yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
propan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2- methylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, tert-butyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
pentyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- methylbutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2,2-dimethylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -chloropropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- chloroethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- chloropropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, cyclopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
(2Z)-hex-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3Z)-hex-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2Z)-pent-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, cyclobutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
(2E)-hex-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3E)-hex-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2E)-pent-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (3E)-pent-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, (2Z)-but-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 3-methylbut-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, benzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
4- methylbenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 3-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 4-chlorobenzyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-oxopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-phenylethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -phenylethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 1 -phenylpropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-phenylpropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, pent-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hex-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, pent-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hex-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, hept-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
oct-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
but-3-yn-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(1 -phenylethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylbut-3-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-hydroxybut-3-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(pyrrolidin-1 -ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
2-cyanoethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-hydroxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-ethoxyethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-(trifluoromethoxy)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- hydroxybut-3-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-amino-3-hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- hydroxypropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- hydroxybutyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3-cyanopropyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
tetrahydrofuran-3-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
1 -methoxypropan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}acetic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}propanoic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}butanoic acid, 3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}-2- methylpropanoic acid,
3-{[3-(cyanomethoxy)-10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-2-yl]oxy}-2-methylbutanoic acid,
ethyl 3-(cyanomethoxy)-7-methylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-ethylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-(propan-2-yl)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-7-cyclopropylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-methylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-ethylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)-6-(propan-2-yl)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(cyanomethoxy)-6-cyclopropylpyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(pyridin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(6-methylpyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[2-(dimethylamino)pyrimidin-4-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(pyrimidin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-methoxypyrimidin-4-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(pyrazin-2-yloxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-cyanopyrazin-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[5-(methoxycarbonyl)pyrazin-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, 5-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}pyrazine-2-carboxylic acid, ethyl 3-[2-(3,4-difluorophenyl)-2-oxoethoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(1 ,3-dimethyl-1 H-pyrazol-5-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(2-methyl-1 ,3-thiazol-4-yl)methoxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-(3-methylbutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(cyclopropylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(4-cyanobutoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[1 -methoxy-1 -oxo-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(piperazin-1 -yl)methanone,
ethyl 3-[(methylsulfonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-{[(3,5-dimethyl-1 ,2-oxazol-4-yl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate,
3-methoxy-N-[2-(pyridin-3-yl)ethyl]pyrido[1 ,2-a]indole-10-carboxamide,
N-benzyl-3-methoxypyrido[1 ,2-a]indole-10-carboxamide,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(morpholin-4-yl)methanone,
t-butyl-4-[(3-methoxypyrido[1 ,2-a]indol-10-yl)carbonyl]piperazine-1 -carboxylate, (3-methoxypyrido[1 ,2-a]indol-10-yl)(piperidin-1 -yl)methanone,
3-methoxy-N,N-dimethylpyrido[1 ,2-a]indole-10-carboxamide,
N-butyl-3-methoxypyrido[1 ,2-a]indole-10-carboxamide,
(3-methoxypyrido[1 ,2-a]indol-10-yl)(pyrrolidin-1 -yl)methanone,
3-(cyanomethoxy)-N-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(ethylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(propylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-(butylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide, 3-(cyanomethoxy)-N-[(4-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-(cyanomethoxy)-N-[(3-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, N-(benzylsulfonyl)-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide,
3-(cyanomethoxy)-N-[(4-methylbenzyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-(cyanomethoxy)-N-[(pyridin-3-ylmethyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, 3-acetyl-N-(methylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(ethylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(propylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(butylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(4-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(3-methylphenyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-(benzylsulfonyl)pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(4-methylbenzyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[(pyridin-3-ylmethyl)sulfonyl]pyrido[1 ,2-a]indole-10-carboxamide, ethyl 3-[(3-acetaminobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-methylsulfonylaminobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-{[(2,4-dimethyl-1 ,3-thiazol-5-yl)sulfonyl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, prop-2-en-1 -yl 3-[(dimethylcarbamoyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, prop-2-en-1 -yl 3-[(morpholin-4-ylcarbonyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate, 2-{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}-3-(pyrrolidin-1 -yl)propanoic acid ethyl 3-{[1 -hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10- carboxylate,
ethyl 3-{[1 -(methanesulfonyloxy)-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole- 10-carboxylate,
ethyl 3-{[1 -cyano-3-(pyrrolidin-1 -yl)propan-2-yl]oxy}pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(tert-butoxycarbonyl)amino]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate,
prop-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
prop-2-yn-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
cyanomethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2-methylprop-2-en-1 -yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(1 -hydroxypropan-2-yl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
10-(methoxycarbonyl)pyrido[1 ,2-a]indole-3-carboxylic acid,
methyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(morpholin-4-yl)carbonyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(methylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(trifluoromethane)sulfonyloxy]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(dimethylcarbamoyl)oxy]-1 -hydroxypyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10-carboxylate,
3-N-[3-(dimethylamino)propyl]-N'-ethylcarbamimidoyl 10-methyl pyrido[1 ,2-a]indole- 3,10-dicarboxylate,
methyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-methanesulfinylpyrido[1 ,2-a]indole-10-carboxylate,
3,10-dimethyl pyrido[1 ,2-a]indole-3,10-dicarboxylate,
methyl 3-methanesulfonylpyrido[1 ,2-a]indole-10-carboxylate,
3-(cyanomethoxy)-N-(2-methoxyethyl)pyrido[1 ,2-a]indole-10-carboxamide,
N-benzyl-3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxamide,
3-(dimethylamino)propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-(pyrrolidin-1 -yl)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
2- (morpholin-4-yl)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- (cyanomethoxy)-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxamide, 2-[benzyl(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-[(carbamoylmethyl)(methyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate,
2-[methyl(pyridin-3-ylmethyl)amino]ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10- carboxylate,
2-{methyl[(1 -methyl-1 H-indol-3-yl)methyl]amino}ethyl 3-(cyanomethoxy)pyrido[1 ,2- a]indole-10-carboxylate,
1 -(dimethylamino)propan-2-yl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-{[(3-cyanophenyl)methyl](methyl)amino}ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole- 10-carboxylate,
2- (dimethylamino)propyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, 2-(methylamino)ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
3- N,10-N-bis[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-3,10-dicarboxamide, 2-(dimethylamino)ethyl 3-[(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
methyl 2-[(2-{[3-(cyanomethoxy)pyrido[1 ,2-a]indol-10- yl]carbonyloxy}ethyl)(methyl)amino]acetate, [2-({3-acetylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl][2-
(dimethylamino)ethyl]dimethylazanium,
2-({10-acetylpyrido[1 ,2-a]indol-3-yl}oxy)acetonitrile,
2-(dimethylamino)ethyl 3-(3-cyanopropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3-methoxypropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-[3-(dimethylamino)propanoyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(4-methoxybutanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-[4-(dimethylamino)butanoyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethyl](methyl)carbamoyl}pyrido[1 ,2- a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[(2-hydroxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
3,10-bis[2-(dimethylamino)ethyl] pyrido[1 ,2-a]indole-3,10-dicarboxylate,
10-[2-(dimethylamino)ethyl] 3-(2-methoxyethyl) pyrido[1 ,2-a]indole-3,10-dicarboxylate, 10-[2-(dimethylamino)ethyl] 3-(2-methanesulfinylethyl) pyrido[1 ,2-a]indole-3,10- dicarboxylate,
2-(dimethylamino)ethyl 3-methanesulfinylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[2-(methylsulfanyl)ethoxy]pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3-cyano-1 -hydroxypropyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-cyanopyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-[(1 -methyl-1 H-imidazol-2-yl)carbonyl]pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(1 -methyl-1 H-imidazol-2-yl)pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(hydroxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(methoxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-methylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(1 H-1 ,2,3,4-tetrazol-5-yl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(2,2,2-trifluoro-1 -hydroxyethyl)pyrido[1 ,2-a]indole-10- carboxylate,
2-(dimethylamino)ethyl 3-(dimethylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(3,3,3-trifluoropropanoyl)pyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-cyclopropanecarbonylpyrido[1 ,2-a]indole-10-carboxylate, 10-[2-(dimethylamino)ethyl] 3-[2-(methylsulfanyl)ethyl] pyrido[1 ,2-a]indole-3,10- dicarboxylate,
10-{[2-(dimethylamino)ethoxy]carbonyl}pyrido[1 ,2-a]indole-3-carboxylic acid,
2-(dimethylamino)ethyl 3-(methylsulfanyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-bromopyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-[(2-methoxyethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate, [2-({3-methanesulfonylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl]dimethylamine oxide, [2-({3-methanesulfinylpyrido[1 ,2-a]indol-10-yl}carbonyloxy)ethyl]dimethylamine oxide, 2-(dimethylamino)ethyl 3-{[2-(dimethylamino)ethyl]carbamoyl}pyrido[1 ,2-a]indole-10- carboxylate,
10-[2-(dimethylamino)ethyl] 3-[2-(2-methoxyethoxy)ethyl] pyrido[1 ,2-a]indole-3,10- dicarboxylate,
methyl 3-(2-cyanoacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[2-(dimethylamino)-1 -hydroxyethyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(3-ethoxy-3-oxopropanoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-formylpyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(difluoromethyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(2-methanesulfinylacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethane)sulfonyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-{[2-(dimethylamino)ethane]sulfonyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(trifluoroacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(dimethylcarbamoyl)carbonyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(dimethylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethyl)(methyl)sulfamoyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(2,2,2-trifluoro-1 -hydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-propanoylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-ethylpyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-ethenylpyrido[1 ,2-a]indole-10-carboxylate, 2-(dimethylamino)ethyl 3-(1 ,2-dihydroxyethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(2-methoxyethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(ethenesulfonyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(acetylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-methoxyethane)sulfinyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(2-chloroethyl)sulfanyl]pyrido[1 ,2-a]indole-10-carboxylate,
2-[10-(methoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]-2-oxoacetic acid,
methyl 3-[methoxy(methyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-{[methoxy(methyl)carbamoyl]carbonyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-{[2-(dimethylamino)ethane]sulfinyl}pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[(2-chloroethane)sulfinyl]pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(1 -hydroxy-2-methanesulfinylethyl)pyrido[1 ,2-a]indole-10-carboxylate,
2- (dimethylamino)ethyl 3-(difluoromethyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-sulfamoylpyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-[(E)-2-methanesulfinylethenyl]pyrido[1 ,2-a]indole-10-carboxylate,
3- [2-(dimethylamino)ethyl] 10-methyl pyrido[1 ,2-a]indole-3,10-dicarboxylate, 10-methyl 3-[2-(methylsulfanyl)ethyl] pyrido[1 ,2-a]indole-3,10-dicarboxylate, methyl 3-(2-hydroxyacetyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methylsulfamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
methyl 3-(methoxycarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate,
2-(dimethylamino)ethyl 3-(dimethylcarbamothioyl)pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-[2-(morpholin-4-yl)acetyl]pyrido[1 ,2-a]indole-10-carboxylate,
2- (dimethylamino)ethyl 3-[methoxy(methyl)carbamoyl]pyrido[1 ,2-a]indole-10- carboxylate,
methyl 3-[methoxy(2-methoxyethyl)carbamoyl]pyrido[1 ,2-a]indole-10-carboxylate, methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate,
3- (cyanomethoxy)-N-methanesulfonylpyrido[1 ,2-a]indole-10-carboxamide,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-(dimethylamino)ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-[(2-methoxyethyl)(methyl)amino]ethan-1 -one, 1 -(10-{[2-(dimethylamino)ethyl]sulfanyl}pyrido[1 ,2-a]indol-3-yl)ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-5-(dimethylamino)pentan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-3-(dimethylamino)propan-1 -one,
3-acetylpyrido[1 ,2-a]indole-10-carbaldehyde,
methyl 3-acetylpyrido[1 ,2-a]indole-10-carboxylate, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-chloroethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-2-{[2-(dimethylamino)ethyl](methyl)amino}ethan-1 - one,
2- {[2-(dimethylamino)ethyl](methyl)amino}ethyl 3-acetylpyrido[1 ,2-a]indole-10- carboxylate,
3- acetyl-N-[2-(dimethylamino)ethyl]-N-methylpyrido[1 ,2-a]indole-10-carbothioamide, 3-acetyl-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carbothioamide,
3-acetyl-N-[2-(dimethylamino)ethyl]pyrido[1 ,2-a]indole-10-carboxamide,
3-acetyl-N-[2-(dimethylamino)ethyl]-N-methylpyrido[1 ,2-a]indole-10-carboxamide, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}propan-1 -one,
2- [(2-methoxyethyl)(methyl)amino]-1 -{3-[1 -(methoxyimino)ethyl]pyrido[1 ,2-a]indol-10- yl}ethan-1 -one,
1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}-4-hydroxybutan-1 -one,
3- hydroxypyrido[1 ,2-a]indole-10-carboximidamide,
1 -{3-[(1 -(hydroxyimino)ethyl]pyrido[1 ,2-a]indol-10-yl}-2-[(2- methoxyethyl)(methyl)amino]ethan-1 -one,
2-(dimethylamino)-1 -{3-[1 -(hydroxyimino)ethyl]pyrido[1 ,2-a]indol-10-yl}ethan-1 -one, 1 -{3-acetylpyrido[1 ,2-a]indol-10-yl}ethan-1 -one
methyl 3-(methanesulfonylcarbamoyl)pyrido[1 ,2-a]indole-10-carboxylate, and
N-methanesulfonylpyrido[1 ,2-a]indole-3-carboxamide.
140. The compound according to any of the preceding claims and a compound selected from the group consisting of: ethyl 3-[(3-chlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-amino-2-oxoethoxy)pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-chloro-6-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
{[10-(ethoxycarbonyl)pyrido[1 ,2-a]indol-3-yl]oxy}acetic acid,
ethyl 3-[(2,6-dichlorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(2-ethoxy-2-oxoethoxy)]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(3-chloro-5-trifluoromethyl-pyridine-2-yl)oxy] pyrido[1 ,2-a]indole-10-carboxylate, ethyl 3-[(3-trifluoromethyl-benzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-methylbenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-[(4-fluorobenzyl)oxy]pyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-(cyanomethoxy)pyrido[1 ,2-a]indole-10-carboxylate, ethyl 2-hydroxy-3-phenylmethoxypyrido[1 ,2-a]indole-10-carboxylate,
ethyl 3-methoxypyrido[1 ,2-a]indole-10-carboxylate, and
ethyl 3-hydroxypyrido[1 ,2-a]indole-10-carboxylate, for the treatment of a HDME dependent disease.
141 . The compound according to claim 140, wherein said compound is for the treatment of cancer.
142. The compound according to claim 140, wherein said compound is for the treatment of squamous cell carcinomas.
143. The compound according to claim 140, wherein said compound is for the treatment of a tumour in the brain.
144. The compound according to claim 140, wherein said compound is for the treatment of breast cancer.
145. The compound according to claim 140, wherein said compound is for the treatment of prostate cancer.
146. The compound according to any of claims 140-145, wherein the compound is administered in combination with one or more further substances.
147. The compound according to claim 146, wherein the one or more further active substances are one or more medications for treatment of cancer.
148. The compound according to claim 146, wherein the one or more further active substances are anti-neoplastic agents.
149. The compound according to claim 146, wherein the one or more further active substances are selected from the group consisting of immune stimulating agents, and cancer vaccines.
150. Use of a compound according to claim 140 for the preparation of a medicament for treatment of a HDME dependent disease.
151 . The use according to claim 150, wherein the HDME dependent disease is as defined in any of claims 141 -145.
152. A pharmaceutical composition comprising at least one compound of Formula (I) according to any of claims 1 -139 and optionally one or more pharmaceutically acceptable excipients, diluents or carriers.
153. The pharmaceutical composition according to claim 152, further comprising one or more further active substances.
154. The pharmaceutical composition according to claim 152, wherein the one or more further active substance are as defined in any of claims 147-149.
155. 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 claim 140 to a subject in need of such treatment.
156. The method according to claim 155, wherein the compound is administered in combination with one or more further active substances as defined in claims 147-149.
157. The method according to claim 155, wherein the HDME dependent disorder is as defined in any of claims 141 -145.
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