WO2004063156A1 - Novel indole derivates as fabp-4 inhibitors - Google Patents

Novel indole derivates as fabp-4 inhibitors Download PDF

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Publication number
WO2004063156A1
WO2004063156A1 PCT/SE2004/000005 SE2004000005W WO2004063156A1 WO 2004063156 A1 WO2004063156 A1 WO 2004063156A1 SE 2004000005 W SE2004000005 W SE 2004000005W WO 2004063156 A1 WO2004063156 A1 WO 2004063156A1
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Prior art keywords
carbazole
tetrahydro
carboxylic acid
methyl
indole
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PCT/SE2004/000005
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French (fr)
Inventor
Tjeerd Barf
Kristin Hammer
Marguerite Luthman
Fredrik Lehmann
Rune Ringom
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Biovitrum Ab
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Priority claimed from SE0300014A external-priority patent/SE0300014D0/en
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2004063156A1 publication Critical patent/WO2004063156A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • Novel i-adole derivates as JJ ⁇ BP-4 iahibitors.
  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4.
  • FAs Fatty acids
  • FABPs are important fuels and cellular regulators that bind to cytoplasmic fatty acid binding proteins (FABPs) in a non-covalent, reversible manner.
  • FABPs are expressed in a tissue-specific manner and the major site of expression of FABP-4 (adipocyte FABP, adipocyte lipid-binding protein, and mouse homologue aP2) is in adipose tissue and in macrophages.
  • the relative expression of the two known FABPs in adipose tissue, FABP-4 and FABP5 differs in adipose tissue of lean as compared to obese individuals, the ratio of FABP- 4/5 being lower in the former (Fisher, R. M. et al, IntemationalJoumal of Obesity 2002, 26, 1379-1385). It is also possible that FABP-4 inhibition with a small molecule causes upregulation of FABP5. Thus it can be anticipated that inhibition of FABP-4 results effectively in a decrease of the active protein' ratio of FABP-4/5, and thus a lowering of body weight.
  • Apolipoprotein E (ApoE)-deficient mice also deficient for FABP-4 showed protection from atherosclerosis.
  • FABP-4-deficient macrophages exhibit reduced inflammatory cytokine production and lowered cholesterol ester loading when exposed to modified lipoproteins (Makowski, L. et al, Nature Medicine 2001, 7, 699-705). FABP-4 inhibition could therefore treat atherosclerosis or prevent the progression of this disease.
  • the Plasminogen activator inhibitor- 1 (PAI-1) gene promoter contains a response element for unsaturated fatty acids. PAI-1 is increased in type 2 diabetic patients and a risk factor for chronic heart disease (Kohler, H. P.; Grant, P. J. The New England Journal of Medicine 2000, 342, 1792-1801). In the presence of FABP-4 inhibitors, Ac-LDL activated macrophages secreted significantly lower amounts of PAl-1, thus FABP-4 inhibitors have a potential of treating cardiovascular disorders such as chronic heart disease (Unpublished data).
  • the compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit FABP-4 and may therefore be of use in the treating disorders such type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, or chronic heart disease.
  • One object of the present invention is a compound of formula (I)
  • R° and R 1 is -COOH, -COOMe, -CH 2 OH, -CONHOH, -NH-SO 2 -C ⁇ -C 6 -alkyl, or -NHSO 2 Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran
  • R 6 -H, -CH 3 , -COCH 3 or is absent;
  • a and B are each a carbon atom not substituted by oxo, -CH or a phenyl group;
  • X -CH, N or is absent;
  • Y is CH 2 or is absent;
  • R 6 -H, -CH 3 , or -COCH 3 ;
  • R 7 and R 8 are each independently -H, -COCF 3 , or -SO 2 -C ⁇ -C 6 -alkyl;
  • R and R are each independently -H, C ⁇ -C 6 -alkyl or Ci-C ⁇ -hydroxyalkyl or R 12 and R 13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, mo ⁇ holinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II), wherein
  • R 9 and R 10 are both -H or both -CI or at least one of R 9 and R 10 is selected from -CH 3 , -OCH 3 , -F, -Br, -CF 3 , -CO 2 H, -NO 2 , -NH 2 , -NHC(O)-C ⁇ -C 6 -alkyl, -CN, -CONH 2 , -OH, -SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , -OCF 3 , -SCF 3 , or -OPh;
  • R 6 -H, -CH 3 , or -COCH 3 ;
  • a and B are each a carbon atom not substituted by oxo;
  • Y is absent
  • R and.R are each independently -H, C ⁇ -C 6 -alkyl or C ⁇ -C 6 -hydroxyalkyl or R 12 and R 13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, mo ⁇ holinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II), wherein
  • R 6 -H, -CH 3 or -COCH 3 ;
  • a and B are each a carbon atom not substituted by oxo;
  • X -CH orN;
  • Y is absent
  • R 7 and R 8 are each independently -H, -COCF 3 , or -SO 2 -C ⁇ -C 6 -alkyl.
  • a and B are each a carbon atom not substituted by oxo;
  • X is -CH orN;
  • a and B are each a -CH or a phenyl group
  • R 6 is absent; Y is absent; then said compound has the formula (IN).
  • R°, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, and B are as defined above.
  • one of R° and R 1 is -COOH, -COOMe, -CH 2 OH, -CONHOH, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R 1 is -H or -CH ;
  • Ar is selected from phenyl, furan, pyridine, and pyrimidine;
  • R 9 and R 10 are each independently -H, -CH 3 , -OCH 3 , -F, -Br, -CI, -CF 3 , -CO H, -NO 2 ,
  • n 0, 1 or 2;
  • R 6 -H, -CH 3 , -COCH 3 or is absent;
  • a and B are each a carbon atom not substituted by oxo, -CH or a phenyl group
  • X CH, N or is absent
  • Y is CH 2 or is absent;
  • R 7 and R 8 are each independently -H, -COCF 3 , methanesulfonyl or are absent.
  • Ar is selected from phenyl, furan, pyridine, and pyrimidine and R 9 and R 10 are both -H or both -CI or at least one of R 9 and R 10 is selected from -CH 3 , -OCH 3 , -F, -Br, -CF 3 , -CO 2 H, -NO 2 , -NH 2 , -NHC(O)CH 3 , -CN, -CONH 2 , -OH, -SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , -OCF 3 , -SCF 3 , or -OPh;
  • R 6 -H, -CH 3 , or -COCH 3 ;
  • a and B are each a carbon atom not substituted by oxo;
  • Y is absent
  • R and R are each independently -H, -COCF 3 , or methanesulfonyl
  • R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, mo ⁇ holinyl and 3-hydroxypiperidinyl; or R 3 is a group of the formula (II), wherein Ar is selected from phenyl, furan, pyridine, and pyrimidine and R and R ° are both
  • R 9 and R 10 is selected from -CH 3 , -OCH 3 , -F, -Br, -CF 3 , -CO 2 H, -NO 2 , -NH 2 , -NHC(O)CH 3 , -CN, -CONH 2 , -OH, -SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , -OCF 3 , -SCF 3 , or -OPh;
  • R 6 -H, -CH 3 , or -COCH 3 ;
  • a and B are each a carbon atom not substituted by oxo;
  • X -CH orN;
  • Y is absent;
  • R 7 and R 8 are each independently -H, -COCF 3 , or methanesulfonyl;
  • R° and R 1 is -COOH, -COOMe, -CH 2 OH, -CONH 2 , -CONHOH, methanesulfonylamino or phenylsulfonylamino, provided that the other of R and R is -H or-CH 3 ;
  • R and R form together a heterocycle selected from pyrrolidinyl, mo ⁇ holinyl and 3- hydroxypiperidinyl; or R 3 is a group of the formula (II), wherein Ar is selected from phenyl, furan, pyridine, and pyrimidine; R 9 and R 10 are each independently selected from -H, -CH 3 , -OCH 3 , -F, -Br, -CI, -CF 3 , -CO 2 H, -NO 2 , -NH 2 , -NHC(O)CH 3 , -CN, -CONH 2 , -OH, -SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , -OCF 3 , -SCF 3 , or -OPh;
  • R 7 and R 8 are each independently -H, -COCF 3 , or methanesulfonyl.
  • the following compounds are especially preferred:
  • the invention also relates to a method of making a compound described herein, including those of any of the formulae herein.
  • the method includes taking a compound delineated in any of the examples herein (including Examples 1-26), and reacting it with one or more chemical reagents in one or more steps to produce a compound of any of the formulae described herein.
  • the method includes taking any one of the intermediate compounds described herein and reacting it with one or chemical reagents in one or more steps to produce a compound described herein.
  • Another object of the present invention is a compound of the formula (I)
  • R°and R 1 is -COOH, -COOMe, -CH 2 OH, -CONHOH, -NHSO 2 CF 3 , -NH-SO 2 -C ⁇ -C 6 -alkyl, tetrazole or -NHSO 2 Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzo
  • Ar is as defined above;
  • a and B are each a carbon atom, -CH or a phenyl group
  • X -CH, N or is absent
  • Y is CH 2 or is absent
  • R° is -COOH;
  • R 1 is -H;
  • R 2 is -H;
  • R 3 is benzyl;
  • n 0;
  • R 4 is -H;
  • R 5 is -H;
  • R 7 is -H;
  • a and B are each -CH;
  • Y is absent; and
  • R is -H; or
  • R° is -COOH;
  • R 1 is -H;
  • R 2 is -H;
  • R 4 is -H;
  • R 5 is -H;
  • R 7 is -H;
  • a and B are each -CH; Y is absent; and
  • R is -H; or
  • R° is -COOMe;
  • R 1 is -H;
  • R 2 is -H;
  • R 4 is -H;
  • R 5 is -H;
  • R 7 is -H;
  • a and B are each -CH; Y is absent; and
  • R 8 is -H; or
  • R 1 is -COOH; R .
  • R°, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, and n are as defined in claim 7.
  • R 6 is absent
  • R°, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, and B are as defined in claim 7. It is even more preferred that: one of R° and R 1 is -COOH, -COOMe, -CH 2 OH, -CONHOH, trifluoromethanesulfonylamino, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R 1 is -H or -CH 3 ;
  • R 12 and R 13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
  • R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, mo ⁇ holinyl and 3-hydroxypiperidinyl; or R 3 is a group of the formula (II), wherein
  • Ar is selected from phenyl, furan, pyridine, and pyrimidine;
  • R 6 -H, -CH 3 , -COCH 3 or is absent;
  • a and B are each a carbon atom, -CH or a phenyl group;
  • X CH, N or is absent; Y is CH or is absent;
  • R is absent and X is absent, then either:
  • R° is -COOH;
  • R 1 is -H;
  • R 2 is -H;
  • R 3 is benzyl;
  • R 4 is -H;
  • R 5 is -H;
  • R 7 is -H;
  • a and B are each -CH;
  • Y is absent; and
  • R 8 is -H; or
  • Another object of the present invention is the compound according to any one of claims 7 to 11 for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of claims 7 to 11 as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
  • Another object of the present invention is a pharmaceutical composition for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
  • the pharmaceutical composition further comprises an additional therapeutically active agent.
  • Another object of the present invention is a method for the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4, which comprises administering to a subject in need of such treatment (e.g., mammal, human, dog, cat, horse, cow, chicken, or pig) an effective amount of a compound according to any one of claims 7 to 11.
  • the aforementioned method includes co-administration with other therapeutic agents.
  • Such co-administration can be simultaneous or sequential, and can also be in a single (e.g., one pill, capsule, or injection) or multiple (e.g., more than one pill, capsule, or injection) dosing.
  • Another object of the present invention is a method for inhibiting FABP-4, which comprises administering to a subject in need of such treatment (e.g., mammal, human, dog, cat, horse, cow, chicken, or pig) an effective amount of a compound according to any one of claims 7 to 11.
  • a subject in need of such treatment e.g., mammal, human, dog, cat, horse, cow, chicken, or pig
  • Another object of the present invention is the use of a compound according to any one of claims 7 to 11 for the manufacture of a medicament for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
  • disorders mentioned above are type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
  • C ⁇ -C 6 -alkyl which may be straight or branched, is an alkyl group having 1-6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.
  • C ⁇ - 6 -alkyl all subgroups thereof are contemplated such as C ⁇ - 5 -alkyl, C ⁇ - 4 -alkyl, C ⁇ _ 3 -alkyl, C ⁇ - 2 -alkyl, C 2 - 6 -alkyl, C 2 .
  • Ci-C ⁇ -hydroxyalkyl which may be straight or branched, is an alkyl group having 1-6 carbon atoms and one or more hydroxy groups.
  • Exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl, hydroxy-tert-butyl, hydroxy-n-pentyl, and hydroxy-n- hexyl.
  • C ⁇ - 6 -hydroxyalkyl For parts of the range "C ⁇ - 6 -hydroxyalkyl" all subgroups thereof are contemplated such as C ⁇ -5-hydroxyalkyl, Ci ⁇ -hydroxyalkyl, C ⁇ - 3 -hydroxyalkyl, C ⁇ - 2 -hydroxyalkyl, C 2 - 6 - hydroxyalkyl, C 2 - 5 -hydroxyalkyl, C 2 - 4 -hydroxyalkyl, C . 3 -hydroxyalkyl, C 3 . 6 -hydroxyalkyl, C 4 -5-hydroxyalkyl, etc.
  • heterocycle refers to a nonaromatic 3-8 membered monocyclic, 8-12 membered bicyclic, or 11 - 14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, Se, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, Se or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent.
  • the compounds useful herein include the compounds of any of the formulae themselves, as well as their prodrugs, if applicable.
  • prodrug forms in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and tli).
  • ester prodrug groups found in the literature are the following substituents for R or R in the compound of formula (I): -COO(C ⁇ -C 6 -alkyl)
  • R x and R y are C ⁇ -C 6 -alkyl or form together with the nitrogen to which they are attached a heterocycle such as mo ⁇ holinyl (see Bundgaard, H.; Nielsen, N.M. J. Med. Chem. 1987, 30, 451-452)
  • N- oxides refers to one or more nitrogen atoms, when present in a compound, that are in N- oxide form, i.e., ⁇ O.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the pu ⁇ oses detailed herein (e.g., treating a disease).
  • abbreviations are meant that the letters (i.e., chemical group) respectively may have no meaning or are not present.
  • Y when Y is absent, this means that A may only be bonded to one or more of the indole ring, R 4 , R 5 , and X.
  • Y when Y is CH 2 , R 4 , R 5 , R 7 and R 8 is absent, this means that A may only be bonded to the indole ring, X, and Y.
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • organic and inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid
  • Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, ⁇ -methylglucamine, choline and the like.
  • Pharmaceutical compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula (I) as described herein above, dissolved or dispersed therein as an active, ingredient.
  • the therapeutic composition is not immunogenic when administered to a human patient for therapeutic pu ⁇ oses, unless that pu ⁇ ose is to induce an immune response.
  • compositions that contains active ingredients dissolved or dispersed therein are well understood in the art.
  • compositions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non- aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared.
  • the preparation can also be emulsified.
  • the active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.
  • Adjuvants may also be present in the composition.
  • liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
  • composition according to one of the preferred embodiments of the present invention comprising compounds comprising the formula (I), may include pharmaceutically acceptable salts of that component therein as set out above.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine
  • this invention covers a method of administering an effective amount of one or more compounds described in the formulae herein to a subject in need of treatment for a disease or disease symptom (e.g., type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, or chronic heart disease).
  • a disease or disease symptom e.g., type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, or chronic heart disease.
  • the method can also include the step of identifying that the subject is in need of treatment for a disease or disease symptom.
  • the identifying can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).
  • treating refers to administering an aforementioned compound to a subject with the pu ⁇ ose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a disease, the symptoms of the disease or the predisposition toward the disease.
  • An effective amount refers to an amount of a compound (including a salt, prodrug form or composition thereof) which confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Other routes which are known for the skilled person in the art are thinkable.
  • compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g.
  • Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g.
  • a pharmaceutical composition according to the present invention may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition.
  • a weight percent is a ratio by weight of total composition.
  • 0.1 weight percent is 0.1 grams of compound comprising the formula (I) per 100 grams of total composition.
  • a suitable daily oral dose for a mammal, preferably a human being, may vary widely depending on the condition of the patient.
  • a dose of compound comprising the formula (II) of about 0.1 to 300 mg/kg body weight may be appropriate.
  • compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier.
  • the compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
  • the compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in- vitro was studied using the following reagents and methods. As can be appreciated by the skilled artisan, the synthetic routes delineated herein are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock,
  • AIBN azoisobutyronitrile
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • DIBAH diisobutylaluminium hydride
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EtOAc ethyl acetate
  • GC-MS gas chromatography-mass spectrometry
  • HOBT 1-hydroxybenzotriazole hydrate
  • HPLC high performance liquid chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • MCPBA m-chloroperbenzoic acid
  • NBS N-bromosuccinimide
  • TBAF tetra-n-butylammonium fluoride
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Example 8 6-iodomethyl-2-methylsulfanylpyrimidin-4-ol 6-chloromethyl-2-methylsulfanylpyrimidin-4-ol (Example 7) (2.0 g, 10.5 mmol) and
  • Example 11 4-[i(tert-butyldimethylsilvDoxy
  • Example 12 2-cvano-4-[irtert-butyldimethylsilyl oxylmethvHpyridine
  • trimethylsilyl cyanide (2.49 g, 25.10 mmol)
  • dimethylcarbamoyl chloride (2.25 g, 20.89 mmol) was added which triggered an exothermic reaction turning the color brown after 10 min. Stirring continued at 60 °C for 18 h.
  • Citrazinic acid (10.35 g, 66.7 mmol) and tetraethylammonium chloride (11.05 g, 66.7 mmol) were suspended in phosphoroxychloride (20 mL, excess) and heated at 130 °C for 18 h and then at 145 °C for 2 h.
  • the reaction mixture was allowed to cool to RT and poured onto crushed ice (150 g).
  • Extraction of ethyl acetate (3 x 100 mL), drying of the combined organic layers (MgSO 4 ) and evaporation in vacuo gave 11.34 g (89 %) of a white solid.
  • BH 3 .DMS (1.0 mL, 10.66 mmol) was refluxed in THF (20 mL) for 30 min (formation of BH 3 .THF).
  • Example 17 (2.0 g, 10.66 mmol in 10 mL THF) was added dropwise, and then the reaction mixture was heated to reflux for 3 h. The solution was allowed to cool to ambient temperature, solid sodium carbonate (0.5 g) and water (5 mL). The resulting mixture was heated for a short while and poored in water (50 mL).
  • Example 19 4-(bromomethyl -2-chloro-6-methoxypyridine To a stirred icebath-cooled solution of triphenylphosphine (1.36 g, 5.19 mmol) in DCM (75 mL) was added bromine (0.83 g, 5.19 mmol) dropwise. Stirring of the resulting colorless solution was continued for 30 min after which time the ice-bath was removed.
  • Example 18 (0.75 g, 4.32 mmol) was added portion- wise and the reaction mixture was stirred for another 2 h. DCM (75 mL) was added and the organic phase was washed with water (100 mL) and brine (100 mL).
  • Example 20 4-nitro-5,6,7-8,9 0-hexahvdrocyclohepta[b]indole 2-nitrophenylhydrazine (5.0 g, 32.6 mmol) and cycloheptanone (3.7 g, 33.0 mmol) were refluxed in ethanol (100 mL) for 3 h. Evaporation in vacuo gave the hydrazone as a red crystalline solid. The hydrazone was taken up in cone. HC1 (90 mL) and refluxed for 3 h on an oil bath, causing a thick orange solid to separate. After cooling to RT, the reaction mixture was poored into water (200 L) and extracted by diethyl ether (3 x 100 mL).
  • Example 21 5-benzyl-4-nitro-5,6,7,8,9,10-hexahvdrocyclohep ' tarblindole
  • KOH powder 170 mg, 3.05 mmol
  • the orange solution was treated with benzyl bromide (145 ⁇ L, 1.22 mmol) turning the reaction mixture black and slowly back to orange again.
  • the reaction was quenched with water (20 mL) and the product was extracted with diethyl ether (3 x 30 mL). The combined organic layers were dried (Na 2 SO 4 ) and evaporated in vacuo.
  • Example 22 5-benzyl-5.6,7,8,9 0-hexahydrocycloheptarb1indol-4-amine
  • ethyl acetate 7 mL
  • tin dichloride hydrate 300 mg, 1.58 mmol
  • the resulting suspension was quenched with water (5 mL) and Na CO 3 (0.5 g, vigorous reaction!) and heated at 70 °C for 10 min.
  • Example 20 A stirred solution of Example 20 (150 mg, 0.65 mmol) in dry DMF (4 mL) was treated with sodium hydride (19 mg, 0.78 mmol) resulting in a dark red solution. 2- trifluoromethylbenzyl bromide (187 mg, 0.78 mmol) in dry DMF (2 mL) was added dropwise over a 5-min period. After stirring for 4 h, the clear solution showed 50% conversion (GC). A second portion of sodium hydride (19 mg, 0.78 mmol) and 2- trifluoromethylbenzyl bromide (187 mg, 0.78 mmol) was added and stirred continued for 18 h after which time the starting material and product composition was unchanged.
  • Example 23 A stirred solution of Example 23 (62 mg, 0.16 mmol) in ethanol (4 mL) was hydrogenated over Pd/C (10%, spatula) under 1 atm of hydrogen. After lh the mixture was filter over Celite and evaporated in vacuo, affording 54 mg (94% of a colorless oil.
  • Benzenesulfonylchloride (0.040 ml, 0.31 mmol) was added to a solution of 5-[2- (trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4-amine (Example 24) (0.055 g, 0.15 mmol) and triethylamine (0.042 ml, 0.31 mmol) in DCM (2 ml) and the reaction was stirred for 1 hour at RT and 50°C overnight. Water and DCM were added and the pH was adjusted to 3 with IN HCl. The organic phase was dried (MgSO ) and evaporated and the crude product was purified by flash chromatography 50 % hexane in DCM to 10 % hexane. Yield: 0.037 g (39 %). White solid.
  • Example 40 To a solution of Example 40 (75 mg, 0.25 mmol) in DCM (3 mL) at 0 °C was added HOBT (34 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol) and Et 3 N (70 ⁇ L, 0.5 mmol). After 5 min of stirring, O-benzylhydroxylamine hydrochloride (47 mg, 0.30 mmol) was added to the clear solution. Stirring continued for 18 h, washed with aqueous HCl (10%, 5 mL). Extraction of the aqueous phase with DCM (2 x 5 mL), drying (Na 2 SO 4 ) of the combined organic phases and evaporation to dryness gave 110 mg of a crude solid. Purification by flash column chromatography over silica gel eluting with a gradient n-hexane / DCM (1:1 v/v) to DCM gave two main products:
  • N-(benzyloxy)-9-benzyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxamide Yellow foam (33 mg, 32%), purity 70%.
  • 1H NMR (400 MHz, CDC1 3 ) ⁇ 1.83-1.95 (m, 4H) ) 2.64 (t, J 6.02 Hz, 2H) 2.75 (t,
  • Example 27 2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid
  • 2-hydrazinobenzoic acid, hydrochloride (40.0 g, 0.212 mol) and cyclohexanone (26 ml, 0.254 mol) in AcOH (500 ml) was refluxed for 3.5 h before the solvent was evaporated and water (200 ml) and EtOAc (1000 ml) was added.
  • Organic layer was extracted with IN NaOH and the combined aqueous layers acidified with 6 N HCl and extracted with EtOAc, organic layers dried (MgSO 4 ) and concentrated. Yield 34.88 g (76%); white solid.
  • Example 28 - methyl 2,3.4,9-tetrahydro-lH-carbazole-8-carboxylate 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (Example 27) (34.88 g, 0.162 mol) was refluxed in MeOH (600 ml) and cone. H 2 SO 4 (100 ml) for 3 h. Some MeOH was evaporated and water added and the aqueous layer extracted with Et 2 O. The combined organic layers were washed with sat. NaHCO 3 and dried (MgSO 4 ). Yield 34.90 g (94%); white solid.
  • Example 29 2,3,4.9-tetrahydro-lH-carbazole-7-carboxylic acid 3-hydrazinobenzoic acid (2.08 g, 13.67 mmol), cone. HCl (1.2 ml) and cyclohexanone (1.70 ml) was refluxed in AcOH (50 ml) for 3.5 h. Solvent evaporated and residue dissolved in water/EtOAc. Organic layer washed with water and dried (MgSO 4 ). Crude compound recryst. from EtOH. Yield: 494 mg (17%) white solid. Mp. 280 °C.
  • Example 32 methyl 2,3 -dimethyl- lH-indole-7-carboxylate 2,3-dimethyl-lH-indole-7-carboxylic acid (Example 31) (1.208 g, 6.38 mmol) was refluxed with cone. H 2 SO 4 (1 ml) in MeOH (10 ml) for 1.5 h. Most of MeOH evaporated and water and Et O added. The organic phase was washed with sat. NaHCO 3 , dried (MgSO 4 ) and evaporated. Yield 1.209 g (93%). Mp. 97-98 °C.
  • CDCI 3 CDCI 3
  • CDCI 3 CDCI 3
  • 106.99 11.51, 51.70, 106.99, 111.26, 118.16, 122.97, 123.41, 130.67, 131.97, 135.28, 168.16.
  • Example 34 methyl 5,6.7,8,9 0-hexahydrocyclohepta[b]indole-4-carboxylate .5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 33) (4.25 g, 18.53 mmol) was refluxed with methanol (100 ml) and cone. H 2 SO 4 (10 ml) for 2 h, when TLC indicated full conversion. Water and Et 2 O was added and the organic layer washed with sat. NaHCO 3 twice and dried (MgSO 4 ). Yield: 3.86 g (91%); yellow solid. Mp. 107 °C.
  • Example 36 6-Methyl-2,3.4.9-tetrahvdro-lH-carbazole-8-carboxylic acid 2-hydrazino-5-methylbenzoic acid hydrochloride (1.93 g, 9.544 mmol) and cyclohexanone (2.00 ml, 19.3 mmol) was heated at 130 °C in AcOH (20 ml) for 3 h. Solvent was evaporated. The product was purified by flash chromatography using 2% and 5% MeOH in DCM. Yield 1.09 g (50%); white solid. Mp. 151 °C.
  • Example 38 - methyl 3-methyl-2.3A9-tetrahvdro-lH-carbazole-8-carboxylate The compound was prepared using analogue procedure for Example 36 starting from hydrazinobenzoic acid hydrochloride and 4-methylcyclohexanone then esterified using the same procedure as for Example 37.
  • Example 39 methyl 9-benzyl-2.3.4,9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (480 mg, 8.55 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (413 mg, 1.810 mmol) in DMSO (5 ml) and the yellow solution stirred for 5 min. Benzyl bromide (500 ⁇ l, 3.59 mmol) was added and the mixture stirred for 10 min and quenched with sat. NH 4 C1 and extracted with Et 2 O.
  • the product was purified by flash chromatography using 2% and 5% EtOAc in hexanes.
  • Example 40 9-benzyl-2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (234 mg, 0.733 mmol) and KOH (188 mg, 3.35 mmol) was refluxed with EtOH (10 ml) and H 2 O (1 ml) for 3.5 h. Some EtOH evaporated and 2 N HCl (3 ml) added. White solid filtered and washed with water and dried under high vacuum. Yield 161 mg (72%) white solid. Mp. 207 °C. l H NMR (400 MHz, DMSO-d 6 ) 6 1.77-1.87 (m, 4 H), 2.63-2.69 (m, 4 H), 5.59 (s, 2
  • Example 42 9-f4-bromobenzyl)-2,3A9-tefrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 41) (327 mg, 0.820 mmol) and KOH (508 mg, 9.05 mmol) was refluxed in EtOH (20 ml) and H 2 O (2 ml) for 3 h. EtOH was evaporated and 2 N HCl and water added. The white solid precipitate was filtered, washed with water and dried under vaccum (50 °C). Yield 115 mg (37%); white solid. Mp. 181 °C. The filtrate was extracted with EtOAc and 186 mg (59%) more material was isolated.
  • Example 44 9-(4-methylbenzyl)-2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(4-methylbenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 43) (303 mg, 0.909 mmol) and KOH (208 mg, 3.71 mmol) was refluxed with EtOH (10 ml) and H O (10 ml) overnight. Most of EtOH evaporated and the solution acidified by addition of 2 N HCl and extraction with EtOAc. The combined organic layers were dried (MgSO 4 ) and evaporated. Yield 265 mg (91%); white solid. Mp. 156 °C.
  • Methyl 9-(3 -methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 47) (230 mg, 0.658 mmol) and KOH (483 mg, 8.608 mmol) in EtOH (20 ml) and H 2 O (2 ml) was refluxed for 3 h. The solution acidified with 2 N HCl and extracted with EtOAc. Organic layers were dried (MgSO 4 ) and evaporated. Collected crystals were washed with Et 2 O. Yield 140 mg (64%); white solid. Mp. 199-201 °C.
  • Example 54 9-( " 2-fluorobenzyl)-2,3,4.9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 53) (109 mg, 0.323 mmol) was hydrolyzed using KOH (0.40 g), H 2 O (2 ml) and EtOH (10 ml). The mixture was refluxed for 2 h. EtOH evaporated and 2 N HCl (6 ml) added. The precipitate filtered, washed with water and dried under vacuum. Yield 82 mg (79%); white solid. Mp. 198 °C.
  • Example 55 methyl 9-(3-fluorobenzylV2,3 A9-tetrahydro-lH-carbazole-8- carboxylate Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 3-fluorobenzyl bromide (428 ⁇ l, 3.489 mmol) was added. The mixture was quenched with sat. NH 4 C1 after 20 min and extracted with Et 2 O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 2-5% EtOAc in hexanes. Yield 502-mg (86%); colorless oil.
  • Example 56 9-(3-fluorobenzyl>2,3 A9-tet ⁇ hydro-lH-carbazole-8-carboxylic acid Methyl 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example
  • Methyl 9-(4-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (90 mg, 0.232 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h. Most of EtOH eavaporated, the solution acidicfied using 2 M HCl and precipitate filtered, washed with water and dried under vacuum. Yield 28 mg (33%); white solid. Mp. 146 °C.
  • Example 60 9-(3-(trifluoromethyl benzyl)-2,3A9-tetrahvdro-lH-carbazole-8- carboxylic acid Methyl 9-(3-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate
  • Example 59 (147 mg, 0.379 mmol) was hydrolyzed using KOH (0.4 g), EtOH (10 ml) and H 2 O (2 ml). The mixture was refluxed for 2 h. Most of EtOH was evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 90 mg (64%); white solid. Mp. 189-190 °C. 1H NMR (400 MHz, DMSO-d 6 ) ⁇ 1.78-1.86 (m, 4 H), 2.60-2.70 (m, 4 H), 5.66 (s, 2
  • Example 61 (140 mg, 0.394 mg) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 96 mg (72%); white solip. Mp. 173-174 °C. 1H NMR (400 MHz, DMSO-d 6 ) ⁇ 1.78-1.86 ( , 4 H), 2.61-2.69 (m, 4 H), 5.62 (s, 2
  • Methyl 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (243 mg, 0.684 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 188 mg (81 %);white solid. Mp. 201 °C.
  • Example 66 9-(4-fluorobenzyl -2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) was added powdered KOH (0.50 g, 8.91 mmol) and the yellow mixture stirred for 3 min before 4-fluoro-benzyl bromide (428 ⁇ l, 3.489 mmol) was added and the mixture stirred at ambient temperature for 5 min before quenched with sat. NH 4 C1 and extracted wtih Et 2 O.
  • Methyl 9-(3-cyanobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (190 mg, 0568 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and H 2 O (2 ml). The mixture was refluxed for 2 h, EtOH evaporated and 2 M HCl (6 ml) added. Precipitate filtered, washed with water and dried under vacuum. Yield: 80 mg (40%); white solid. Mp. 261 °C.
  • Example 69 methyl 9-butyl-2.3 A9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (357 mg, 6.36 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (359 mg, 1.565 mmol) in DMSO (3 ml) and the mixture stirred for 3 min at ambient temperature before 1-iodobutane (358 ⁇ l, 3.13 mmol) was added. The mixture was quenched with sat. NH C1 after 10 min stirring at ambient temperature and extracted with Et O.
  • Example 70 9-butyl-2.3 A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-butyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 69) (190 mg, 0.665 mmol) and KOH (0.5 g) was refluxed with EtOH (20 ml) and H 2 O (2 ml) for 3 h. Most of EtOH evaporated and solution made acidic using 2 N HCl and extracted with EtOAc. Yield 180 mg (100%); white solid. Mp. 121 °C.
  • Example 72 9-propyl-2,3A9-tefrahydro-lH-carbazole-8-carboxylic acid Methyl 9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 71) (340 mg, 1.252 mmol) and KOH (503 mg, 8.96 mmol) was refluxed in EtOH (20 ml) and H 2 O (2 ml) for 5 h. Most of EtOH evaporated and solution made acidic using 2 N HCl and the mixture extracted with EtOAc and the combined organic layers dried (MgSO 4 ) and evaporated. Yield 283 mg (88%); white solid. Mp. 159 °C.
  • Example 74 9-pentyl-2,3A9-tetrahvdro-lH-carbazole-8-carboxylic acid Methyl 9-pentyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 73) (212 mg, 0.708 mmol) was hydrolyzed using KOH (20 mg, 3.70 mmol) in refluxing EtOH/H 2 O (10 ml : 1ml) for 3.5 h. Most of EtOH evaporated and 2 M HCl added and the mixture extracted with EtOAc dried and evaporated. Yield 196 mg (97%).
  • Example 75 methyl 9-ethyl-2,3A9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (522 mg, 9.30 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (540 mg, 2.355 mmol) in DMSO (5 ml) and the yellow mixture was stirred for 5 min before ethyl iodide (470 ⁇ l, 5.83 mmol) was added and stirring continued for 10 min and the reaction quenced with sat. NH 4 C1 and extracted with Et O.
  • Methyl 9-ethyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (450 mg, 1.748 mmol) was hydrolyzed using KOH (0.80 g) in EtOH (20 ml) and H 2 O (2 ml). The mixture was refluxed for 3 h, most of solvent evaporated and 2 M HCl added. The white precipitate was filtered and washed with water and dried under vacuum. Yield 361 mg
  • Oxalyl chloride (0.040 ml, 0.45 mmol) was added to a solution of [8- (methoxycarbonyl)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]acetic acid (Example 78) (0.1 g, 0.35 mmol) in DCM followed by one drop of DMF. After 10 minutes the mixture was 5 evaporated and dissolved in DCM (1 ml) and used immediately.
  • Methyl 9-(2-morpholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate (Example 80) (0.1 g, 0.3 mmol) and 2 N NaOH (0.5 ml) was dissolved in MeOH '(4 ml) and heated at 45 °C overnight. After evaporation the residue was diluted with water and washed with diethyl ether (2x). 2 N HCl was added dropwise and the white crystals were filtered off and washed with water (2x) and dried (vacum). Yield 0.045 g. (47%). White solid.
  • Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (0.2 g, 0.87 mmol) was added to a suspension of KOH (0.244 g, 4.35 mmol) in DMSO and stirred for 5 minutes before N-(2-chloroacetyl)-diethylamine (0.26 g, 1.74 mmol) was added. The reaction was stirred for 2 minutes before 1 N HCl was added dropwise to pH was adjusted to 3. The mixture was partitioned between water and diethyl ether, washed with water (3x), dried (MgSO 4 ) and evaporated.
  • Example 83 9-r2-(diethylaminoV2-oxoethyl " l-2,3 A9-tetrahydro-lH-carbazole-8- carboxylic acid Same experimental as for Example 82. Recrystallization from DCM/hexane. Yield
  • Oxalyl chloride (0.040 ml, 0.45 mmol) was added to a solution of [8- (methoxycarbonyl)-l, 2,3, 4-tetrahydro-9H-carbazol-9-yl] acetic acid (Example 78) (0.1 g, 0.35 mmol) in DCM followed by one drop of DMF. After 10 minutes the mixture was evaporated and dissolved in DCM (1 ml) and splitted in 2 parts. 2 N NH 3 (0.2 ml) was added and the reaction was stirred for lh and evaporated. The crude product hydrolyzed for 2 days in 0.2 N NaOH (1 ml) in MeOH (1 ml) at 50 °C. After evaporation, 1 N HCl was added and the white solid precipitate was collected and recrystallized from DCM/hexane. Yield 0.016 g (34%). White solid.
  • Example 87 9-.2-r(2-hydroxyethyl)amino1-2-oxoethyl)-2.3,4.9-tetrahvdro-lH- carbazole-8-carboxylic acid Experimental: See Example 86. Yield 20 mg (18%).
  • Example 88 methyl 9-benzyl-2,3 A9-tetrahvdro-lH-carbazole-7-carboxylate Powdered KOH (244 mg, 4.35 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-7-carboxylate (Example 30) (257 mg, 1.120 mmol) in DMSO (5 ml) and the yellow solution stirred for 3 min before addition of benzyl bromide (260 ⁇ l, 2.25 mmol) and stirring was continued for 5 min and mixture quenched with sat. NH 4 C1 and extracted with Et 2 O. The product was purified by flash chromatography using hexanes/Et 2 O 9:1. Yield 219 mg (61%); white solid. Mp. 165 °C.
  • Methyl 5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 90) (135 mg, 0.473 mmol) was hydrolyzed using KOH (0.4 g) in EtOH (10 ml) and H 2 O (2 ml). The mixture was refluxed for 2 h before most of EtOH was evaporated, solution acidified using 2 M HCl, aqueous phase extracted with EtOAc, combined organic layers dried (MgSO 4 ) and evaporated. Yield 108 mg (84%); white solid. Mp. 121-122 °C.
  • Example 94 5-benzyl-5.6.7.8,9 0-hexahydrocyclohepta[b]indole-4-carboxylic acid Methyl 5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 93) (211 mg, 0.632 mmol) was refluxed with KOH (0.40 g), EtOH (10 ml) and H 2 O (2 ml) for 3 h. Most of EtOH was evaporated and 2 N HCl added. The acidic solution was extracted with EtOAc and dried (MgSO 4 ). The residue was purified by flash chromatography using 2% MeOH in DCM. Yield 104 mg (51%); white solid. Mp. 140-141 °C.
  • Example 96 -5-[3-faminocarbonyDbenzyl]-5.6.7.8.9.10-hexahydrocyclo- hepta[b]indole-4-carboxylate Methyl 5-(3-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate
  • Example 95 (1.788 g, 4.988 mmol) was hydrolyzed using KOH (2.80 g, 49.9 mmol), EtOH (100 ml) and H 2 O (20 ml). The mixture was refluxed for 3 h and acidified with 6 M HCl, precipitate filtered and washed with water. HPLC revealed two products. The collected material was refluxed in EtOH (20 ml) and filtered, and dried. Yield 1.271 g (70%); white solid (99% pure, HPLC). Mp. 271 °C.
  • Example 34 (534 mg, 2.194 mmol) in dry DMSO (15 ml) was added powdered KOH (0.59 g, 10.5 mmol) at RT and the mixture stirred for 5 min before 5-bromovaleronitrile (384 ⁇ l, 3.298 mmol) was added and the mixture stirred for 15 min more before quenched with sat. NH 4 C1 and extracted with diethyl ether. The wanted product isolated by flash chromatography using 15% and 20% EtOAc in hexanes. Yield: 306 mg (43%); yellow oil. Recovered starting material: 70 mg (13%).
  • Example 98 5-(5-amino-5-oxopentylV5.6 .8.9,10-hexahvdrocycloheptarb]indole-4- carboxylic acid and Example 99 - 5-(4-cyanobutyl)-5, 6,7,8.9, 10-hexahydrocyclohepta[b]mdole-4- carboxylic acid
  • Example 34 A stirred solution of Example 34 (200 mg, 0.82 mmol) in wet DMSO (5 mL) was treated with KOH powder (230 mg, 4.10 mmol). After 5 min the dark brown solution was treated with 2-cyanobenzyl bromide (322 mg, 1.64 mmol). Stirring continued for 10 min and then the reaction mixture was poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 30 mL), the combined organic layers dried (Na 2 SO 4 ) and evaporated in vacuo.
  • Example 102 A stirred solution of Example 102 (75 mg, 0.22 mmol) in ethanol (5 mL) and water (1 mL) was treated with KOH powder (122 mg, 2.2 mmol) and refluxed for 2 h in a seal-capped tube. After cooling, the ethanol was evaporated and the residue was acidified with aqueous HCl (10%) until pH 3. The precipitate that formed was collected on a filter and recrystallized from acetonitrile (hot filtration!). This afforded 11 mg (14%>) of the title compound as a yellow solid: Mp 154-155 °C.
  • Example 104 methyl 4-oxo-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxylate DDQ (9.91 g, 43.64 mmol) in THF (50 ml) was added dropwise to a solution of methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (5.05 g, 21.82 mmol) in
  • Example 105 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 104) (95 mg,
  • Methyl 4-hydroxyimino-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 106) (97 mg, 0.376 mmol) was refluxed with KOH (0.33 g, 5.88 mmol) in EtOH (5 ml) and H 2 O (1 ml) for 1.5 h. EtOH was evaporated and the solution made acidic using 2 M HCl. The precipitated material was washed with water and dried under vacuum. Yield 50 mg (54%); white solid. Mp. 206 °C.
  • Example 109 methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate DDQ (2.77 g, 12.23 mmol) in THF (20 ml) was added dropwise to a solution of methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (1.95 g, 6.114 mmol) in THF (50 ml) and H 2 O (8 ml) at 0 °C and the mixture stirred for 3 h. K 2 CO 3 (8 g) was added and mixture stirred for 2 h. Water and DCM were added.
  • Example 110 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 109) (98 mg, 0.294 mmol) was hydrolyzed using KOH (0.20 g), EtOH (5 ml) and water (1 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, solution made acidic using
  • Example 112 9-benzyl-4-(T ⁇ ydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid Methyl 9-benzyl-5-hydroxyimino-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate
  • Example 111 (100 mg, 0.287 mmol) was hydrolyzed using KOH (0.20 g), EtOH (5 ml) and water (1 ml). Most of EtOH evaporated and solution made acidic using 2 M HCl. The precipitate was filtered, washed with water and dried under vacuum. Yield 59 mg (61%); white solid. Mp. 221 °C. 1HNMR (400 MHz, DMSO-d 6 ) 6 1.91-1.94 (m, 2 H), 2.68-2.70 (m, 2 H), 2.80-2.82
  • Example 114 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
  • Methyl 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 113) (131 mg, 0.459 mmol) was hydrolyzed using KOH (0.2 g), EtOH (5 ml) and water (1 ml). The mixture was refluxed for 2.5 h. Most of EtOH evaporated and the solution acidified using 2 M HCl. The precipitate was filtered and washed with water and dried under vacuum. Yield 85 mg (69%); white solid. Mp. 256 °C.
  • Methyl 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 113) (933 mg, 3.27 mmol), hydroxylamine hydrochloride (908 mg, 13.07 mmol) and sodium acetate (10.80 g, 13.07 mmol) was refluxed in EtOH (30 ml) and water (15 ml) for 4 h. Most of EtOH evaporated and water (20 ml) was added. Precipitate was filtered, washed with water and dried under vacuum. Yield 808 mg (82%); white solid. Mp. 164-165 °C.
  • CDCI3 ⁇ 10.93, 21.65, 23.12, 24.80, 25.73, 43.01, 46.51, 52.55, 115.63, 116.65, 121.19,
  • DMSO-d 6 6 10.66, 21.20, 22.83, 24.33, 24.71, 42.51, 45.72, 114.44, 118.75, 120.89, 123.77, 123.83, 128.04, 131.48, 150.87, 169.57, 196.95. MS: 286 (M+l).
  • Example 123 9-benzyl-l-oxo-2.3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (0.10 g; 0.31 mmol) in pyridine (0.5 ml) was added dropwise to TFA-anhydride (0.5 ml) at 0°C and stirred at 25°C for 20 hours. Water was added carefully and the solid was filtered off and taken up in DCM. The organic phase was washed with water (2x), dried (MgSO ) and evaporated. Yield of intermediate 0.098 g.
  • the intermediate was dissolved in ethanol (1 ml) and IN NaOH (1 ml) was added and the mixture was stirred at 20°C overnight.
  • the mixture was evaporated and partitioned between water and DCM and acidified to pH 5 with IN HCl, extracted with DCM (2x) and the combined organic phases were dried (MgSO 4 ) and evaporated.
  • the crude product was purified by flash chromatography 2.5 % MeOH in DCM to 5 % MeOH in DCM. Yield: 0.030 g (31%). Yellow solid.
  • Example 135 5-(pyridin-2-ylmethylV5.6.7,8,9,10-hexahydrocyclohepta[b1indole-4- carboxylic acid
  • ethanol 5 mL
  • water 1 mL
  • KOH powder 150 mg, 2.70 mmol
  • refluxed for 2 h in a seal- capped tube After cooling, the ethanol was evaporated, water (2 mL) was added, and the clear solution was neutralized with aqueous HCl (10%).
  • the precipitate that formed was collected on a filter, washed with water and dried in a vacuum oven at 40 °C. This afforded 80 mg (93%) of the title compound as an off-white solid: Mp °C.
  • Example 137 5-[r6-chloropyridin-3-yl ' )methyl]-5.6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylic acid
  • the preparation of the title compound was performed according to the synthetis described for Example 135, using Example 136 (100 mg, 0.26 mmol) and KOH (145 mg, 2.60 mmol) in ethanol (5 mL) and water (1 mL). After workup the crude material was purified by flash column chromatography on silica gel eluting with DCM / methanol (9:1 v/v) giving 48 mg (52%) of a yellow solid.
  • 1HNMR 400 MHz, CDC1 3
  • 6 1.73-1.83 (m, 4H) 1.87-1.93 (m, 2H) 2.79-2.81 (m,
  • Example 34 200 mg, 0.82 mmol.
  • Example 14 (242 mg, 1.23 mmol) was added resulting in a deep blue reaction mixture.
  • Stirring continued for 10 more min and was then poured into water (50 mL) and acidified with aqueous HCl (10 mL).until pH 3.
  • the aqueous phase was extracted with ethyl acetate (3 x 20 mL), the combined organic layers dried (Na SO 4 ) and evaporated in vacuo leaving 0.5 g of a crude brown oil.
  • Example 138 To a solution of Example 138 (70 mg, 0.20 mmol) in ethanol (2 mL) and water (0.5 mL) was added KOH (56 mg, 1.00 mmol). The resulting reaction mixture was refluxed in a seal-capped tube for 1 h. The ethanol was evaporated and water (2 mL) was added. The aqueous phase was acidified with HCl (10%) until pH 3. The solid that precipitated was collected on a filter and consisted of product and the di-carboxylic acid derivative (1 :2 H NMR, HPLC). The title compound was isolated through preparative RP-HPLC (5-20% acetonitrile in water, 0.1% AcOH) followed by freeze drying. This procedure gave 7 mg (10%) of an off-white solid.
  • Example 140 methyl 5-[(6-cvanopyridin-2-vDmethyll-5.6,7.8.9.10- hexahydrocyclohepta[b1indole-4-carboxylate
  • Example 34 To a solution of Example 34 (550 mg, 2.26 mmol) in dry DMSO (20 mL) was added
  • Example 140 To a solution of Example 140 (200 mg, 0.56 mmol) in ethanol (5 mL) and water (1 mL) was added KOH (157 mg, 2.80 mmol). The resulting reaction mixture was refluxed in a seal-capped tube for 30 min. The ethanol was evaporated and water (2 mL) was added. The aqueous phase was acidified with HCl (10%) until pH 3. The solid that precipitated was collected on a filter and recrystallized from ethanol, affording 25 mg (12%) of the title compound as white crystals: Mp 259.1-259.2 °C.
  • Example 34 To a solution of Example 34 (300 mg, 1.23 mmol) in dry DMSO (25 mL) was added KOH (173 mg, 3.08 mmol). After stirring for 5 min (clear yellow solution) 4-(bromomethyl)- 2-chloro-6-methoxypyridine (Example 19) (350 mg, 1.48 mmol) in DMSO (2 mL) was added dropwise over a 5-min period. The resulting darkbrown solution was stirred for 10 min, and then poured in saturated aqueous NH 4 C1 (50 mL) giving a suspension. The aqueous phase was extracted with diethyl ether (3 x 30 mL) and the combined organic phases were dried (MgSO ), and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica gel eluting with DCM/isohexane (1/1 v/v) to give 120 mg (24%) of a yellow oil.
  • Example 143 ( " 9-be ⁇ zyl-2,3 A9-tefrahydro-lH-carbazol-8-vDmethanol DIBAH 20 % w in toluene (2.07 ml, 2.5 mmol) was added dropwise to a solution of methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (0.2 g, 0.62 mmol) in toluene (2 ml) at 0°C and the mixture was stirred overnight at RT. Water was carefully added dropwise and pH was adjusted to 5 with IN HCl. The mixture was diluted with THF and filtered through a short plug of silica.
  • Methansulfonylchloride (0.02 lg, 0.18 mmol) was added to a solution of 5-benzyl- 5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4-amine (Example 22) (0.054 g, 0.15 mmol) and triethylamine (0.026 ml, 0.18 mmol) in DCM (1 ml) and the reaction was stirred for 2 hours and diluted with water and DCM. The organic phase was dried (MgSO 4 ) and evaporated. The crude product was purified by flash chromatography 5 % EtOAc in hexane. Yield: 0.025 g (32 %). Grey solid.
  • Example 22 A stirred solution of Example 22 (63 mg, 0.22 mmol) in DCM (5 mL) was cooled to 0 °C and triethylamine (38 ⁇ L, 0.24 mmol) was added followed by dropwise treatment of triflic anhydride (39 ⁇ L, 0.24 mmol). The resulting black solution was stirred for 3 h at RT, and then washed with aqueous HCl (5%, 5 mL). The acidic aqueous phase was extracted with DCM (2 x 5 mL) and the combined DCM layers were dried (Na 2 SO ) and evaporated to dryness.
  • Example 24 The preparation of the title compound was performed according to the synthetis described for Example 148, using Example 24 (54 mg, 151 ⁇ mol), triethylamine (26 ⁇ L, 166 ⁇ mol) and triflic anhydride (27 ⁇ L, 166 ⁇ mol). After the purification step the product was recrystallized from DCM / isohexanes to give 18 mg (24%) grayish crystals: Mp 166.8-166.9 °C.
  • Example 150 9-benzyl-N-hvdroxy-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxamide
  • methanol 3 mL
  • Pd/C 10%, spatula
  • the mixture was filter over Celite and evaporated in vacuo, affording 22 mg of a white solid, with HPLC purity of 86%.
  • Example 151 4-benzyl-l,2,3,4-tetrahvdrocvclopentarb]indole-5-carboxylic acid 2-hydrazinobezoic acid hydrochloride (3.44 g, 18.23 mmol) and cyclopentanone (2.0 ml, 21.88 mmol) was refluxed in EtOH (30 ml) and cone. H 2 SO 4 (3 ml) for 4 h. Cone. H 2 SO 4 (2 ml) was added and the mixture refluxed for 30 min more. Water and Et O was added and organic phase washed with 1 M NaOH. The product was purified by flash chromatography. Yield 0.59 g (14%, -70% pure).
  • Example 152 - l-benzyl-2,3-dimethyl-lH-indole-7-carboxylic acid Powdered KOH (600 mg, 10.69 mmol) was added to solution of methyl 2,3-dimethyl- lH-indole-7-carboxylate (Example 32) (601 mg, 2.957 mmol) in DMSO (5 ml) and the bright yellow mixture was stirred for 5 min. and benzyl bromide (880 ⁇ l, 7.39 mmol) was added and stirring continues for 10 min before quenced with sat. NH 4 C1 and extracted with Et O. TLC and GC revealed a mixture of compounds.
  • Example 28 was dissolved in DMF (20 ml) and NaH (48 mg, 1.2 mmol, -60 % in oil) was added. After two min, 2-chlorobenzyl bromide (250 mg, 1.22 mmol) was added slowly and the reaction stirred at ambient temperature for 20 minutes. Water (40 ml) and ethyl acetate (40 ml) was added and the phases separated. The aqueous phase was extracted with ethyl acetate (40 ml) and diethyl eter (40 ml), the combined organic phases was washed with brine and evaporated.
  • the crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) and dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1 : 1 : 1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) to afford the title product. Yield 14 mg (4 %); colorless oil.
  • Example 158 9-C3-bromobenzyl -2.3A9-tetrahvdro-lH-carbazole-8-carboxylic acid Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (220 mg, 0.96 mmol) was dissolved in DMF (20 ml) and NaH (48 mg, 1.2 mmol, -60 % in oil) was added. After two min, 3-bromobenzyl chloride (250 mg, 1.22 mmol) was added slowly and the reaction stirred at ambient temperature for 20 minutes. Water (40 ml) and ethyl acetate (40 ml) was added and the phases separated.
  • the aqueous phase was extracted with ethyl acetate (40 ml) and diethyl eter (40 ml), the combined organic phases was washed with brine and evaporated.
  • the crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) and dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1 : 1 : 1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated.
  • Examples 160-199 were prepared in the following manner:
  • the starting material 120 mg was dissolved in DMSO and KOH (5 equivalents) was added. After 5 min, the electrophile (1.2 eq.) was added and the reaction was stirred at ambient temperature for 15 min. The reaction was quenched with sat. NH 4 C1 and extracted twice with ethyl acetate. After evaporation of the solvent, the crude mixture was dissolved in THF: MeOH: LiOH (2M, 20 mL) 1:1:1 and stirred over night. The reaction mixture was acidified and extracted twice with ethyl acetate. The combined organic phases were evaporated and the crude product purified by preparative HPLC giving the title compounds.
  • Example 34 was reacted with 2-fluorobenzylbromide. Yield: 20 mg (12%).
  • Example 34 was reacted with 3-fluorobenzylbromide. Yield: 20 mg (12%).
  • Example 162 5-(4-fluorobenzylV5,6,7,8,9,10-hexahvdrocyclohepta[b]indole-4- carboxylic acid
  • Example 34 was reacted with 4-fluorobenzylbromide. Yield: 20 mg (12%).
  • Example 163 5-(2,4-difluorobenzyl -5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid
  • Example 34 was reacted with 2,4-difluorobenzylbromide. Yield: 20 mg (11%).
  • Example 34 was reacted with 2,5-difluorobenzylbromide. Yield: 10 mg (6%).
  • Example 34 was reacted with 3-(trifluoromethyl)benzylbromide. Yield: 10 mg (5%).
  • Example 34 was reacted with 4-(trifluoromethyl)benzylbromide. Yield: 10 mg (5%).
  • Example 30 was reacted with 2,6-difluorobenzylbromide. Yield: 130 mg (73%). Mp. 282-284°C.
  • Example 168 9-(2-fluorobenzyl -2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid
  • Example 30 was reacted with 2-fluorobenzylbromide. Yield: 3 mg (2%). MS: 324 (M+l).
  • Example 169 9-(3-fluorobenzyl)-2,3,4,9-tetrahvdro-lH-carbazole-7-carboxylic acid
  • Example 30 was reacted with 3-fluorobenzylbromide. Yield: 3 mg (2%). !
  • Example 170 9-(4-fluorobenzyl)-2,3,4,9-tetrahvdro-lH-carbazole-7-carboxylic acid
  • Example 30 was reacted with 4-fluorobenzylbromide. Yield: 3 mg (2%). MS: 324 (M+l).
  • Example 171 9-(2.5-difluorobenzyl)-2.3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid
  • Example 30 was reacted with 2,5-difluorobenzylbromide. Yield: 100 mg (59%). Mp. 234°C. 1H NMR (400 MHz, DMSO-d6) 1.75 - 1.85 (m, 4H), 2.65 - 2.73 (m, 4H), 5.46 (s,
  • Example 30 was reacted with 2,3-difluorobenzylbromide. Yield: 2 mg (1%).
  • Example 30 was reacted with 2,4-difluorobenzylbromide. Yield: 2 mg (1%).
  • Example 174 9-r2-( " trifluoromethyl)benzyll-2,3,4,9-tetrahvdro-lH-carbazole-7- carboxylic acid
  • Example 30 was reacted with 2-(trifluoromethyl)benzylbromide. Yield: 10 mg (7%).
  • Example 30 was reacted with 4-(trifluoromethyl)benzylbromide. Yield: 10 mg (7%).
  • Example 176 5-(2,3-difluorobenzylV5.6,7.8,9.10-hexahvdrocvclohepta[blindole-4- carboxylic acid
  • Example 34 was reacted with 2,3-difluorobenzylbromide. Yield: 10 mg (6%).
  • Example 28 was reacted with 2,6-difluorobenzylbromide. Yield: 11 mg (7%>).
  • Example 28 was reacted with 2,5-difluorobenzylbromide. Yield: 40 mg (27%).
  • ⁇ NMR (400 MHz, DMSO-d6) 1.65 - 1.68 (m, 2H), 1.70 - 1.74 (m, 2H), 2.49 (t,
  • Example 28 was reacted with 3-methylbenzylbromide. Yield: 50 mg (31%).
  • Example 159 was reacted with 3-fluorobenzylbromide. Yield: 50 mg (30%).
  • Example 181 5-(4-fluorobenzylV5,6,7,8,9,10-hexahvdrocyclohepta[b]indole-3- carboxylic acid
  • Example 159 was reacted with 4-fluorobenzylbromide. Yield: 50 mg (30%).
  • Example 28 was reacted with 3-(trifluoromethoxy)benzylbromide. Yield: 20 mg (10%).
  • Example 159 was reacted with 2-fluorobenzylbromide. Yield: 10 mg (6%).
  • Example 28 was reacted with 3-fluoro-5-(trifluoromethyl)benzylbromide. Yield: 20 mg (10%).
  • Example 28 was reacted with 2-fluoro-6-(trifluoromethyl)benzylbromide. Yield: 20 mg (10%).
  • Example 28 was reacted with 2-methylbenzylbromide. Yield: 20 mg (13%).
  • Example 28 was reacted with 2,5-dichlorobenzylbromide. Yield: 20 mg (11%).
  • Example 188 9-(3,4-difluorobenzyl -2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
  • Example 28 was reacted with 3,4-difluorobenzylbromide. Yield: 20 mg (12%).
  • Example 38 was reacted with 2,3-difluorobenzylbromide. Yield: 10 mg (7%).
  • Example 190 9-(2-fluoro-3-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid
  • Example 28 was reacted with 2-fluoro-3-methylbenzylbromide. Yield: 10 mg (6%).
  • Example 28 was reacted with 2,5-dimethoxybenzylbromide. Yield: 12 mg (7%). M+l 366.
  • Example 28 was reacted with 2-fluoro-5-fluorobenzylbromide. Yield: 1.1 mg (0.5%). M+l 403.
  • Example 28 was reacted with 3-phenoxybenzylbromide. Yield: 1.9 mg (1%). M+l 398.
  • Example 38 was reacted with 2-fluorobenzylbromide. Yield: 2 mg (1%). M+l 338.
  • Example 38 was reacted with 3-fluorobenzylbromide. Yield: 10 mg (5%). M+l 338.
  • Example 38 was reacted with 4-fluorobenzylbromide. Yield: 1 mg (0.5%). M+l 338.
  • Example 197 9-(2,4-difluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid
  • Example 38 was reacted with 2,4-difluorobenzylbromide. Yield: 0.6 mg (0.3%).
  • Example 34 was reacted with 3-methy ⁇ benzylbromide. Yield: 0.4 mg (0.2%). M+l 334.
  • Example 34 was reacted with 4-methylbenzylbromide. Yield: 2 mg (1%). M+l 334.
  • the active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
  • the magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
  • Inhibitor assays were performed in 96-well format. The reactions contained 100 nM (0.53 ⁇ Ci) of a [ 3 H] labelled compound (Biovitrum, Chemical Process Development), 50 nM human FABP-4(His) 8 (Biovitrum, Target Expression and Purification), 50 ⁇ g YSi copper his- tag SPA beads (Amersham #RPNQ 0096) and serial dilutions of inhibitor.
  • the assay buffer 11 100 nM (0.53 ⁇ Ci) of a [ 3 H] labelled compound (Biovitrum, Chemical Process Development), 50 nM human FABP-4(His) 8 (Biovitrum, Target Expression and Purification), 50 ⁇ g YSi copper his- tag SPA beads (Amersham #RPNQ 0096) and serial dilutions of inhibitor.
  • the assay buffer 11 100 nM (0.53 ⁇ Ci) of a [ 3 H] labelled compound (Biovitrum, Chemical Process Development), 50 nM human FA

Abstract

The present invention relates to novel compounds (I) wherein R0, R1, R2, R3, R4, R5, R6, R7, R8, A, B, n, X, and Y are as defined in the description and claims; and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4. The present invention relates to novel compounds (I) wherein R0, R1, R2, R3, R4, R5, R6, R7, R8, A, B, n, X, and Y are as defined in the description and claims; and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4.

Description

Novel i-adole derivates as JJΑBP-4 iahibitors.
RELATED APPLICATIONS
This application claims priority to Swedish application number 0300014-8, filed on
January 8, 2003, and U.S. provisional application 60/462,476, filed on April 11, 2003, the contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4.
BACKGROUND
Fatty acids (FAs) are important fuels and cellular regulators that bind to cytoplasmic fatty acid binding proteins (FABPs) in a non-covalent, reversible manner. FABPs are expressed in a tissue-specific manner and the major site of expression of FABP-4 (adipocyte FABP, adipocyte lipid-binding protein, and mouse homologue aP2) is in adipose tissue and in macrophages.
Insulin Resistance
Dysregulation of FA metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to type 2 diabetes. Hotamisligil, G. S. et al, Science 1996, 274, 1377-1379, showed that adipocyte FABP-4 null mice, remain insulin sensitive and appear protected against type 2 diabetes despite diet-induced obesity. Importantly, the phenotype of the heterozygotes showed the intermediate state of insulin resistance associated markers, as compared to wt and null mice. Inhibition of FABP-4 by blocking FA binding could therefore be therapeutically effective in the treatment of type 2 diabetes or effectively prevent this disorder. Obesity
The relative expression of the two known FABPs in adipose tissue, FABP-4 and FABP5 (keratinocyte FABP, keratinocyte lipid-binding protein, and mouse homologue mall), differs in adipose tissue of lean as compared to obese individuals, the ratio of FABP- 4/5 being lower in the former (Fisher, R. M. et al, IntemationalJoumal of Obesity 2002, 26, 1379-1385). It is also possible that FABP-4 inhibition with a small molecule causes upregulation of FABP5. Thus it can be anticipated that inhibition of FABP-4 results effectively in a decrease of the active protein' ratio of FABP-4/5, and thus a lowering of body weight.
Atherosclerosis
Apolipoprotein E (ApoE)-deficient mice also deficient for FABP-4 showed protection from atherosclerosis. FABP-4-deficient macrophages exhibit reduced inflammatory cytokine production and lowered cholesterol ester loading when exposed to modified lipoproteins (Makowski, L. et al, Nature Medicine 2001, 7, 699-705). FABP-4 inhibition could therefore treat atherosclerosis or prevent the progression of this disease.
Chronic heart disease
The Plasminogen activator inhibitor- 1 (PAI-1) gene promoter contains a response element for unsaturated fatty acids. PAI-1 is increased in type 2 diabetic patients and a risk factor for chronic heart disease (Kohler, H. P.; Grant, P. J. The New England Journal of Medicine 2000, 342, 1792-1801). In the presence of FABP-4 inhibitors, Ac-LDL activated macrophages secreted significantly lower amounts of PAl-1, thus FABP-4 inhibitors have a potential of treating cardiovascular disorders such as chronic heart disease (Unpublished data).
Cerri, R et al., Farmaco, Edizione Scientifica (1988), 43(1), 91-101, GB 1482771 A, DE 2431292 Al, US 4775680 A, EP 0300676 A2, WO 9632379 Al, US 4009181 A, EP 0705831 A2, EP 0753517 A2, EP 0802197 Al, WO 9603377 Al, and WO 0316277 Al disclose compounds as having anti-inflammatory effect, effect against atherosclerosis, diabetic complications, heart diseases, and Alzheimers disease. None of these documents mentions FABP-4 inhibition. Furthermore, the FABP-4 inhibitors claimed are novel. While the concept of FABP-4 inhibition has been described in literature and a number of patent applications (WO 00/47734, WO 00/15229, WO 00/15230, WO 02/40448, WO 01/54694, and WO 00/59506) have been filed, the FABP-4 inhibitors claimed are novel.
SUMMARY
The compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit FABP-4 and may therefore be of use in the treating disorders such type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, or chronic heart disease.
One object of the present invention is a compound of formula (I)
Figure imgf000004_0001
wherein one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NH-SO2-Cι-C6-alkyl, or -NHSO2Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5- naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene, and the other of R° and R1 is -H or-CH3; R2= -H; R3= -H, -CO-Ci-Ce-alkyl, -SO2-Cι-C6-alkyl, -CH(Rn)(CH2)mZ, wherein R11 = -H or C,-C6-alkyl, m= 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR12R13, wherein R12 and R13 are each independently -H, Cι-C6-alkyl or Cι-C6-hydroxyalkyl or R12 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, morpholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II):
Figure imgf000005_0001
wherein Ar is as defined above;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or-OPh; n = 0, 1 or 2; R and R5 are each independently -Hor are absent, or R and R5 taken together are
=NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom not substituted by oxo, -CH or a phenyl group; X = -CH, N or is absent; Y is CH2 or is absent;
R7 and R8 are each independently -H, -COCF3, -SO2-Cι-C6-alkyl or are absent; or pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof. It is preferred that when: R6 is absent and X is absent, then R1 is -COOH, R3 is benzyl; n=0; R4 is -H; R5 is -H;
R7 is -H; A and B are each -CH; Y is absent; and R8 is -H; Y is CH2, R4, R5, R7 and R8 are absent, then R1 is -COOH, R3 is benzyl; n=l; R6 is - H; A and B are each -CH; and X is -CH; with the proviso that when:
• n = 0, then either: R° is -COOH; R1 is -H; R3 is benzyl; R4 is -H; R5 is -H; R6 is absent; A and B are each -CH; X is absent; Y is absent; R7 is -H; and R8 is -H; or one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2-Cι-C6-alkyl, or -NHSO2Ar, wherein Ar is as defined above, and the other of R° and R1 is -H or -CH3; R2 = -H; R3= -CO-Ci-Cβ-alkyl, -SO2-Cι-C6-alkyl, -CH(Rn)(CH2)mZ, wherein Ru = -H or Q- Cs-alkyl, m= 1 , 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR12R13, wherein R12 and R13 are each independently -H, Cι-C6-alkyl or Cι-C6-hydroxyalkyl or R 2 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, morpholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II), wherein
Ar is as defined above and R9 and R10 are both -H or both -CI or at least one of R9 and R10 is selected from -CH3, -OCH3, -F, -Br, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-C C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or-OPh; R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or
=NO-CH2-Ph;
R6 = -H, -CH3, or -COCH3;
A and B are each a carbon atom not substituted by oxo; X = -CH orN; Y is absent;
R7 and R8 are each independently -H, -COCF3, or -SO2-Cι-C6-alkyl;
• n = 1, then either:
R° is -COOH; R1 is -H; R3 is benzyl; R4 and R5 are absent; Rδ is -H; A and B are each -CH; X is -CH; Y is CH2; and R7 and R8 are absent; or one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2-Cι-C6-alkyl, or -NHSO Ar, wherein Ar is as defined above, and the other of R° and R1 is -H or -CH3; R2 = -H; R3= -CO-Ci-Cβ-alkyl, -SO2-Cι-C6-alkyl, -CH(Rπ)(CH2)mZ, wherein Ru = -H or Ci-Cβ-alkyl. m= 1, 2, 3 or 4, Z = -CN, -COOH, -COC1 or -CONR12R13,
19 1 " wherein R and R are each independently -H, Cι-C6-alkyl or Ci-Cδ-hydroxyalkyl or R12 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II), wherein
Ar is as defined above and R9 and R10 are both -H or both -CI or at least one of R9 and R10 is selected from -CH3, -OCH3, -F, -Br, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh;
R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, or -COCH3; A and B are each a carbon atom not substituted by oxo;
X = -CH orN;
Y is absent;
R7 and R8 are each independently -H, -COCF3, or -SO2-Cι-C6-alkyl; • n = 2, then one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2-Cι-C6-alkyl, or -NHSO2Ar, wherein Ar is as defined above, and the other of R° and R1 is -H or -CH3; R2 = -H; R3= -H, -CO-Cι-C6-alkyl, -SO2-Cι-C6-alkyl, -CH(Rπ)(CH2)mZ, wherein R11 = -H or Ci-Ce-alkyl, m= 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR12R13,
19 1 wherein R and.R are each independently -H, Cι-C6-alkyl or Cι-C6-hydroxyalkyl or R12 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II), wherein
Ar is as defined above and R9 and R10 are each independently -H, -CH3, -OCH , -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3 or -COCH3;
A and B are each a carbon atom not substituted by oxo; X = -CH orN;
Y is absent;
R7 and R8 are each independently -H, -COCF3, or -SO2-Cι-C6-alkyl.
If in the compound of formula (I) A and B are each a carbon atom not substituted by oxo; X is -CH orN;
Y is absent; then said compound has the formula (III)
Figure imgf000008_0001
wherein R°, R1, R2, R3, R4, R5, R6, R7, R8, X, and n are as defined above. If in the compound of formula (I)
A and B are each a -CH or a phenyl group;
X is absent; n = 0;
R6 is absent; Y is absent; then said compound has the formula (IN).
Figure imgf000009_0001
wherein R°, R1, R2, R3, R4, R5, R7, R8, A, and B are as defined above.
It is more preferred that: one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R1 is -H or -CH ;
R = -H;
RJ= -H, -CH(R .πu)(CH2)mZ, wherein R .1u1 = H or methyl, m= 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or-CONR12R13, wherein R12 and R13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or R12 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and 3-hydroxypiperidinyl; or R is a group of the formula (II), wherein
Ar is selected from phenyl, furan, pyridine, and pyrimidine; R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO H, -NO2,
-NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; n= 0, 1 or 2;
R4 and R5 are each independently -H, or are absent, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom not substituted by oxo, -CH or a phenyl group;
X = CH, N or is absent;
Y is CH2 or is absent; R7 and R8 are each independently -H, -COCF3, methanesulfonyl or are absent.
It is even more preferred that when: R6 is absent and X is absent, then R1 is -COOH, R3 is benzyl; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R8 is -H;
Y is CH2, R4, R5, R7 and R8 is absent, then R1 is -COOH, R3 is benzyl; n=l; R6 is -H; A and B are each -CH; and X is -CH; with the proviso that when:
• n = 0, then either:
R° is -COOH; R1 is -H; R3 is benzyl; R4 is -H; R5 is -H; R6 is absent; A and B are each -CH; X is absent; Y is absent; R is -H; and R is -H; or one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2-C,-C6-alkyl, or -NHSO2Ar, wherein Ar is as defined above, and the other of R° and R1 is -H or -CH3; R2 = -H; R3= -CH(Rπ)(CH2)mZ, wherein R11 - -H or methyl, m= 1, 2 , 3 or 4, Z = -H, -CN, - COOH, -COC1 or-CONR12R13, wherein R12 and R13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or R12 and R13 form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and 3-hydroxypiperidinyl; or R is a group of the formula (II), wherein
Ar is selected from phenyl, furan, pyridine, and pyrimidine and R9 and R10 are both -H or both -CI or at least one of R9 and R10 is selected from -CH3, -OCH3, -F, -Br, -CF3, -CO2H, -NO2, -NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh;
R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, or -COCH3; A and B are each a carbon atom not substituted by oxo;
X = -CH orN;
Y is absent;
R and R are each independently -H, -COCF3, or methanesulfonyl;
• n = 1, then either: R° is -COOH; R1 is -H; R3 is benzyl; R4 and R5 are absent; R6 is -H; A and B are each -CH; X is -CH; Y is CH2; and R7 and R8 are absent; or one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2-Cι-C6-alkyl, or -NHSO2Ar, wherein Ar is as defined above, and the other of R° and R1 is -H or -CH3; R2 = -H; R3= -CH(Rn)(CH2)mZ, wherein R11 = -H or methyl, m= 1, 2, 3 or 4, Z = -CN, -COOH, -COC1 or-CONR12R13, wherein R12 and R 3 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
1 13
R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and 3-hydroxypiperidinyl; or R3 is a group of the formula (II), wherein Ar is selected from phenyl, furan, pyridine, and pyrimidine and R and R ° are both
-H or both -CI or at least one of R9 and R10 is selected from -CH3, -OCH3, -F, -Br, -CF3, -CO2H, -NO2, -NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh;
R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, or -COCH3;
A and B are each a carbon atom not substituted by oxo; X = -CH orN; Y is absent; R7 and R8 are each independently -H, -COCF3, or methanesulfonyl;
• n = 2, then either of R° and R1 is -COOH, -COOMe, -CH2OH, -CONH2, -CONHOH, methanesulfonylamino or phenylsulfonylamino, provided that the other of R and R is -H or-CH3;
R2 = - H; R3= -H or -CH(Rn)(CH2)mZ, wherein R11 = -H or methyl, m= 1, 2, 3 or 4, Z = H, -CN, -COOH, -COC1 or -CONR12R13, wherein R12 and R13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
1 1
R and R form together a heterocycle selected from pyrrolidinyl, moφholinyl and 3- hydroxypiperidinyl; or R3 is a group of the formula (II), wherein Ar is selected from phenyl, furan, pyridine, and pyrimidine; R9 and R10 are each independently selected from -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh;
R4 and R5 are each independently -H, or R4 and R5 taken together are =NOH, or =NO-CH2-Ph; R6 = -H, -CH3, or -COCH3;
A and B are each a carbon atom not substituted by oxo; X = -CH orN; Y is absent;
R7 and R8 are each independently -H, -COCF3, or methanesulfonyl. The following compounds are especially preferred:
5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate, methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • methyl 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(4-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(4-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(4-cyanobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, • 9-[4-(aminocarbonyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(3-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(3-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(4-methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate, 9-(4-methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, • methyl 9-(2-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, • 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(4-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(4-(trifluoromethyl)benzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 9-(3-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(3-(trifluoromethyl)benzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 9-(2,4-difluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate, 9-(2,4-difluorobenzyl)-2,3,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-[2-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • 9-(4-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(3 -cyanobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate, 9-(3-carboxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, [8-(methoxycarbonyl)- 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]acetic acid, methyl 9-(2-chloro-2-oxoethyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate, • methyl 9-(2-moφholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2-moφholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(dimethylamino)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(diethylamino)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2-amino-2-oxoethyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, • 9-(2-oxo-2-pyrrolidin-l-ylethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(3-hydroxypiperidin-l-yl)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid,
9-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylate, 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, methyl 5-propyl-5,6,7,8,9, 10-hexahydrocycloheptaP->]indole-4-carboxylate, 5-propyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate, 5-benzyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, 5-[3-(aminocarbonyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, methyl 5-(4-cyanobutyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate, 5-(5-amino-5-oxopentyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(4-cyanobutyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, 5-(3-methoxybenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, • 5-(2-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
5-[2-(aminocarbonyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
9-benzyl-4-benzyloxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-benzyl-4-(hydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, • 9-benzyl-4-(hydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
5-benzyl- 10-(hydroxyimino)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
9-benzyl- 1 -(trifluoroacetyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyano-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate, • 5-[3-(aminocarbonyl)-5-methoxybenzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate, methyl 5-[(5-cyano-2-furyl)methyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate, 5-{[(5-aminocarbonyl)-2-furyl]methyl}-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 5-(4,6-dimethoxy-pyrimidin-2-ylmethyl)-5,6,7,8,9,10-hexahydro-cyclohepta[b]indole-4- carboxylic acid,
5- { [6-hydroxy-2-(methylthio)pyrimidin-4-yl]methyl} -5,6,7,8,9, 10- hexahydrocyclohepta[b]indole-4-carboxylic acid,
5-[(4-hydroxy-6-methoxypyrimidin-2-yl)methyl]-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(pyridin-2-ylmethyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate
5-(pyridin-2-ylmethyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-[(6-chloropyridin-3-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-[(6-chloropyridin-3-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
5-[(2-cyanopyridin-4-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
5- { [2-(aminocarbonyl)pyridin-4-yl]methyl} -5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylic acid, methyl 5-[(6-cyanopyridin-2-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-{[6-(aminocarbonyl)pyridin-2-yl]methyl}-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-
4-carboxylic acid, methyl 5-(2-chloro-6-methoxypyridin-4-yl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylate,
(9-benzyl-2,3,4,9-tetrahydro-lH-carbazol-8-yl)methanol,
N-hydroxy-5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahycuOcyclohepta[b]indole-4- carboxamide,
N-[5-benzyl-6-(methylsulfonyl)-5, 6,7,8,9, 10-hexahydrocyclohepta[b]indol-4- yljmethanesulfonamide,
N-(5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4- yl)methanesulfonamide, N-(5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4- yljbenzenesulfonamide,
9-benzyl-N-hydroxy-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxamide, 4-benzyl-l,2,3,4-tetrahydrocyclopenta[b]indole-5-carboxylic acid, 1 -benzyl-2, 3 -dimethyl- 1 H-indole-7-carboxylic acid,
2-acetyl-5-benzyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole-6-carboxylic acid, methyl 9-(3-nitrobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-[3-(acetylamino)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-nitrobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carboxylate, 5-(2-fluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(4-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2,4-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2,5-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-[3-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
5-[4-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
9-(2,6-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2-fluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-7-carboxylic acid, 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(4-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2, 5-difluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-7-carboxylic acid, 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-[2-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-[4-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 5-(2,3-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-(2,6-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,5-difluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(3-methylbenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 5-(3-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 5-(4-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 9-[3-(trifluoromethoxy)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 5-(2-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 9-[3-fluoro-5-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • 9-[2-fluoro-6-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
9-(2-methylbenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(2,5-dichlorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • 9-(2,3-difluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2-fluoro-3-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2, 5-dimethoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(2-bromo-5-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-phenoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • 9-(2-fluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-fluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(4-fluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,4-difluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 5-(3-methylbenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, and • 5-(4-methylbenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid. The invention also relates to a method of making a compound described herein, including those of any of the formulae herein. The method includes taking a compound delineated in any of the examples herein (including Examples 1-26), and reacting it with one or more chemical reagents in one or more steps to produce a compound of any of the formulae described herein. Alternatively, the method includes taking any one of the intermediate compounds described herein and reacting it with one or chemical reagents in one or more steps to produce a compound described herein.
Another object of the present invention is a compound of the formula (I)
Figure imgf000018_0001
wherein one of R°and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2CF3, -NH-SO2-Cι-C6-alkyl, tetrazole or -NHSO2Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H- 1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene, and the other of R° and R1 is -H or -CH3;
R2= -H or -CH3, provided that if one of R° and R1 is -CH3, then R2 is -H; R3= -H, -CO-Ci-Cβ-alkyl, -SO2-Cι-C6-alkyl, -CH(Rn)(CH2)mZ, wherein R11 = -H or Ci-Ce-alkyl, m= 0, 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR12R13, wherein R12 and R13 are each independently -H, Cι-C6-alkyl or Ci-Cδ-hydroxyalkyl or R12 and R13 form with the nitrogen to which they are both attached together a heterocycle selected from pyrrolidinyl, moφholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R3 is a group of the formula (II):
Figure imgf000019_0001
wherein
Ar is as defined above;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or-OPh; n = 0, 1 or 2;
R4 and R5 are each independently -H, or are absent, or R4 and R5 taken together are =O, =NOH, or =NO-CH2-Ph; R6 - -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom, -CH or a phenyl group;
X = -CH, N or is absent;
Y is CH2 or is absent;
R7 and R8 are each independently -H, -COCF3, -SO2-Cι-C6-alkyl or are absent, or R7 and R8 taken together are =O; or pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof; for use in therapy.
It is preferred that when: R is absent and X is absent, then either:
R° is -COOH; R1 is -H; R2 is -H; R3 is benzyl; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R is -H; or
R° is -COOH; R1 is -H; R2 is -H; R3 is -H; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R is -H; or R° is -COOMe; R1 is -H; R2 is -H; R3 is -H; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R8 is -H; or R1 is -COOH; R . i1 i ■s -H; R2 is -H; R3 is -H; n=0; R4, R5, R7 and R8 are absent; A and B are each a phenyl group; and Y is absent;
Y is CH2, R4, R5, R7 and R8 are absent, then R1 is -COOH, R2 is -H, R3 is benzyl; n=l; R6 is -H; A and B are each -CH; and X is -CH.
If in the compound of formula (I) A and B are each a carbon atom; X is -CH orN; Y is absent; then said compound has the formula (III)
Figure imgf000020_0001
wherein R°, R1, R2, R3, R4, R5, R6, R7, R8, X, and n are as defined in claim 7.
If in the compound of formula (I) A and B are each a -CH or a phenyl group; X is absent; n = 0;
R6 is absent;
Y is absent; then said compound has the formula (IN)
Figure imgf000020_0002
wherein R°, R1, R2, R3, R4, R5, R7, R8, A, and B are as defined in claim 7. It is even more preferred that: one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, trifluoromethanesulfonylamino, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R1 is -H or -CH3;
R2= -H or -CH3, provided that if one of R° and R1 is -CH3, then R2 is -H; R3= -H, -CH(R11)(CH2)mZ, wherein R1 ' = H or methyl, m= 0, 1 , 2, 3 or 4, Z = -H,
-CN, -COOH, -COC1 or-CONR12R13, wherein R12 and R13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
19 1
R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, moφholinyl and 3-hydroxypiperidinyl; or R3 is a group of the formula (II), wherein
Ar is selected from phenyl, furan, pyridine, and pyrimidine;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; n= 0, 1 or 2;
R and R5 are each independently -H, or are absent, or R4 and R5 taken together are =O, =NOH, or -NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent; A and B are each a carbon atom, -CH or a phenyl group;
X = CH, N or is absent; Y is CH or is absent;
R7 and R8 are each independently -H, -COCF3, methanesulfonyl or are absent, or R7 and R taken together are =O. It is preferred that when:
R is absent and X is absent, then either:
R° is -COOH; R1 is -H; R2 is -H; R3 is benzyl; n-0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R8 is -H; or
R° is -COOH; R1 is -H; R2 is -H; R3 is -H; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R8 is -H; or R° is -COOMe; R1 is -H; R2 is -H; R3 is -H; n=0; R4 is -H; R5 is -H; R7 is -H; A and B are each -CH; Y is absent; and R8 is -H; or
R1 is -COOH; R1 is -H; R2 is -H; R3 is -H; n=0; R4, R5, R7 and R8 are absent; A and B are each a phenyl group; and Y is absent;
Y is CH2, R4, R5, R7 and R8 are absent, then R1 is -COOH, R2 is -H, R3 is benzyl; n=l ; R6 is -H; A and B are each -CH; and X is -CH.
Specific examples of compounds according to the present invention are given above and also the following compounds:
• 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid,
• methyl 2,3,4,9-tetrahydro-lH-carbazole-7-carboxylate,
• 2,3-dimethyl-lH-indole-7-carboxylic acid,
• methyl 2,3-dimethyl-lH-indole-7-carboxylate,
• 2,3-diphenyl-lH-indole-7-carboxylic acid,
• 6-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 6-methyl-2,3 ,4,9-tetrahydro- lH-carbazole-8-carboxylate,
• methyl 3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• methyl 9-butyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-butyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-propyl-2,3,4,9-tetrahydro- lH-carbazole-8-carboxylate,
• 9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-pentyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-pentyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-ethyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-ethyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid,
• 9-isopropyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 4-hydroxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 4-hydroxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 4-oxo-9-propyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate, 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 4-(hydroxyimino)-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, methyl 10-oxo-5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate, 10-oxo-5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-benzyl- 10-oxo-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate, • 5-benzyl- 10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyanobenzyl)- 10-oxo-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-[3-(aminocarbonyl)benzyl]- 10-oxo-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylic acid, • 9-benzyl-l-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, N-(5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-yl)- 1,1,1- trifluoromethanesulfonamide,
N-[2-(trifluoromethyl)benzyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-yl)-l , 1,1- trifluoromethanesulfonamide, and • 9-(2-chlorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid.
Another object of the present invention is the compound according to any one of claims 7 to 11 for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
Another object of the present invention is a pharmaceutical composition comprising a compound according to any one of claims 7 to 11 as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
Another object of the present invention is a pharmaceutical composition for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
It is preferred that the pharmaceutical composition further comprises an additional therapeutically active agent. Another object of the present invention is a method for the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4, which comprises administering to a subject in need of such treatment (e.g., mammal, human, dog, cat, horse, cow, chicken, or pig) an effective amount of a compound according to any one of claims 7 to 11. Optionally, the aforementioned method includes co-administration with other therapeutic agents. Such co-administration can be simultaneous or sequential, and can also be in a single (e.g., one pill, capsule, or injection) or multiple (e.g., more than one pill, capsule, or injection) dosing.
It is preferred that the subject is a human. Another object of the present invention is a method for inhibiting FABP-4, which comprises administering to a subject in need of such treatment (e.g., mammal, human, dog, cat, horse, cow, chicken, or pig) an effective amount of a compound according to any one of claims 7 to 11.
It is preferred that the subject is a human. Another object of the present invention is the use of a compound according to any one of claims 7 to 11 for the manufacture of a medicament for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
Examples of disorders mentioned above are type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
Other features and advantages of the invention will be apparent from the detailed description and the claims.
DETAILED DESCRIPTION OF THE INVENTION
First, the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
Cι-C6-alkyl, which may be straight or branched, is an alkyl group having 1-6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl. For parts of the range "Cι-6-alkyl" all subgroups thereof are contemplated such as Cι-5-alkyl, Cι-4-alkyl, Cι_3-alkyl, Cι-2-alkyl, C2-6-alkyl, C2.5- alkyl, C2- -alkyl, C2-3-alkyl, C3-6~alkyl, C4-5-alkyl, etc. Ci-Cό-hydroxyalkyl, which may be straight or branched, is an alkyl group having 1-6 carbon atoms and one or more hydroxy groups. Exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl, hydroxy-tert-butyl, hydroxy-n-pentyl, and hydroxy-n- hexyl. For parts of the range "Cι-6-hydroxyalkyl" all subgroups thereof are contemplated such as Cι-5-hydroxyalkyl, Ci ^-hydroxyalkyl, Cι-3 -hydroxyalkyl, Cι-2-hydroxyalkyl, C2-6- hydroxyalkyl, C2-5-hydroxyalkyl, C2-4-hydroxyalkyl, C .3-hydroxyalkyl, C3.6-hydroxyalkyl, C4-5-hydroxyalkyl, etc.
The term "heterocycle" refers to a nonaromatic 3-8 membered monocyclic, 8-12 membered bicyclic, or 11 - 14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, Se, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, Se or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent. The compounds useful herein include the compounds of any of the formulae themselves, as well as their prodrugs, if applicable. The term "prodrug forms" in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and tli
Gilman's, The Pharmacological basis of Therapeutics,
Figure imgf000025_0001
ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15). Examples of ester prodrug groups found in the literature are the following substituents for R or R in the compound of formula (I): -COO(Cι-C6-alkyl)
-COO(Cι-C6-alkylene)C(O)NRxRy, wherein Rx and Ry are Cι-C6-alkyl or form together with the nitrogen to which they are attached a heterocycle such as moφholinyl (see Bundgaard, H.; Nielsen, N.M. J. Med. Chem. 1987, 30, 451-452)
-COO(Cι-C6-alkylene)C(O)(Cι-C6-alkyl) (see Nudelman, A.; Rephaeli, A., J. Med. Chem. 2000, 43, 2962-2966)
-COO(Cι-C6-alkylene)C(O)(Cι-C6-alkyl)NRxRy, wherein Rx and Ry form together with the nitrogen to which they are attached moφholinyl or 4-methylpiperazinyl (see Rautio j. et al. J. Med. Chem. 2000, 43, 1489-1494). In addition, some of the compounds have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. Further, the aforementioned compounds also include their N-oxides. The term "N- oxides" refers to one or more nitrogen atoms, when present in a compound, that are in N- oxide form, i.e., Ν→ O.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the puφoses detailed herein (e.g., treating a disease).
By the expression "absent" is meant that the letters (i.e., chemical group) respectively may have no meaning or are not present. For example, in Formula (I) when Y is absent, this means that A may only be bonded to one or more of the indole ring, R4, R5, and X. Likewise, when Y is CH2, R4, R5, R7 and R8 is absent, this means that A may only be bonded to the indole ring, X, and Y.
"Pharmaceutically acceptable" means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, Ν-methylglucamine, choline and the like. Pharmaceutical compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula (I) as described herein above, dissolved or dispersed therein as an active, ingredient. In a preferred embodiment, the therapeutic composition is not immunogenic when administered to a human patient for therapeutic puφoses, unless that puφose is to induce an immune response.
The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art. Typically such compositions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non- aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.
The active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. Adjuvants may also be present in the composition.
Pharmaceutically acceptable carriers are well known in the art. Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
The pharmaceutical composition according to one of the preferred embodiments of the present invention comprising compounds comprising the formula (I), may include pharmaceutically acceptable salts of that component therein as set out above.
Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
Further, this invention covers a method of administering an effective amount of one or more compounds described in the formulae herein to a subject in need of treatment for a disease or disease symptom (e.g., type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, or chronic heart disease). The method can also include the step of identifying that the subject is in need of treatment for a disease or disease symptom. The identifying can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).
The term "treating" or "treated" refers to administering an aforementioned compound to a subject with the puφose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a disease, the symptoms of the disease or the predisposition toward the disease. "An effective amount" refers to an amount of a compound (including a salt, prodrug form or composition thereof) which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
The preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously. Other routes which are known for the skilled person in the art are thinkable.
The orally administrable compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g. magnesium stearate, talc, polyethylene glycol or silica; disintegrants e.g. potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g. lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or coloring agents. A pharmaceutical composition according to the present invention, may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition. A weight percent is a ratio by weight of total composition. Thus, for example, 0.1 weight percent is 0.1 grams of compound comprising the formula (I) per 100 grams of total composition. A suitable daily oral dose for a mammal, preferably a human being, may vary widely depending on the condition of the patient.
However a dose of compound comprising the formula (II) of about 0.1 to 300 mg/kg body weight may be appropriate.
The compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier. The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
The compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in- vitro was studied using the following reagents and methods. As can be appreciated by the skilled artisan, the synthetic routes delineated herein are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock,
Comprehensive Organic Transformations, NCH Publishers (1989); T.W. Greene andP.G.M.
Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L.
Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995) and subsequent editions thereof.
All publications mentioned herein are hereby incoφorated by reference. By the expression "comprising" we understand the phrase to mean including but not limited to.
Thus, other non-mentioned substances, additives or carriers may be present. The invention will now be described in reference to the following Examples. These
Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.
EXPERIMENTAL METHODS
List of abbreviations
AIBN = azoisobutyronitrile
DCM = dichloromethane
DDQ = 2,3-dichloro-5,6-dicyano-l,4-benzoquinone DIBAH = diisobutylaluminium hydride
DMF = dimethylformamide
DMS = dimethyl sulfide
DMSO = dimethyl sulfoxide
EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc = ethyl acetate
GC-MS = gas chromatography-mass spectrometry HOBT = 1-hydroxybenzotriazole hydrate HPLC = high performance liquid chromatography LC-MS = liquid chromatography-mass spectrometry MCPBA = m-chloroperbenzoic acid NBS = N-bromosuccinimide
RP-HPLC = reversed-phase high performance liquid chromatography RT = room temperature TBAF = tetra-n-butylammonium fluoride TFA = trifluoroacetic acid THF = tetrahydrofuran
TLC = thin layer chromatography
Synthesis of starting materials (Examples 1-26)
Example 1 - l-bromo-3-fbromomethyl -5-methoxybenzene l-bromo-3-methoxy-5-methylbenzene (Chan et. al., J. Med. Chem. 2001, 44, 1866 -
1882) (1.456 g, 7.286 mmol) and NBS (1.68 g, 9.46 mmol) in CC14 (20 ml) was irradiated (Rayonet, Photochemical Reactors) in a closed "Stemblock tube" overnight. A mixture of compounds was obtained as indicated by GC-MS of the reaction mixture. Flash chromatography using 2% EtOAc in hexanes gave 806 mg (38%) of a colorless oil; ~80% pure estimated from NMR.
1H NMR (400 MHz, CDC13) δ 3.79 (s, 3 H), 4.37 (s, 2 H), 6.84 (d, J=1.7 Hz, 1 H), 6.97-6.98 (m, 1 H), 7.12-7.12 (m, 1 H).
Example 2 - 3-methoxy-5-methylbenzonitrile Three parallels of l-bromo-3-methoxy-5-methylbenzene (Chan et ah, supra) (2.00 g,
9.94 mmol) and CuCN (1.34 g, 15.0 mmol) in DMF (25 ml) was heated at 160 °C in sealed "Stemblock tubes" for 20 h. The parallels were combined, EtOAc was added and the mixture was filtered through a short plug of silica. The filtrate was purified by flash chromatography using 2-10% EtOAc in hexanes. Yield 2.88 g (66°/o); white solid. Η NMR (400 MHz, CDC13) δ 2.33 (s, 3 H) 3.79 (s, 3 H) 6.92 (s, 2 H) 7.03 (s, 1 H). 13C NMR (100 MHz, CDCI3) δ 21.19, 55.40, 112.74, 113.88, 118.88, 120.01, 125.08, 140.75, 159.53. GC-MS: 100%; 147 (W?).
Example 3 - 3-(bromomethyl -5-methoxybenzonitrile
3-methoxy-5-methylbenzonitrile (Example 2) (666 mg, 2.089 mmol) and NBS (0.97 g, 5.43 mmol) in CC14 (20 ml) was irradiated (Rayonet, Photochemical Reactors) for 20 h. Di- and-monobrominated compounds was separated by flash chromatography using 5 - 10% EtOAc in hexanes. First eluated 471 mg (34%) 3-(dibromomethyl)-5-methoxybenzonitrile. Second eluated 368 mg (36%) title compound as a colorless oil.
1HNMR (400 MHz, CDC13) δ 3.84 (s, 3 H), 4.41 (s, 2 H), 7.07 (s, 1 H), 7.14 (s, 1 H), 7.26 (s, 1 H).
Example 4 - 3-hydroxy-5-methylbenzonitrile BC13 (50 ml, 50 mmol, 1 M in DCM) was added dropwise to a solution of 3-methoxy-
5-methylbenzonitrile (Example 2) (2.101 g, 14.27 mmol) and Bu4NI (5.80 g, 15.7 mmol) in dry DCM (50 ml) at -78 °C. The cold bath was removed and the mixture stirred at ambient temperature for 30 min. Ice was added and the mixture stirred 20 min, and neutralized with sat. NaHCO3. Organic layer separated and product isolated by flash chromatography using 1- 2% MeOH in DCM. Yield 1.465 g (77%), white solid, -80% pure by NMR.
1H NMR (400 MHz, CDCI3) δ 2.33 (s, 3 H), 6.89 (s, 1 H), 6.92 (s, 1 H), 7.03 (s, 1 H). 13C NMR (100 MHz,CDCl3) δ 21.12, 112.79, 115.85, 118.70, 121.19, 125.27, 141.20, 155.81.
Example 5 - 3-cyano-5-methylphenyl acetate
Acetyl chloride (731 μl, 10.28 mmol) was added to a solution of 3-hydroxy-5- methylbenzonitrile (Example 4) (1.141 g, 8.56 mmol) and Et3N (1.5 ml) in DCM (50 ml) and the mixture was stirred overnight. Et2O was added and the mixture filtered, evaporated and product isolated by flash chromatography using hexanes/EtOAc 9:1 and 4:1. Yield 1.051 g (70%). 1H NMR (400 MHz, CDC13) δ 2.30 (s, 3 H), 2.39 (s, 3 H), 7.15 (s, 1 H), 7.21 (s, 1 H), 7.32 (s, 1 H). 13C NMR (100 MHz, CDC13) δ 20.92, 21.04, 113.04, 117.95, 122.40, 127.22, 130.01, 141.05, 150.60, 168.75. GC-MS: 100%; 175 (M ).
Example 6 - 3-(bromomethyl -5-cyanophenyl acetate
3-cyano-5-methylphenyl acetate (Example 5) (366 mg, 2.089 mmol), NBS (483 mg, 2.716 mmol) and AIBN (10 mg) in CC14 (20 ml) was irradiated (Rayonet, Photochemical Reactors) for 4 h. The products were separated by flash chromatography using 10% EtOAc in hexanes. First eluated: 254 mg (37%); 3-cyano-5-(dibromomethyl)phenyl acetate. Second eluated: 249 mg (47%); title compound; -75% pure by NMR.
1H NMR (400 MHz, CDC13) δ 2.27 (s, 3 H), 4.39 (s, 2 H), 7.31 (s, 1 H), 7.36 (s, 1 H), 7.49 (s, 1 H). 13C NMR (100 MHz, CDC13) δ 20.74, 30.37, 113.45, 117.12, 124.90, 126.85, 129.49, 140.65, 150.67, 168.30
Example 7 - 6-chloromethyl-2-methylsulfanylpyrimidin-4-ol
Ethyl 4-chloroacetoacetate (6.4 g, 39 mmol) was added to a stirred suspension of methyl-2-thiopseudourea sulphate (10 g, 36 mmol) and Ca(OH)2 (3 g, 40 mmol) in water (60 ml) and ethanol (180 ml). The mixture was stirred for 36 h and acidified with 2N HC1 and extracted with EtOAc. After drying (MgSO4) and evaporation the crude product was suspended in DCM and filtered. Yield 3.1 g (45%).
1H NMR (400 MHz, CDC13) δ 2.58 (s, 3 H) 4.34 (s, 2 H) 6.40 (s, 1 H) 12.82 (br. s., 1 H). MS (70eV) m z (%) 189 (M",100)
Example 8 - 6-iodomethyl-2-methylsulfanylpyrimidin-4-ol 6-chloromethyl-2-methylsulfanylpyrimidin-4-ol (Example 7) (2.0 g, 10.5 mmol) and
Kl (8.7 g, 52.4 mmol) was suspended in acetone (120 ml) and heated to 50 °C for 3 h. The mixture was evaporated and suspended in water and filtered. The solid was washed with water (3x) and DCM (2x) and dried. Yield 1.87 g (63 %).
1HNMR (400 MHz, CDCI3) δ 2.60 (s, 3 H) 4.13 (s, 2 H) 6.23 (s, 1 H) 12.07 (br. s., 1 H). MS (70eV) m/z (%) 283 (M+, 100). Example 9 - 6-chloromethyl-2-methoxy-pyrimidin-4-ol
Oxone (0.8 g, 1.3 mmol) was added to a solution of the 6-chloromethyl-2- methylsulfanylpyrimidin-4-ol (Example 7) (0.1 g, 0.52 mmol) in MeOH/water 8:2 (10 ml) and stirred overnight. The mixture was evaporated to half its volume and partitioned between DCM and water. The organic phase was dried (MgSO4) and evaporated giving the title product as a white solid. Yield 35 mg (39 %).
1H NMR (400 MHz, CDC13) δ 4.00 (s, 3 H) 4.30 (s, 2 H) 6.32 (s, 1 H) 12.16 (br. s., 1
H). MS (70eV) m/z (%) 175 (M+,100).
Example 10 - 4-[(ftert-butyldimethylsilvDoxylmethyl1pyridine
This is a modified procedure from Hadri, A. E.; Leclerc, G. J. Heterocyclic Chem. 1993, 30, 631-635. To a mixture of 4-(hydroxymethyl)pyridine (7.42 g, 68.0 mmol) and imidazole (9.72 g, 142.8 mmol) in dry DMF (70 mL) was added dropwise over a 15-min period tert-butyldimethylsilyl chloride (10.76 g, 71.4) in dry DMF (30 mL). The clear solution was stirred for 3 h, poured in water (500 mL) and extracted with toluene (3 x 200 mL). The combined organic phases were dried (MgSO4) and reduced to dryness affording 15.69 g (100%) a colorless oil containing little toluene.
1HNMR (400 MHz, CDCI3) δ 0.10 (s, 6H) 0.94 (s, 9H) 4.73 (s, 2H) 7.24 (d, j=6.02 Hz, 1H) 8.53 (d, j=6.02 Hz, 1H).
Example 11 - 4-[i(tert-butyldimethylsilvDoxy|methyl1pyridine N-oxide To a solution of Example 10 (15.61 g, 68.0 mmol) in DCM (150 mL) stirred at 0 °C was added MCPBA (25.0 g, 57-85%) portion- ise over a 15-min period. The clear solution was stirred for 24 h at ambient temperature. Sodium thiosulfate (5 g, to destroy excess MCPBA) and DCM (150 mL) were added. The organic phase was washed with aqueous NaOH (10%, 200 mL). The basic phase was extracted with DCM (2 x 200 mL) and the combined organic layers were dried (Na2SO4) and evaporated in vacuo yielding 14.63 g (90%>) of a colorless oil that solidified immediately. This material was used without further purification. Η NMR (400 MHz, CDCI3) δ 0.10 (s, 6H) 0.93 (s, 9H) 4.68 (s, 2H) 7.22 (d, j=7.03
Hz, 1H) 8.16 (d, J=7.03 Hz, 1H). Example 12 - 2-cvano-4-[irtert-butyldimethylsilyl oxylmethvHpyridine To a solution of Example 11 (5.0 g, 20.89 mmol) in toluene (20 mL) was added trimethylsilyl cyanide (2.49 g, 25.10 mmol). Subsequently dimethylcarbamoyl chloride (2.25 g, 20.89 mmol) was added which triggered an exothermic reaction turning the color brown after 10 min. Stirring continued at 60 °C for 18 h. The reaction mixture was allowed to cool to RT and ethyl acetate (150 mL) was added. The organic phase was washed with aqueous NaOH (10%, 50 mL). The basic phase was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (MgSO4) and evaporated in vacuo to give 5.38 g of an orange oil. Purification by flash column chromatography on silica gel eluting with diethyl ether / isohexanes (1:2 v/v) afforded the title compound as a colorless oil (3.1 g, 60%).
1H NMR (400 MHz, CDC13) δ 0.12 (s, 6H) 0.94 (s, 9H) 4.77 (s, 2H) 7.45 (d, J=5.27 Hz, 1H) 7.66 (s, 1H) 8.63 (d, J=5.27 Hz, 1H); MS (EI+) m/z 249.2.
Example 13 - 4-(hydroxymethyl)pyridine-2-carbonitrile
This procedure was adapted with modification from Ewing, W. R. et al. J. Med. Chem. 1999, 42, 3557-3571. Example 12 (3.0 g, 12.1 mmol) and cation exchanger Dowex 50 W x 2, H+ (3.6 g, thoroughly washed with methanol) in methanol (60 mL) were slowly rotated in a round-bottomed flask on a rotavapor at atmospheric pressure. After 18 h the Dowex was filtered off and the filtrate was evaporated to dryness leaving 1.51 g (93%) of a white solid.
1HNMR (400 MHz, CDC13) δ 2.18 (s, 1H) 4.82 (s, 2H) 7.51 (d, J=5.27 Hz, 1H) 7.72 (s, 1H) 8.67 (d, J=5.27 Hz, 1H); MS (Ef) m/z 135.2.
Example 14 - 4-(bromomethyl)pyridine-2-carbonitrile
A stirred solution of triphenylphospine (3.53 g, 13.46 mmol) in DCM (80 mL) was cooled to 0 °C on an ice bath. Bromine (2.15 g, 13.45 mmol) was added drop- wise resulting in a white suspension. After 30 min Example 13 (1.5 g, 11.2 mmol) was added portion-wise, and stirring continued for 2 h. DCM (100 mL) was added and the organic phase was washed with water (2 x 100 mL) and brine (100 mL). The DCM-layer was dried (MgSO4) and reduced to dryness leaving a colorless oil. Purification by flash column chromatography on silica gel eluting with diethyl ether / isohexanes (1:1 v/v) gave 2.21 g ( 100%) of a white solid.
1H NMR (400 MHz, CDC13) δ 4.40 (s, 2H) 7.52 (dd, Jl=5.02, J2=1.76 Hz, 1H) 7.71 (s, 1H) 8.69 (d, J=5.02 Hz, 1H).
Example 15 - 2-(bromomethyl)pyridine-2-carbonitrile
The title compound was prepared in five steps according to the synthesis as described ' for Example 14 starting from 2-(hydroxymethyl)pyridine (10.2 g, 93.5 mmol). This procedure gave a white solid (5.43 g, 65% overall yield). 1H NMR (400 MHz, CDC13) δ 4.54 (s, 2H) 7.62 (dd, Jl=7.53, J2=1.00 Hz, 1H) 7.69
(d, J=7.53 Hz, 1H) 7.85 (t, J=7.78 Hz, 1H).
Example 16 - 2,6-dichloroisonicotinic acid
Citrazinic acid (10.35 g, 66.7 mmol) and tetraethylammonium chloride (11.05 g, 66.7 mmol) were suspended in phosphoroxychloride (20 mL, excess) and heated at 130 °C for 18 h and then at 145 °C for 2 h. The reaction mixture was allowed to cool to RT and poured onto crushed ice (150 g). Extraction of ethyl acetate (3 x 100 mL), drying of the combined organic layers (MgSO4) and evaporation in vacuo gave 11.34 g (89 %) of a white solid.
1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H) 13.90 (br s, OH).
Example 17 - 2-chloro-6-methoxyisonicotinic acid
Freshly prepared sodium methoxide (from 1.5 g sodium in 15 mL dry methanol) was added dropwise to a solution of Example 16 (5.0 g, 26 mmol) in dry methanol (25 mL). The reaction mixture was refluxed for 24 h, allowed to cool to RT and poured in aqueous HC1 (10%, 100 mL). A pinkish solid separated and was collected on a filter, washed with water and air-dried (4.0 g, 82%).
1HNMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H) 7.17 (s, 1H) 7.39 (s, 1H) 13.96 (br s, OH). Example 18 - (2-chloro-6-methoxypyridin-4-vDmefhanol
BH3.DMS (1.0 mL, 10.66 mmol) was refluxed in THF (20 mL) for 30 min (formation of BH3.THF). At RT, Example 17 (2.0 g, 10.66 mmol in 10 mL THF) was added dropwise, and then the reaction mixture was heated to reflux for 3 h. The solution was allowed to cool to ambient temperature, solid sodium carbonate (0.5 g) and water (5 mL). The resulting mixture was heated for a short while and poored in water (50 mL). Extraction with ethyl acetate (3 x 50 mL), drying of the combined organic layers (Na2SO4) and evaporation in vacuo gave a 1 :1 mixture of starting material and product. Purification by flash column chromatography over silica gel eluting with ethyl acetate gave 780 mg (42 %) of an off-white solid.
1H NMR (400 MHz, CDC13) δ 3.92 (s, 3H) 4.66 (s, 2H) 6.64 (s, 1H) 6.89 (s, 1H).
Example 19 - 4-(bromomethyl -2-chloro-6-methoxypyridine To a stirred icebath-cooled solution of triphenylphosphine (1.36 g, 5.19 mmol) in DCM (75 mL) was added bromine (0.83 g, 5.19 mmol) dropwise. Stirring of the resulting colorless solution was continued for 30 min after which time the ice-bath was removed. Example 18 (0.75 g, 4.32 mmol) was added portion- wise and the reaction mixture was stirred for another 2 h. DCM (75 mL) was added and the organic phase was washed with water (100 mL) and brine (100 mL). Drying (Na2SO4) of the DCM-layer and evaporation in vacuo gave " a solid residue that was purified by flash column chromatography over silica gel eluting with DCM giving 350 mg (34 %) of a white solid.
1H NMR (400 MHz, CDC13) δ 3.93 (s, 3H) 4.27 (s, 2H) 6.64 (s, 1H) 6.92 (s, 1H).
Example 20 - 4-nitro-5,6,7-8,9 0-hexahvdrocyclohepta[b]indole 2-nitrophenylhydrazine (5.0 g, 32.6 mmol) and cycloheptanone (3.7 g, 33.0 mmol) were refluxed in ethanol (100 mL) for 3 h. Evaporation in vacuo gave the hydrazone as a red crystalline solid. The hydrazone was taken up in cone. HC1 (90 mL) and refluxed for 3 h on an oil bath, causing a thick orange solid to separate. After cooling to RT, the reaction mixture was poored into water (200 L) and extracted by diethyl ether (3 x 100 mL). Combined ether layers were dried (Na2SO4) and reduced to dryness. Flash column chromatography on silica gel eluting with DCM gave 5.3 g (71%) of an orange solid: Mp 159-160 °C. 1HNMR (400 MHz, CDC13) δ 1.78-1.87 (m, 4H) 1.93-1.98 (m, 2H) 2.83-2.86 (m, 2H), 2.93-2.96 (m, 2H) 7.15 (t, J=7.91 Hz, 1H) 7.80 (d, J=7.53 Hz, 1H) 8.06 (d, J=8.03 Hz, 1H) 9.51 (br s, 1H); 13C NMR (100 MHz, CDC13) δ 24.95, 27.57, 28.81, 29.73, 31.89, 115.47, 118.15, 118.72, 125.99, 128.18, 133.55, 140.61; MS (El*) m/z 231.2; Anal. Calc. (found) for Cι3Hι N2O2: C 67.81 (67.8) H 6.13 (6.3) N 12.17 (12.1).
Example 21 - 5-benzyl-4-nitro-5,6,7,8,9,10-hexahvdrocyclohep'tarblindole A stirred solution of Example 20 (140 mg, 0.61 mmol) in dry DMSO (2 mL) was treated with KOH powder (170 mg, 3.05 mmol). After 5 min the orange solution was treated with benzyl bromide (145 μL, 1.22 mmol) turning the reaction mixture black and slowly back to orange again. After 10 min the reaction was quenched with water (20 mL) and the product was extracted with diethyl ether (3 x 30 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The residual orange oil was purified by flash column chromatography on silica gel eluting with n-hexane / toluene (2: 1 v/v) to give 163 mg (84%) of a yellow oil. The oil solidified on standing: Mp 69-70 °C.
1H NMR (400 MHz, CDCI3) δ 1.71-1.83 (m, 4H) 1.87-1.91 (m, 2H), 2.82-2.88 (m, 4H) 5.38 (s, 2H) 6.77-6.79 (m, 2H) 7.07 (t, J=7.78 Hz, 1H) 7.16-7.22 (m, 3H) 7.59 (dd, Jl=7.91, J2=1.13 Hz, 1H) 7.74 (dd, Jl=7.78, J2=1.00 Hz, 1H); 13C NMR (100 MHz, CDC13) 6 24.19, 26.84, 26.92, 28.13, 31.34, 48.79, 116.47, 118.30, 119.15, 123.62, 126.17, 126.76, 127.52, 128.93, 133.21, 137.08, 138.12, 143.49; MS (El4) m/z 321.2; Anal. Calc. (found) for C20H20N2O2: C 74.98 (75.1) H 6.26 (6.7) N 8.74 (9.3).
Example 22 - 5-benzyl-5.6,7,8,9 0-hexahydrocycloheptarb1indol-4-amine A stirred solution of Example 21 (100 mg, 0.31 mmol) in ethyl acetate (7 mL) was treated with tin dichloride hydrate (300 mg, 1.58 mmol) and heated to reflux until the yellow color had dissappeared. The resulting suspension was quenched with water (5 mL) and Na CO3 (0.5 g, vigorous reaction!) and heated at 70 °C for 10 min. The reaction mixture was allowed to cool to RT and extracted with ethyl acetate (3 x 5 mL), the combined organic layers were dried (Na2SO4), and evaporated to give 100 mg of crude product. Purification by flash column chromatography on silica gel eluting with n-hexane / diethyl ether (2:1 v/v) afforded 63 mg (70%) of a pale brown solid: MS (EI+) m/z 291.2. Example 23 - 4-nitro-5-r2-ftrifluoromethyl,benzyll-5,6.7,8.9.10- hexahydrocycloheptarblindole
A stirred solution of Example 20 (150 mg, 0.65 mmol) in dry DMF (4 mL) was treated with sodium hydride (19 mg, 0.78 mmol) resulting in a dark red solution. 2- trifluoromethylbenzyl bromide (187 mg, 0.78 mmol) in dry DMF (2 mL) was added dropwise over a 5-min period. After stirring for 4 h, the clear solution showed 50% conversion (GC). A second portion of sodium hydride (19 mg, 0.78 mmol) and 2- trifluoromethylbenzyl bromide (187 mg, 0.78 mmol) was added and stirred continued for 18 h after which time the starting material and product composition was unchanged. The mixture was washed with aqueous HC1 (5%, 10 mL) and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The residual yellow oil was purified by flash column chromatography on silica gel eluting with n-hexane / diethyl ether (2:1 v/v) to give 100 mg (40%) of a yellow solid: Mp 111.5-111.6 °C.
1HNMR (400 MHz, CDC13) δ 1.63-1.68 (m, 2H) 1.76-1.81 (m, 2H) 1.84-1.89 (m, 2H) 2.63-2.66 (m, 2H) 2.86-2.88 (m, 2H) 5.51 (s, 2H) 6.55-6.57 ( , IH) 7.13 (t, J=7.91 Hz, IH) 7.31-7.37 (m, 2H) 7.67-7.70 (m, 2H) 7.78 (dd, Jl=7.78, J2=1.00 Hz, IH); MS (EI+) m/z 389.0.
Example 24 - 5-[2-(trifluoromethyl benzyl]-5.6 ,8,9 0-hexahvdrocvclo- hepta[b]mdol-4-amine
A stirred solution of Example 23 (62 mg, 0.16 mmol) in ethanol (4 mL) was hydrogenated over Pd/C (10%, spatula) under 1 atm of hydrogen. After lh the mixture was filter over Celite and evaporated in vacuo, affording 54 mg (94% of a colorless oil.
1H NMR (400 MHz, CDCI3) δ 1.64-1.70 (m, 2H) 1.75-1.81 (m, 2H) 1.84-1.89 (m, 2H) 2.62-2.65 (m, 2H) 2.82-2.85 (m, 2H) 3.27 (br s, 2H) 5.86 (s, 2H) 6.41 (dd, Jl=7.53, J2=1.00 Hz, IH) 6.67 (d, J=7.28 Hz, IH) 6.89-6.92 (m, IH) 7.08 (dd, Jl=7.91, J2=0.88 Hz, IH) 7.33-7.41 (m, 2H) 7.72 (d, J=6.78 Hz, IH); 13C NMR (100 MHz, CDC13) δ 24.32, 25.80, 27.02, 28.23, 31.45, 44.47, 110.28, 110.50, 115.26, 119.76, 124.37 (q, J=274.1 Hz, CF3), 126.08, 126.13, 126.48, 127.12, 127.28, 130.07, 131.60, 132.80, 138.39, 139.34; MS (El4) m/z 359.0.
Example 25 - N-(5-r2-(trifluoromethyl)benzyll-5,6.7,8,9.10-hexahvdrocyclo- heptarblindol-4-yl)dibenzenesulfonamide
Benzenesulfonylchloride (0.040 ml, 0.31 mmol) was added to a solution of 5-[2- (trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4-amine (Example 24) (0.055 g, 0.15 mmol) and triethylamine (0.042 ml, 0.31 mmol) in DCM (2 ml) and the reaction was stirred for 1 hour at RT and 50°C overnight. Water and DCM were added and the pH was adjusted to 3 with IN HCl. The organic phase was dried (MgSO ) and evaporated and the crude product was purified by flash chromatography 50 % hexane in DCM to 10 % hexane. Yield: 0.037 g (39 %). White solid.
1H NMR (400 MHz,CDCl3) δ 1.22-1.38 (m, 1 H) 1.46-1.60 (m, 1 H) 1.61-1.88 (m, 4 H) 2.16-2.29 (m, 1 H) 2.43-2.55 (m, 1 H) 2.72-2.94 (m, 2 H) 4.91 (d, J=18.32 Hz, 1 H) 5.90 (d, J=18.32 Hz, 1 H) 6.04-6.13 (m, 1 H) 6.49-6.51 (m, 1 H) 6.94 (t, J=7.78 Hz, 1 H) 7.23- 7.38 (m, 5 H) 7.40-7.50 (m, 2 H) 7.55 (t, J=7.40 Hz, 1 H) 7.51-7.72 (m, 4 H) 7.81 (d, J=7.53 Hz, 2 H), MS (70eV) m/z (%) 639 (M+,100).
Example 26 - N-(benzyloxy -9-benzyl-2,3 A9-tefrahvdro-lH-carbazole-8- carboxamide
To a solution of Example 40 (75 mg, 0.25 mmol) in DCM (3 mL) at 0 °C was added HOBT (34 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol) and Et3N (70 μL, 0.5 mmol). After 5 min of stirring, O-benzylhydroxylamine hydrochloride (47 mg, 0.30 mmol) was added to the clear solution. Stirring continued for 18 h, washed with aqueous HCl (10%, 5 mL). Extraction of the aqueous phase with DCM (2 x 5 mL), drying (Na2SO4) of the combined organic phases and evaporation to dryness gave 110 mg of a crude solid. Purification by flash column chromatography over silica gel eluting with a gradient n-hexane / DCM (1:1 v/v) to DCM gave two main products:
8- [( 1 H- 1 ,2,3 -benzotriazol- 1 -yloxy)carbonyl]-9-benzyl-2,3 ,4,9-tetrahydro- 1 H- carbazole: Yellowish solid (40 mg, 38%); Mp 116.7-118.4 °C. Η NMR (400 MHz, CDC13) δ 1.90-2.03 (m, 4H) ) 2.72 (t, J=6.02 Hz, 2H) 2.84 (t, J=5.90 Hz, 2H) 5.61 (s, 2H) 6.70-6.76 (m, 3H) 7.27-7.30 (m, 4H) 7.39-7.44 (m, 2H) 7.92 (dd, Jl=7.78, J2=1.25 Hz, IH) 8.06-8.10 (m, IH) 8.13 (dd, Jl=7.65, J2=1.13 Hz, IH); 13C NMR (100 MHz, CDC13) 6 20.21, 21.80, 22.18, 22.59, 47.11, 107.91, 108.40, 110.92, 117.61, 119.62, 123.98, 124.55, 124.96, 125.25, 126.36, 127.76, 128.09, 128.20, 130.19, 133.40, 137.48, 138.36, 142.80, 162.12; MS (El ) m/z 423.0; Anal. Calc. (found) for C26H22N2O2 • 0.1 DCM: C 72.61 (72.9) H 5.19 (5.4) N 12.97 (13.0).
N-(benzyloxy)-9-benzyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxamide: Yellow foam (33 mg, 32%), purity 70%. 1H NMR (400 MHz, CDC13) δ 1.83-1.95 (m, 4H) ) 2.64 (t, J=6.02 Hz, 2H) 2.75 (t,
J=5.77 Hz, 2H) 4.70 (s, 2H) 5.53 (s, 2H) 6.76-6.78 (m, 2H) 6.97-7.00 (m, 2H) 7.14-7.21 (m, 5H) 7.30-7.31 (m, 3H) 7.58-7.60 (m, IH) 7.83 (s, NH); MS (El4) m/z 411.2.
Synthesis of active compounds (Examples 27-199)
Example 27 - 2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid A solution of 2-hydrazinobenzoic acid, hydrochloride (40.0 g, 0.212 mol) and cyclohexanone (26 ml, 0.254 mol) in AcOH (500 ml) was refluxed for 3.5 h before the solvent was evaporated and water (200 ml) and EtOAc (1000 ml) was added. Organic layer was extracted with IN NaOH and the combined aqueous layers acidified with 6 N HCl and extracted with EtOAc, organic layers dried (MgSO4) and concentrated. Yield 34.88 g (76%); white solid.
1H NMR (400 MHz, DMSO-d6) δ 1.77-1.80 (m, 4 H), 2.61-2.64 (m, 2 H), 2.75 (m, 2 H), 7.01 (t, J=8 Hz, 1 H), 7.58 (d, J=8 Hz, 1 H), 7.63 (d, J=8 Hz, 1 H), 10.56 (s, 1 H), 12.81 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.39, 22.70, 22.87, 108.46, 112.51, 117.50, 122.28, 122.64, 128.82, 134.73, 136.26, 168.10. CAS[65764-56-9]
Example 28 - methyl 2,3.4,9-tetrahydro-lH-carbazole-8-carboxylate 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (Example 27) (34.88 g, 0.162 mol) was refluxed in MeOH (600 ml) and cone. H2SO4 (100 ml) for 3 h. Some MeOH was evaporated and water added and the aqueous layer extracted with Et2O. The combined organic layers were washed with sat. NaHCO3 and dried (MgSO4). Yield 34.90 g (94%); white solid.
1H NMR (400 MHz, CDC13) δ 1.86-1.94 (m, 4 H), 2.70-2.79 (m, 4 H), 3.97 (s, 3 H), 7.08 (t, J=8 Hz, 1 H), 7.65 (d, J=8 Hz, 1 H), 7.78 (d, J=8 Hz, 1 H), 9.37 (s, 1 H). 13C NMR (100 MHz, CDCI3) 620.78, 23.10, 23.19, 57.71, 110.03, 111.52, 118.22, 123.02, 123.20, 129.06, 135.39, 135.75, 168.16. CAS[59003-26-8]
Example 29 - 2,3,4.9-tetrahydro-lH-carbazole-7-carboxylic acid 3-hydrazinobenzoic acid (2.08 g, 13.67 mmol), cone. HCl (1.2 ml) and cyclohexanone (1.70 ml) was refluxed in AcOH (50 ml) for 3.5 h. Solvent evaporated and residue dissolved in water/EtOAc. Organic layer washed with water and dried (MgSO4). Crude compound recryst. from EtOH. Yield: 494 mg (17%) white solid. Mp. 280 °C.
Η NMR (400 MHz, DMSO-d6) δ 1.79-1.84 (m, 4 H), 2.61-2.64 (m, 2 H), 2.72-2.75 (m, 2 H), 7.36 (d, J=8 Hz, 1 H), 7.54 (dd, J=8, 1 Hz, 1 H), 7.87 (s, 1 H), 10.99 (s, 1 H), 12.29 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 620.45, 22.56, 22.83, 108.81, 112.44, 116.48, 119.28, 121.96, 130.49, 134.80, 138.55, 168.48.
Beilsteinno 190295, no CAS number
Example 30 - methyl 2,3A9-tetrahydro-lH-carbazole-7-carboxylate
3-hydrazinobenzoic acid (8.19 g, 53.83 mmol), cone. HCl (4.5 ml) and cyclohexanone (5.56 ml, 53.81 mmol) was refluxed in AcOH (200 ml) for 3 h. Solvent evaporated and EtOAc (300 ml) and water (100 ml) added. Organic layer filtered and extracted with 2 N NaOH (3 x 75 ml). The alkaline layers made acidic by addition 2 N HCl, extracted with Et2O, dried and concentrated. The crude mixture was dissolved in MeOH (150 ml) and cone. H2SO4 (25 ml) was added. The mixture was refluxed for 2 h, most of solvent evaporated and water added. The mixture was extracted with Et2O and the products isolated by flash chromatography using hexanes/EtOAc 7:1 and 4:1. First eluated: 1.69 g; methyl 2,3,4,9-tetrahydro-lH-carbazole-5-carboxylate. Second eluated 6.80 g; 1 : 1 mixture of methyl 2,3,4,9-tetrahydro-lH-carbazole-5-carboxylate and methyl 2,3,4,9-tetrahydro-lH- carbazole-7-carboxylate. Third eluated: 3.10 g; pale yellow solid, title compound. Mp 154 °C.
1H NMR (400 MHz, CDC13) δ 1.86-1.92 (m, 4 H), 2.70-2.77 (m, 4 H), 3.92 (s, 3 H), 7.45 (d, J=8 Hz, 1 H), 7.77 (dd, J=8, 2 Hz, 1 H), 7.93 (s, 1 H), 8.01 (s, 1 H).13C NMR (100 MHz, CDC13) δ 20.80, 22.95, 23.09, 23.41, 51.79, 110.89, 112.54, 117.16, 120.48, 122.49, 131.47, 134.92, 138.10, 168.42. MS: 230 (M+l). Found: C, 73.22; H, 6.76; N, 5.85%. Calc. for Ci4Hi5NO2: C, 73.34; H, 6.59; N, 6.11%. CAS [92247-98-8]
Example 31 - 2.3-dimethyl-lH-indole-7-carboxylic acid 2-hydrazinobenzoic acid hydrochloride (5.00 g, 26.51 mmol) and 2-butanone (10 ml,
110 mmol) in AcOH (50 ml) was refluxed for 3.5 h. Most of solvent evaporated and crude compound dissolved in water/EtOAc. Organic layer evaporated and crude material recryst. in EtOH. Yield 1.96 g (39%). Mp. 216 °C.
1H NMR (400 MHz, DMSO-d6) δ 2.16 (s, 3 H), 2.36 (s, 3 H), 7.02 (t, J=8 Hz, 1 H), 7.62 (m, 2 H), 10.50 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 8.14, 11.12, 105.53, 112.33, 117.52, 122.52, 122.60, 130.42, 133.18, 134.27, 168.10. CAS: [103986-07-8]
Example 32 - methyl 2,3 -dimethyl- lH-indole-7-carboxylate 2,3-dimethyl-lH-indole-7-carboxylic acid (Example 31) (1.208 g, 6.38 mmol) was refluxed with cone. H2SO4 (1 ml) in MeOH (10 ml) for 1.5 h. Most of MeOH evaporated and water and Et O added. The organic phase was washed with sat. NaHCO3, dried (MgSO4) and evaporated. Yield 1.209 g (93%). Mp. 97-98 °C.
1H NMR (400 MHz, CDC13) δ 2.24 (s, 3 H), 2.40 (s, 3 H), 3.97 (s, 3 H), 7.09 (t, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 H), 7.78 (d, J=8 Hz, 1 H), 9.36 (s, 1 H). 13C NMR (100 MHz,
CDCI3) 6 8.32, 11.51, 51.70, 106.99, 111.26, 118.16, 122.97, 123.41, 130.67, 131.97, 135.28, 168.16. CAS[105908-32-5]
Example 33 - 5,6,7,8,9,10-hexahydrocyclohepta[T-'1indole-4-carboxylic acid 2-hydrazinobenzoic acid hydrochloride (10.00 g, 53.0 mmol) and cycloheptanone
(7.50 ml, 7.12 g, 63.6 mmol) in acetic acid (250 ml) was refluxed for 3.5 h. The solvent evaporated and the residue dissolved in ethyl acetate. The organic layer was extracted with three times with IN NaOH. The combined aqueous layers were acidified with 2N HCl and extracted with Et2O and dried (MgSO4). Yield: 5.72 g (47%); pale brown solid. Mp. 230-231 °C.
'H NMR (400 MHz, DMSO-d6) δ 1.66-1.67 (m, 4 H), 1.82-1.83 (m, 2 H), 2.72-2.75 (m, 2 H), 2.94-2.97 (m, 2 H), 7.01 (t, J=8 Hz, 1 H), 7.61 (d, J=7 Hz, 1 H), 7.64 (d, J=8 Hz, 1 H), 10.54 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 24.15, 27.08, 27.88, 28.48, 31.58, 112.49, 112.57, 117.60, 122.39, 122.47, 130.16, 133.24, 139.93, 168.16. MS: 230 (M+l). 228 (M-l).
Example 34 - methyl 5,6.7,8,9 0-hexahydrocyclohepta[b]indole-4-carboxylate .5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 33) (4.25 g, 18.53 mmol) was refluxed with methanol (100 ml) and cone. H2SO4 (10 ml) for 2 h, when TLC indicated full conversion. Water and Et2O was added and the organic layer washed with sat. NaHCO3 twice and dried (MgSO4). Yield: 3.86 g (91%); yellow solid. Mp. 107 °C.
1H NMR (400 MHz, CDC13) δ 1.76-1.79 (m, 4 H), 1.88-1.93 (m, 2 H), 2.80-2.83 (m, 2 H), 2.87-2.90 (m, 2 H), 3.97 (s, 3 H), 7.09 (t, J=8 Hz, 1 H), 7.68 (d, J=8 Hz, 1 H), 7.77 (d, J=8 Hz, 1 H), 9.38 (s, 1 H). 13C NMR (100 MHz, CDCI3) δ 24.60, 27.38, 28.65, 29.42, 31.69, 51.73, 111.38, 113.58, 118.16, 122.74, 123.15, 130.41, 134.20, 138.71, 168.16. MS: 244 (M+l). Found: C, 74.11; H, 6.58; N, 5.51%. Calc. for Cι5Hι7NO2: C, 74.05; H, 7.04; N, 5.76%.
Example 35 - 2.3-diphenyl-lH-indole-7-carboxylic acid
2-hydrazinobenzoic acid hydrochloride (5.00 g, 30.08 mmol) and deoxybenzoin (5.90 g, 30.08 mmol) was refluxed in AcOH (100 ml) for 30 min, cone. HCl (50 ml) was added and mixture refluxed for 4 h. Water (800 ml) was added and a white solid precipitated. The solid was filtered, washed with water and recryst. from EtOAc (100 ml). Yield 2.23 g (24%); white solid. Mp. 262 °C.
1H NMR (400 MHz, DMSO-d6) 6 7.18 (t, J=8 Hz, 1 H), 7.27-7.47 (m, 10 H), 7.75 (d, J=8 Hz, 1 H), 7.82 (d, J=8 Hz, 1 H), 10.73 (s, 1 H), 13.19 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 113.80, 113.99, 119.68, 124.08, 124.72, 126.47, 127.97, 128.48, 128.72, 129.36, 129.86, 131.69, 134.35, 135.05, 135.38, 167.94. Found: 313.1117 (M4). Calc. for C2ιHι5NO2: 313.1103. CAS [197313-74-9].
Example 36 - 6-Methyl-2,3.4.9-tetrahvdro-lH-carbazole-8-carboxylic acid 2-hydrazino-5-methylbenzoic acid hydrochloride (1.93 g, 9.544 mmol) and cyclohexanone (2.00 ml, 19.3 mmol) was heated at 130 °C in AcOH (20 ml) for 3 h. Solvent was evaporated. The product was purified by flash chromatography using 2% and 5% MeOH in DCM. Yield 1.09 g (50%); white solid. Mp. 151 °C.
'HNMR (400 MHz, DMSO-d6) δ 1.76-1.80 (m, 4 H), 2.38 (s, 3 H), 2.60 (t, J=5.3 Hz, 2 H), 2.73 (t, J=5.1 Hz, 2 H), 7.38 (s, 1 H), 7.46 (s, 1 H), 10.34 (s, 1 H). 13C NMR (100 MHz, DMSO-de) δ 20.35, 20.74, 22.69, 22.79, 22.85, 107.92, 112.08, 122.32, 123.56, 126.02, 129.11, 133.28, 136.25, 168.03. MS: 230 (M+l). Found: 229.1107 (M+). Calc. for Cι4Hι5NO2: 229.1103.
Example 37 - methyl 6-methyl-2.3 A9-tetrahydro-lH-carbazole-8-carboxylate
6-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (Example 36) (950 mg, 4.14 mmol) was refluxed with dry MeOH (20 ml) and cone. H2SO (2 ml) for 2.5 h. Water (5 ml) and diethyl ether (150 ml) was added, the organic layer washed with sat. NaHCO3 (50 ml) and concentrated. The product was purified by flash chromatography using 5% EtOAc in hexanes as eluent. Yield 724 mg; white solid. Mp. 109 °C.
1H NMR (400 MHz, CDC13) 6 1.87-1.92 (m, 4 H) 2.46 (s, 3 H) 2.67-2.77 (m, 4 H) 3.96 (s, 3 H) 7.45 (s, 1 H) 7.61 (s, 1 H) 9.21 (s, 1 H). 13C NMR (100 MHz, CDCI3) δ 20.77, 21.25, 23.10, 23.20, 51.69, 109.46, 111.03, 123.45, 123.95, 127.46, 129.28, 134.16, 135.49, 168.14. MS: 244 (M+l). Found: C, 73.56; H, 6.60; N, 5.36%. Calc. for Cι5H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: 243.1262 (Ivf4). Calc. for Cι5H17NO2: 243.1259.
Example 38 - methyl 3-methyl-2.3A9-tetrahvdro-lH-carbazole-8-carboxylate The compound was prepared using analogue procedure for Example 36 starting from hydrazinobenzoic acid hydrochloride and 4-methylcyclohexanone then esterified using the same procedure as for Example 37. Example 39 - methyl 9-benzyl-2.3.4,9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (480 mg, 8.55 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (413 mg, 1.810 mmol) in DMSO (5 ml) and the yellow solution stirred for 5 min. Benzyl bromide (500 μl, 3.59 mmol) was added and the mixture stirred for 10 min and quenched with sat. NH4C1 and extracted with Et2O.
The product was purified by flash chromatography using 2% and 5% EtOAc in hexanes.
Yield 429 mg (74%); colorless oil.
1H NMR (400 MHz, CDC13) 6 1.77-1.84 (m, 4 H), 2.54-2-56 ( , 2 H), 2.67-2.68 (m,
2 H), 3.55 (s, 3 H), 5.41 (s, 2 H), 6.69 (d, J=7 Hz, 2 H), 6.96 (t, J= 8 Hz, 1 H), 7.08 (m, 3 H), 7.38 (dd, J=8, 1 Hz, 1 H), 7.55 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) δ 20.92,
22.49, 22.96, 23.32, 47.91, 51.85, 110.76, 116.27, 117.93, 121.72, 123.73, 125.89, 126.74,
128.34, 130.11, 133.18, 138.05, 138.76, 168.44.
Example 40 - 9-benzyl-2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (234 mg, 0.733 mmol) and KOH (188 mg, 3.35 mmol) was refluxed with EtOH (10 ml) and H2O (1 ml) for 3.5 h. Some EtOH evaporated and 2 N HCl (3 ml) added. White solid filtered and washed with water and dried under high vacuum. Yield 161 mg (72%) white solid. Mp. 207 °C. lH NMR (400 MHz, DMSO-d6) 6 1.77-1.87 (m, 4 H), 2.63-2.69 (m, 4 H), 5.59 (s, 2
H), 6.73 (d, J=7 Hz, 2 H), 7.02 (t, J=8 Hz, 1 H), 7.11-7.21 (m, 3 H), 7.40 (m, 1 H), 7.60 (d, J=8 Hz, 1 H), 12.74 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.43, 21.90, 22.47, 22.78, 46.99, 110.00, 117.28, 117.73, 121.22, 123.39, 125.79, 126.66, 128.36, 129.55, 132.66, 137.88, 138.87. MS: 306 (M+l). Found: C, 77.83; H, 6.21; N, 4.39%. Calc. for C20Hι9NO2y4H2O: C, 77.51; H, 6.34; N, 4.54%.
Example 41 - methyl 9-C4-bromobenzyl)-2.3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH (308 mg, 5.49 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (348 mg, 1.518 mmol) in DMSO (5 ml) and the yellow mixture stirred for 3 min. 4-bromobenzyl bromide (830 mg, 3.32 mmol) was added and the mixture stirred for 5 min before quenched with sat. NH4C1 and extracted with Et O. The product was purified by flash chromatography using 2% and 5% Et O in hexanes. Yield 368 mg (61%); white solid. Mp. 128 °C.
1H NMR (400 MHz, CDC13) δ 1.89-1.97 (m, 4 H), 2.63-2.65 (m, 2 H), 2.77-2.80 (m, 2 H), 3.71 (s, 3 H), 5.49 (s, 2 H), 6.70 (d, J=8 Hz, 2 H), 7.10 (t, J=8 Hz, 1 H), 7.34 (d, J=8 Hz, 2 H), 7.53 (dd, J=8, 1 Hz, 1 H), 7.68 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 620.90, 22.50, 22.93, 23.30, 47.54, 51.98, 111.13, 116.07, 118.15, 120.59, 122.00, 124.12, 127.70, 130.19, 131.50, 133.25, 138.00, 168.34. Found: C, 63.35; H, 5.00; N, 3.51%. Calc. for C2ιH20BrNO2: C, 63.35; H, 5.06; N, 3.52%.
Example 42 - 9-f4-bromobenzyl)-2,3A9-tefrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 41) (327 mg, 0.820 mmol) and KOH (508 mg, 9.05 mmol) was refluxed in EtOH (20 ml) and H2O (2 ml) for 3 h. EtOH was evaporated and 2 N HCl and water added. The white solid precipitate was filtered, washed with water and dried under vaccum (50 °C). Yield 115 mg (37%); white solid. Mp. 181 °C. The filtrate was extracted with EtOAc and 186 mg (59%) more material was isolated.
1H NMR (400 MHz, DMSO-d6) 6 1.79-1.84 (m, 4 H), 2.62-2.67 (m, 4 H), 5.54 (s, 2 H), 6.67 (d, J=8 Hz, 2 H), 7.03 (t, J=8 Hz, 1 H), 7.40 (m, 3 H), 7.61 (d, J=8 Hz, 1 H), 12.77 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 20.42, 21.84, 22.44, 22.76, 46.64, 110.16, 117.19, 117.90, 119.71, 121.35, 123.49, 128.02, 129.57, 131.27, 132.55, 137.79, 138.40, 168.90. Found: C, 62.69; H, 4.64; N, 3.62%. Calc. for C20Hι8BrNO2: C, 62.51; H, 4.72; N, 3.64%.
Example 43 - methyl 9-(4-methylbenzylV2.3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH (305 mg, 5.44 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (330 mg, 1.439 mmol) in DMSO (5 ml) and the yellow mixture stirred for 3 min before 4-methyl-benzyl bromide (759 mg, 4.10 mmol) was added and stirring was continued for 5 min before the mixture was quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 2% and 5% EtOAc in hexanes. Yield 316 mg (66°/0); white solid. Mp. 80 °C. 1H NMR (400 MHz, CDC13) 6 1.92-1.99 (m, 4 H), 2.31 (s, 3 H), 2.69-2.71 (m, 2 H), 2.82-2.83 (m, 2 H), 3.73 (s, 3 H), 5.52 (s, 2 H), 6.75 (d, J=8 Hz, 2 H), 7.04 (d, J=8 Hz, 2 H), 7.11 (t, J=8 Hz, 1 H), 7.54 (d, J=7 Hz, 1 H), 7.70 (d, J=7 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 6 20.88, 20.91, 22.45,22.93, 23.28, 47.61, 51.81, 110.63, 116.20, 117.82, 121.65, 123.67, 125.80, 128.97, 130.06, 133.16, 135.63, 136.19, 138.03 168.39. Found: C, 79.38; H, 7.15; N, 4.03%. Calc. for C22H23NO2: C, 79.25; H, 6.95; N, 4.20%.
Example 44 - 9-(4-methylbenzyl)-2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(4-methylbenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 43) (303 mg, 0.909 mmol) and KOH (208 mg, 3.71 mmol) was refluxed with EtOH (10 ml) and H O (10 ml) overnight. Most of EtOH evaporated and the solution acidified by addition of 2 N HCl and extraction with EtOAc. The combined organic layers were dried (MgSO4) and evaporated. Yield 265 mg (91%); white solid. Mp. 156 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.77-1.85 (m, 4 H), 2.17 (s, 3 H), 2.65 (m, 4 H), 5.52 (s, 2 H), 6.62 (d, J=8 Hz, 2 H), 6.97-7.03 (m, 3 H), 7.39 (d, J=8 Hz, 1 H), 7.59 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.45, 20.51, 21.94, 22.49, 22.81, 46.72, 109.96, 117.27, 117.69, 121.21, 123.36, 125.81, 128.94, 129.56, 132.64, 135.74, 135.78, 137.90, 168.97.
Example 45 - methyl 9-.4-cyanobenzyl)-2,3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH (305 mg, 5.44 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (302 mg, 1.317 mmol) in DMSO (5 ml) and the yellow mixture stirred for 3 min before 4-cyanobenzyl bromide (602 mg, 3.07 mmol) was added and the mixture stirred 5 min and quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 10% and 20% EtOAc in hexanes as eluents. Yield 308 mg (68%); white solid. Mp. 170 °C.
1H NMR (400 MHz, CDCI3) δ 1.86-1.95 (m, 4 H), 2.57-2.59 (m, 2 H), 2.74-2.77 (m,
2 H), 3.66 (s, 3 H), 5.59 (s, 2 H), 6.89 (d, J=8 Hz, 2 H), 7.09 (t, J=8 Hz, 1 H), 7.48 (d, J=8 Hz, 2 H), 7.54 (dd, J=8, 1 Hz, 1 H), 7.67 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 6
20.81, 22.41, 22.82, 23.21, 47.95, 51.96, 110.72, 111.44, 115.83, 118.36, 118.68, 122.25, 124.46, 126.62, 130.22, 132.22, 133.30, 137.63, 144.73, 168.10. Found: C, 79.39; H, 5.87; N, 8.11%. Calc. for C22N20N2O2: C, 76.72; H, 5.85; N, 8.13%.
Example 46 - 9- 4-(aminocarbonvDbenzyl]-2.3 A9-tetøhydro-lH-carbazole-8- carboxylic acid
Methyl 9-(4-cyanobenzyl)-2,3,4,9-tetrahydro- lH-carbazole-8-carboxylate (Example 45) (254 mg, 0.737 mmol) and KOH (205 mg, 3.65 mmol) was refluxed in EtOH (20 ml) and H2O (2 ml) for 6 h. 2 N HCl was added and the precipitate filtered and washed with water and Et2O and recryst.from EtOH. Yield 86 mg (35%); white solid. Mp. 279°C. Η NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.62-2.70 (m, 4 H), 5.63 (s, 2
H), 6.77 (d, J=8 Hz, 2 H), 7.04 (t, J=8 Hz, 1 H), 7.24 (s, 1 H), 7.40-7.42 (m, 1 H), 7.62 (m, 1 H), 7.68 (d, J=8 Hz, 2 H), 7.80 (s, 1 H), 12.76 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 620.42, 21.87, 22.45, 22.76, 46.96, 110.13, 117.20, 117.86, 121.34, 123.49, 125.53, 127.59, 129.56, 132.67, 132.83, 137.86, 142.21, 167.49, 168.89. MS: 347 (M-l). Found: C, 71.45; H, 5.61; N, 7.87%. Calc. for C2ιH20N2O3 1/4H2O: C, 71.46; H, 5.86; N, 7.94%.
Example 47 - methyl 9-(3-methoxybenzyl -2,3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH was added to a solution of methyl 2,3 ,4,9-tetrahydro- lH-carbazole-8- carboxylate (Example 28) (600 mg, 2.62 mmol) in DMSO (10 ml) and the mixture stirred for 5 min at ambient temperature before 3-methoxybenzyl chloride (1.00 ml, 5.53 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 5% EtOAc in hexanes. Yield 508 mg (55%); colorless oil. Small impurities.
1H NMR (400 MHz, CDC13) δ 1.86-1.95 (m, 4 H), 2.65-2.68 (m, 2 H), 2.74-2.77 (m, 2 H), 3.67 (s, 3 H), 3.68 (s, 3 H), 5.48 (s, 2 H), 6.36 (m, 2 H), 6.69 (dd, J=8, 2 Hz, 1 H), 7.04- 7.11 (m, 2 H), 7.48 (dd, J=7, 1 Hz, 1 H), 7.64 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 620.93, 22.51, 22.98, 23.35, 47.86, 51.92, 55.04, 110.85, 111.90, 111.92, 116.23, 117.94, 118.26, 121.78, 123.81, 129.40, 130.16, 133.31, 138.06, 140.54, 159.70, 168.46. Example 48 - 9-(3-Methoxybenzyl>2,3 A9-tefrahydro-lH-carbazole-8-carboxylic acid
Methyl 9-(3 -methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 47) (230 mg, 0.658 mmol) and KOH (483 mg, 8.608 mmol) in EtOH (20 ml) and H2O (2 ml) was refluxed for 3 h. The solution acidified with 2 N HCl and extracted with EtOAc. Organic layers were dried (MgSO4) and evaporated. Collected crystals were washed with Et2O. Yield 140 mg (64%); white solid. Mp. 199-201 °C.
1HNMR (400 MHz, DMSO-d6) δ 1.78-1.85 (m, 4 H), 2.65-2.69 (m, 4 H), 3.62 (s, 2 H), 5.55 (s, 2 H), 6.27 (d, J=8 Hz, 2 H), 6.71 (dd, J=8, 2 Hz, 1 H), 7.01-7.21 (m, 2 H), 7.41 (d, J=8 Hz, 2 H), 7.61 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.42, 21.88, 22.48, 22.78, 46.88, 54.74, 110.04, 111.65, 111.88, 117.22, 117.75, 117.89, 121.26, 123.44, 129.50, 129.55, 132.73, 137.90, 140.51, 159.20, 168.92. MS: 336 (M+l).
Example 49 - methyl 9-.4-methoxybenzviy2,3A9-tefrahydro-lH-carbazole-8- carboxylate
Powdered KOH (249 mg, 5.24 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (296 mg, 1.29 mmol) in DMSO (5 ml) and the yellow solution stirred for 5 min before 4-methoxybenzyl chloride (440 μl, 3.23 mmol) was added and stirring was continued for 20 min at ambient temperature. Sat. NH4C1 was added and the mixture was extracted with Et2O. The product was purified by flash chromatography using 5% EtOAc in hexanes. Yield 286 mg; colorless oil.
1HNMR (400 MHz, CDC13) 6 1.86-1.95 (m, 4 H), 2.68 (t, J=6.0 Hz, 2 H), 2.77 (t, J=6.0 Hz, 2 H), 3.71 (s, 3 H), 3.72 (s, 3 H), 5.45 (s, 2 H), 6.73 (s, 4 H), 7.07 (t, J=7.7 Hz, 1 H), 7.48 (dd, J=7.5, 1.3 Hz, 1 H), 7.65 (dd, J=7.7, 1.1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 20.92, 22.54, 22.97, 23.34, 47.30, 51.90, 55.10, 110.71, 113.76, 116.25, 117.86, 121.68, 123.69, 127.09, 129.34, 130.12, 130.69, 133.12, 138.05, 158.42, 168.45.
Example 50 - 9-(4-methoxybenzyl)-2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(4-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate
(Example 49) (286 mg, 0.818 mmol) and KOH (533 mg, 9.50 mmol) was refluxed with EtOH (20 ml) and H2O (2 ml) for 3 h. Most of solvent evaporated, solution made acidic by addition of 2 N HCl and extracted with EtOAc, dried (MgSO4) and evaporated. The crude material was washed with Et2O. Yield 27 mg (10%); white solid. Mp. 135 °C.
!H NMR (400 MHz, DMSO-d6) 6 1.79-1.85 (m, 4 H), 2.67 (m, 4 H), 3.64 (s, 3 H), 5.49 (s, 2 H), 6.68 (d, J=9 Hz, 2 H), 6.75 (d, J=9 Hz, 2 H), 7.01 (t, J=8 Hz, 1 H), 7.39 (d, J=6 Hz, 1 H), 7.59 (dd, J=6 Hz, 1 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.43, 21.97, 22.48, 22.80, 46.35, 54.88, 109.95, 113.79, 117.28, 117.65, 121.16, 123.30, 127.12, 129.56, 130.57, 132.55, 137.84, 158.00, 168.97. Found: C, 73.91; H, 6.13: N, 3.73%. Calc. for C2ιH2ιNO3'1/4H2O: C, 74.20; H, 6.36; N, 4.12%.
Example 51 - methyl 9-f2-methoxybenzyl)-2,3A9-tetøhydro-lH-carbazole-8- carboxylate
Powdered KOH was added to a solution of methyl 2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate (Example 28) (451 mg, 1.967 mmol) in DMSO (5 ml) and the mixture stirred for 5 min at ambient temperature before 2-methoxybenzyl chloride (550 μl, 3.50 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 2-5% EtOAc in hexanes. Yield 270 mg (39%); colorless oil. 1H NMR (400 MHz, CDC13) δ 1.87-1.93 (m, 4 H), 2.61-2.61 (m, 2 H), 2.77-2.80 (m,
2 H), 3.56 (s, 3 H), 3.89 (s, 3 H), 5.45 (s, 2 H), 6.25 (dd, J=8, 1 Hz, 1 H), 6.73 (t, J=7 Hz, 1 H), 6.86 (d, J=8 Hz, 1 H), 7.11 (m, 1 H), 7.18 (m, 1 H), 7.49 (dd, J=8, 1 Hz, 1 H), 7.68 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) δ 20.89, 22.22, 22.93, 23.22, 43.79, 51.58, 55.16, 109.45, 110.53, 116.24, 117.79, 120.43, 121.49, 123.53, 126.16, 126.84, 127.56, 129.80, 133.31, 138.17, 156.05, 168.63.
Example 52 - 9-(2-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
Methyl 9-(2-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 51) (270 mg, 0.772 mmol) and KOH (0.83 g) was refluxed with EtOH (10 ml) and H2O (2 ml) for 2 h. Most of EtOH evaporated and the solution was acidified with 2 N HCl and extracted with EtOAc. The product was purified by chromatography (YMC-gel) using 2% MeOH in DCM as eluent. Yield 163 mg (63%); white solid. Mp. 178-179 °C.
1HNMR (400 MHz, DMSO-d6) δ 1.76-1.79 (m, 4 H), 2.53-2.69 (m, 4 H), 3.81 (s, 3 H), 5.55 (s, 2 H), 5.77-5.79 (m, 1 H), 6.63 (t, J=7 Hz, 1 H), 6.94 (d, J=8 Hz, 1 H), 7.03 (t, J=8 Hz, 1 H), 7.10-7.14 (m, 1 H), 7.40 (dd, J=8, 1Hz, 1 H), 7.61-7.63 (m, 1 H). 13C NMR (100 MHz, DMSO-d6) 620.53, 21.67, 22.57, 22.81, 43.00, 55.29, 109.99, 110.33, 117.76, 120.25, 121.28, 123.39, 125.11, 126.65, 127.76, 129.38, 132.94, 138.02, 155.93, 169.01. MS: 336 (M+l). Found: C, 74.89; H, 6.44; N, 3.92%. Calc. for C2ιH2ιNO3: 75.20; H, 6.31; 4.18%.
Example 53 - methyl 9-C2-fluorobenzylV2.3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH was added to a solution of methyl 2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 2-fluorobenzyl bromide (428 μl, 3.489 mmol) was added. The mixture was quenched with sat. NH C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 2-5% EtOAc in hexanes. Yield 478 mg (81%); colorless oil.
1H NMR (400 MHz, CDC13) δ 1.86-1.93 (m, 4 H), 2.62 (t, J=5.9 Hz, 2 H), 2.76 (t, J=5.9 Hz, 2 H), 3.65 (s, 3 H), 5.55 (s, 2 H), 6.32-6.34 (m, 1 H), 6.86-6.89 (m, 1 H), 7.02-7.16 (m, 3 H), 7.50-7.52 (m, 1 H), 7.66 (dd, J=7.8, 1.0 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 20.89, 22.27, 22.60, 22.90, 23.25, 42.32, 42.37, 51.89, 111.04, 114.72, 114.93, 116.06, 118.13, 121.88, 124.05, 124.16, 124.20, 125.84, 125.98, 127.38, 127.43, 128.26, 128.34, 130.06, 133.36, 138.00, 158.46, 160.90, 168.40, MS: 338 (M+l)
Example 54 - 9-("2-fluorobenzyl)-2,3,4.9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 53) (109 mg, 0.323 mmol) was hydrolyzed using KOH (0.40 g), H2O (2 ml) and EtOH (10 ml). The mixture was refluxed for 2 h. EtOH evaporated and 2 N HCl (6 ml) added. The precipitate filtered, washed with water and dried under vacuum. Yield 82 mg (79%); white solid. Mp. 198 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.62-2.70 (m, 4 H), 5.67 (s, 2 H), 6.07 (t, J=7 Hz, 1 H), 6.91-6.95 (m, 1 H), 7.05 (t, J=6 Hz, 1 H), 7.12-7.22 (m, 2 H), 7.43 (dd, J=7, 1 Hz, 1 H), 7.64 (dd, J=8, 1 Hz, 1 H), 12.79 (s, 1 H). ,3C NMR (100 MHz, DMSO- d6) 6 20.48, 21.67, 22.50, 22.79, 110.18, 115.01, 115.22, 117.19, 118.01, 121.52, 123.68, 124.49, 124.52, 125.79, 125.93, 126.80, 126.84, 128.62, 128.70, 129.61, 132.74, 138.04, 158.00, 168.88. MS: 324 (M+l).
Example 55 - methyl 9-(3-fluorobenzylV2,3 A9-tetrahydro-lH-carbazole-8- carboxylate Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 3-fluorobenzyl bromide (428 μl, 3.489 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 2-5% EtOAc in hexanes. Yield 502-mg (86%); colorless oil.
1H NMR (400 MHz, CDC13) 6 1.86-1.95 (m, 4 H), 2.63-2.66 (m, 2 H), 2.75-2.78 (m,
2 H), 3.68 (s, 3 H), 5.51 (s, 2 H), 6.50 (d, J=10 Hz, 1 H), 6.57 (d, J=8 Hz, 1 H), 6,84-7.18 (m,
3 H), 7.50 (d, J=7 Hz, 1 H), 7.66 (m, 1 H). 13C NMR (100 MHz, CDC13) δ 20.87, 22.43, 22.90, 23.28, 47.55, 47.57, 51.97, 111.06, 112.89, 113.10, 113.61, 113.82, 116.06, 118.11,
121.49, 121.51, 121.96, 124.02, 129.84, 129.93, 130.17, 133.13, 137.83, 141.62, 141.68, 161.71, 164.16, 168.36. MS: 338 (M+l)
Example 56 - 9-(3-fluorobenzyl>2,3 A9-tetøhydro-lH-carbazole-8-carboxylic acid Methyl 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example
55) (100 mg, 0.296 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h. Most of EtOH evaporated and the solution acidified using 2 M HCl. Precipitate was filtered, washed with water and dried under vacuum. Yield 45 mg (47%); white solid. Mp.191-192 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.63-2.69 (m, 4 H), 5.60 (s, 2
H), 6.52 (d, J=8.0 Hz, 2 H), 6.97-7.05 (m, 2 H), 7.21-7.26 (m, 1 H), 7.41 (d, J=6.5 Hz, 1 H), 7.61 (d, J=6.5 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.47, 21.88, 22.50, 22.81, 46.76, 110.21, 112.55, 112.77, 113.48, 113.69, 117.57, 117.98, 121.31, 121.83, 123.54, 129.57, 130.45, 130.53, 132.61, 137.82, 142.05, 142.12, 160.96, 163.39, 169.06. MS: 324 (M+l).
Example 57 - methyl 9-(4- trifluoromethyl benzylV2,3 A9-tetrahydro-lH-carbazole-
8-carboxylate
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 4- (trifluoromethyl)benzyl bromide (834 mg, 3.489 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 5% EtOAc in hexanes. Yield 441 mg (65%); colorless oil.
Η NMR (400 MHz, CDC13) δ 1.79-1.87 (m, 4 H), 2.53-2.54 (m, 2 H), 2.68-2.71 (m, 2 H), 3.57 (s, 3 H), 5.52 (s, 2 H), 6.83 (d, J=8 Hz, 2 H), 7.02 (t, J=8 Hz, 1 H), 7.38 (d, J=8 Hz, 2 H), 7.45 (dd, J=8, 1 Hz, 1 H), 7.60 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 20.87, 22.45, 22.89, 23.27, 47.80, 51.98, 111.27, 115.98, 118.25, 122.13, 124.25, 125.32, 125.36, 125.40, 125.44, 126.18, 127.61, 129.33, 130.19, 133.26, 137.80, 143.17, 168.31.
Example 58 - 9-(4-(trifluoromethyl)benzyl)-2,3,4,9-tetrahvdro-lH-carbazole-8- carboxylic acid
Methyl 9-(4-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 57) (90 mg, 0.232 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h. Most of EtOH eavaporated, the solution acidicfied using 2 M HCl and precipitate filtered, washed with water and dried under vacuum. Yield 28 mg (33%); white solid. Mp. 146 °C.
1H NMR (400 MHz, DMSO-d6) 6 1.77-1.84 (m, 4 H), 2.53-2.67 (m, 4 H), 5.72 (s, 2 H), 6.93-7.02 (m, 3 H), 7.35 (d, J=7 Hz, 1 H), 7.54-7.73 (m, 3 H). 13C NMR (100 MHz, DMSO-d6) 6 20.51, 21.85, 22.52, 22.81, 46.87, 70.81, 110.05, 117.94, 123.20, 125.26, 126.64, 127.86, 129.30, 132.57, 137.36, 144.30, 169.55. MS: 374 (M+l). Example 59 - methyl 9-(3- trifluoromethv benzyl)-2.3 A9-tetrahvdro-lH-carbazole- 8-carboxylate
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 3-
(trifluoromethyl)benzyl bromide (834 mg, 3.489 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 5% EtOAc in hexanes. Yield 630 mg (93%); colorless oil. Purity -80%.
1H NMR (400 MHz, CDC13) δ 1.90-2.00 (m, 4 H), 2.67-2.68 (m, 2 H), 2.80-2.81 (m, 2 H), 3.68 (s, 3 H), 5.59 (s, 2 H), 6.78 (d, J=8 Hz, 1 H), 7.11 (t, J=8 Hz, 1 H), 7.30 (m, 2 H), 7.57 (m, 3 H). 13C NMR (100 MHz, CDC13) δ 21.20, 22.84, 23.23, 23.61, 48.02, 52.26, 111.56, 116.37, 118.55, 122.40, 123.41, 123.45, 123.48, 123.52, 124.01, 124.05, 124.08, 124.12, 124.48, 124.61, 124.65, 124.91, 124.95, 129.27, 129.31, 129.35, 129.50, 130.57, 130.77, 131.09, 131.16, 131.17, 133.49, 138.12, 139.18, 140.34, 168.62. MS: 388 (M+l).
Example 60 - 9-(3-(trifluoromethyl benzyl)-2,3A9-tetrahvdro-lH-carbazole-8- carboxylic acid Methyl 9-(3-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate
(Example 59) (147 mg, 0.379 mmol) was hydrolyzed using KOH (0.4 g), EtOH (10 ml) and H2O (2 ml). The mixture was refluxed for 2 h. Most of EtOH was evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 90 mg (64%); white solid. Mp. 189-190 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.60-2.70 (m, 4 H), 5.66 (s, 2
H), 6.87 (d, J=8 Hz, 1 H), 7.05 (t, J=8 Hz, 1 H), 7.24 (s, 1 H), 7.42 (t, J=7 Hz, 2 H), 7.53 (d, J=8 Hz, 1 H), 7.64 (dd, J=8, 1 Hz, 1 H), 12.83 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 20.46, 21.91, 22.49, 22.80, 46.97, 110.38, 117.15, 118.08, 121.57, 123.72, 129.63, 137.86, 140.55, 168.99. MS: 374 (M+l). Example 61 - methyl 9-(2A-difluorobenzyl)-2,3A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 2,4- difluorobenzyl bromide (500 μl, 3.5 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 446 mg (72%); colorless oil. 1HNMR (400 MHz, CDC13) δ 1.86-1.94 (m, 4 H), 2.59-2.60 (m, 2 H), 2.73-2.76 (m,
2 H), 3.70 (s, 3 H), 5.50 (s, 2 H), 6.30-6.31 (m, 1 H), 6.61 (dd, J=8, 2 Hz, 1 H), 6.77-6.81 (m, 1 H), 7.09 (t, J=8 Hz, 1 H), 7.53 (d, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, CDCI3) δ 20.85, 22.26, 22.86, 23.22, 41.93, 41.98, 51.97, 103.18, 103.43, 103.68, 111.11, 111.14, 111.24, 111.32, 111.35, 115.92, 118.25, 121.74, 121.78, 121.89, 121.93, 122.04, 122.32, 124.24, 128.24, 128.30, 128.34, 128.40, 130.11, 133.36, 137.87, 158.22, 158.33, 160.55, 160.67, 160.68, 160.80, 163.01, 163.13, 168.32.
Example 62 -9-( 4-difluorobenzviy2,3A9-tetrahvdro-lH-carbazole-8-carboxylic acid Methyl 9-(2,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate
(Example 61) (140 mg, 0.394 mg) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 96 mg (72%); white solip. Mp. 173-174 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.86 ( , 4 H), 2.61-2.69 (m, 4 H), 5.62 (s, 2
H), 6.09-6.15 (m, 1 H), 6.82-6.87 (m, 1 H), 7.03-7.07 (m, 1 H), 7.17-7.23 (m, 1 H), 7.42-7.44 (m, 1 H), 7.63 (dd, J=8, 1 Hz, 1 H), 12.83 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 21.30, 22.50, 23.31, 23.62, 104.39, 104.65, 104.90, 111.09, 112.17, 112.21, 112.39, 112.42, 118.08, 118.93, 122.35, 122.96, 123.00, 123.11, 123.14, 124.51, 128.77, 128.83, 128.87, 128.93, 130.47, 133.45, 138.81, 158.68, 158.80, 160.73, 160.85, 161.14, 161.26, 163.29, 169.72. MS: 342 (M+l). Example 63 - 9-[2-rtrifluoromethyl)benzyl1-2,3A9-tetrahydro-lH-carbazole-8- carboxylic acid
Methyl 2,3 ,4,9-tetrahydro- lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) was added powdered KOH (0.50 g, 8.91 mmol) and the yellow mixture stirred for 3 min before 2-trifluoromethyl-benzyl bromide (834 mg, 3.489 mmol) was added and the mixture stirred at ambient temperature for 5 min before quenched with sat. NH4C1 and extracted wtih Et2O. The ether layer was evaporated and the crude material hydrolyzed using KOH (0.80 g), EtOH (20 ml) and H2O (2 ml). The mixture was refluxed for 2 h, acidified using 2 M HCl and extracted with EtOAc. The product was purified by flash chromatography using 1% and 5% MeOH in DCM. Yield 159 mg (28%); white solid. Mp. 242 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.76-1.81 (m, 4 H), 2.49-2.71 (m, 4 H), 5.75-5.92 (m, 3 H), 7.09 (t, J=8 Hz, 1 H), 7.37-7.39 (m, 2 H), 7.49 (d, J=8 Hz, 1 H), 7.68-7.74 (m, 2 H), 12.81 (s, 1 H). 13CNMR (100 MHz, DMSO-d6) δ 20.43, 21.38, 22.41, 22.65, 44.52, 110.72, 117.04, 118.23, 121.77, 124.08, 125.62, 127.16, 129.47, 132.92,- 133.16, 137.68, 168.67. MS: 374 (M+l). Found: 373.1295 (M4). Calc. for C2ιHι8F3NO2: 373.1290.
Example 64 - methyl 9-(2,3-difluorobenzyl)-2,3 A9-tetrahydro-lH-carbazole-8- carboxylate
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 2,3- difluorobenzyl bromide (500 μl, 3.5 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 509 mg (82%); colorless oil.
1H NMR (400 MHz, CDC13) δ 1.84-1.93 (m, 4 H), 2.59-2.60 (m, 2 H), 2.73-2.76 (m, 2 H), 3.70 (s, 2 H), 5.59 (s, 2 H), 6.07-6.10 (m, 1 H), 6.80-6.81 (m, 1 H), 6.97-7.11 (m, 3 H), 7.54 (dd, J=8, 1 Hz, 1 H), 7.66 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) δ 20.85, 22.27, 22.86, 23.23, 42.14, 42.17, 42.20, 42.23, 52.00, 111.30, 115.52, 115.68, 115.92, 118.29, 122.08, 122.13, 124.00, 124.05, 124.07, 124.12, 124.32, 128.59, 130.15, 133.46, 137.87, 168.26.
Example 65 - 9- 2,3-difluorobenzyl)-2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid
Methyl 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 64) (243 mg, 0.684 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and water (2 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, the solution acidified using 2 M HCl, precipitate filtered, washed with water and dried under vacuum. Yield 188 mg (81 %);white solid. Mp. 201 °C.
1H NMR (400 MHz, DMSO-d6) 6 1.78-1.86 (m, 4 H), 2.62-2.70 (m, 4 H), 5.71 (s, 2 H), 5.89 (t, J=7.15 Hz, 1 H), 6.92-6.97 (m, 1 H), 7.03-7.07 (m, 1 H), 7.24 (q, J=8 Hz, 1 H), 7.43 (dd, J=7, 1 Hz, 1 H), 7.64 (dd, J=8, 1 Hz, 1 H), 12.83 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 20.45, 21.64, 22.47, 22.77, 41.59, 41.62, 41.67, 110.27, 115.69, 115.86, 117.17, 118.14, 121.57, 121.88, 121.91, 123.75, 124.77, 124.81, 124.84, 124.88, 128.72, 128.83, 129.67, 132.63, 138.00, 145.47, 145.60, 147.92, 148.05, 148.26, 148.38, 150.70, 150.82, 168.85. MS: 342 (M+l).
Example 66 - 9-(4-fluorobenzyl -2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) was added powdered KOH (0.50 g, 8.91 mmol) and the yellow mixture stirred for 3 min before 4-fluoro-benzyl bromide (428 μl, 3.489 mmol) was added and the mixture stirred at ambient temperature for 5 min before quenched with sat. NH4C1 and extracted wtih Et2O. The ether layer was evaporated and the crude material hydrolyzed using KOH (0.80 g), EtOH (20 ml) and H2O (2 ml). The mixture was refluxed for 2 h, acidicfied using 2 M HCl and precipitate filtered. The product was purified by flash chromatography using 1% and 2% MeOH in DCM. Yield 152 mg (27%); white solid. Mp. 200 °C.
1HNMR (400 MHz, DMSO-d6) 6 1.77-1.87 (m, 4 H), 2.63-2.69 (m, 4 H), 5.55 (s, 2 H), 6.75 (dd, J=9, 6 Hz, 2 H), 7.01-7.06 (m, 3 H), 7.41 (dd, J=8, 1 Hz, 1 H), 7.61 (dd, J=8, 1 Hz, 1 H), 12.82 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 620.48, 21.93, 22.50, 22.82, 46.46, 110.15, 115.13, 115.34, 117.29, 117.90, 121.38, 123.49, 127.76, 127.84, 129.62, 132.54, 134.99, 135.01, 137.86, 159.80, 162.21, 169.02. MS: 324 (M+l).
Example 67 - methyl 9-f3-cyanobenzyl)-2,3A9-tefrahydro-lH-carbazole-8- carboxylate
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (400 mg, 1.75 mmol) in DMSO (5 ml) and the mixture stirred for 5 min at ambient temperature before 3-cyanobenzyl bromide (684 mg, 3.49 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with Et2O. The combined ether layers were washed with water and brine and evaprated. The product was purified by flash chromatography using 5-10% EtOAc in hexanes. Yield 190 mg (32%); colorless oil.
1HNMR (400 MHz, CDC13) δ 1.86-1.96 (m, 4 H), 2.59-2.62 (m, 2 H), 2.76-2.78 (m, 2 H), 3.68 (s, 3 H), 5.55 (s, 2 H), 7.01 (d, J=8 Hz, 1 H), 7.08 (t, J=8 Hz, 1 H), 7.12 (s, 1 H), 7.29 (t, J=8 Hz, 1 H), 7.46 (d, J=8 Hz, 1 H), 7.52 (dd, J=8, 1 Hz, 1 H), 7.67 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 620.83, 22.48, 22.84, 23.24, 47.51, 52.05, 111.51, 112.48, 115.80, 118.38, 118.71, 122.36, 124.48, 129.24, 129.69, 130.27, 130.53, 130.68, 133.17, 137.57, 140.75, 168.20.
Example 68 - 9-(3-carboxybenzyl>2,3 A9-tetrahydro-lH-carbazole-8-carboxylic acid
Methyl 9-(3-cyanobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 67) (190 mg, 0568 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and H2O (2 ml). The mixture was refluxed for 2 h, EtOH evaporated and 2 M HCl (6 ml) added. Precipitate filtered, washed with water and dried under vacuum. Yield: 80 mg (40%); white solid. Mp. 261 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.63-2.70 (m, 4 H), 5.64 (s, 2 H), 6.89 (d, J=8 Hz, 1 H), 7.04 (t, J=8 Hz, 1 H), 7.32 (t, J=8 Hz, 1 H), 7.41 (dd, J=7, 1 Hz, 1 H), 7.46 (s, 1 H), 7.62 (dd, J=8, 1 Hz, 1 H), 7.73 (d, J=8 Hz, 1 H), 12.85 (s, 2 H). 13CNMR (100 MHz, DMSO-d6) 6 20.48, 21.94, 22.50, 22.81, 47.02, 110.16, 117.20, 117.92, 121.44, 123.56, 126.85, 127.76, 128.74, 129.60, 130.18, 130.90, 132.65, 137.87, 139.55, 167.09, 168.98. Example 69 - methyl 9-butyl-2.3 A9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (357 mg, 6.36 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (359 mg, 1.565 mmol) in DMSO (3 ml) and the mixture stirred for 3 min at ambient temperature before 1-iodobutane (358 μl, 3.13 mmol) was added. The mixture was quenched with sat. NH C1 after 10 min stirring at ambient temperature and extracted with Et O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 198 mg (44%); colorless oil. 1H NMR (400 MHz, CDC13) δ 0.87 (t, J=7 Hz, 3 H), 1.22-1.25 (m, 2 H), 1.47-1.53
(m, 2 H), 1.85-1.95 (m, 4 H), 2.70-2.73 (m, 4 H), 3.95 (s, 3 H), 4.19-4.23 ( , 2 H), 7.04 (t, J=8 Hz, 1 H), 7.52 (d, J=8 Hz, 1 H), 7.60 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 6 13.87, 20.00, 20.91, 22.72, 23.02, 23.43, 32.10, 44.31, 52.16, 110.30, 115.87, 117.54, 121.67,, 123.53, 130.02, 132.61, 137.57, 168.79.
Example 70 - 9-butyl-2.3 A9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-butyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 69) (190 mg, 0.665 mmol) and KOH (0.5 g) was refluxed with EtOH (20 ml) and H2O (2 ml) for 3 h. Most of EtOH evaporated and solution made acidic using 2 N HCl and extracted with EtOAc. Yield 180 mg (100%); white solid. Mp. 121 °C.
1HNMR (400 MHz, DMSO-d6) δ 0.82 (t, J=7 Hz, 3 H), 1.14-1.19 (m, 2 H), 1.43-1.45 (m, 2 H), 1.77-1.88 (m, 4 H), 2.63-2.72 (m, 4 H), 4.21 (t, J=7 Hz, 2 H), 7.00 (m, 1 H), 7.39 (d, J=7 Hz, 1 H), 7.54 (d, J=8 Hz, 1 H), 12.90 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 13.62, 19.30, 20.43, 21.89, 22.50, 22.86, 31.66, 43.48, 109.23, 117.24, 117.31, 120.79, 122.54, 129.26, 131.72, 137.36, 169.40. MS: 272 (M+l). Found: C, 74.36; H, 7.86; N, 5.04. Calc. for Cι7H2ιNO2y4H2O: C, 74.06; H, 7.86; N, 5.04.
Example 71 - methyl 9-propyl-2,3 A9-tetrahydro-lH-carbazole-8-carboxylate
Powdered KOH (3.63 g, 64.7 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (3.24 g, 14.13 mmol) in DMSO (30 ml) and the mixture was stirred for 5 min before 1-iodopropane (7.76 ml, 28.26 mmol) was added. Stirring was continued for 10 min and the mixture was quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 2% EtOAc in hexanes. First eluated: 562 mg (13%) propyl 9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate. The title compound was then eluated: yield 2.267 g (56%); colorless oil.
1H NMR (400 MHz, CDC13) δ 0.80 (t, J=7 Hz, 3 H), 1.53-1.58 (m, 2 H), 1.85-1.97 (m, 4 H), 2.70-2.73 (m, 4 H), 3.95 (s, 3 H), 4.16-4.19 (m, 2 H), 7.05 (t, J=8 Hz, 1 H), 7.53 (dd, J=7, 1 Hz, 1 H), 7.61 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 11.03, 20.90, 22.74, 23.01, 23.19, 23.42, 45.97, 52.16, 110.21, 115.86, 117.54, 121.66, 123.55,129.98, 132.60, 137.63, 168.78.
Example 72 - 9-propyl-2,3A9-tefrahydro-lH-carbazole-8-carboxylic acid Methyl 9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 71) (340 mg, 1.252 mmol) and KOH (503 mg, 8.96 mmol) was refluxed in EtOH (20 ml) and H2O (2 ml) for 5 h. Most of EtOH evaporated and solution made acidic using 2 N HCl and the mixture extracted with EtOAc and the combined organic layers dried (MgSO4) and evaporated. Yield 283 mg (88%); white solid. Mp. 159 °C.
1H NMR (400 MHz, DMSO-d6) 6 0.72 (t, J=7 Hz, 3 H), 1.46-1.52 (m, 2 H), 1.76-1.89 (m, 4 H), 2.62-2.72 (m, 4 H), 4.15-4.19 (m, 2 H), 7.00 (t, J= 8 Hz, 1 H), 7.39 (dd, J=8, 1 Hz, 1 H), 7.54 (d, J=8 Hz, 1 H), 12.91 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 10.69, 20.43, 21.93, 22.51, 22.77, 22.87, 45.13, 109.13, 117.25, 117.32, 120.78, 122.54, 129.24, 131.71, 137.45, 169.41. Found: C, 74.54; H, 7.59; N, 5.14%. Calc. for Cι6Hι9NO2: C, 74.68; H, 7.44; N, 5.44.
Example 73 - methyl 9-pentyl-2,3 A9-tetrahydro-lH-carbazole-8-carboxylate
Powdered KOH (380 mg, 6.77 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (330 mg, 1.439 mmol) in DMSO (3 ml) and the yellow mixture was stirred for 2 min before 1-iodopentane (380 μl, 2.88 mmol) was added. After 5 min the mixture was quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 2% and 5% Et O in hexanes as eulents. Yield 231 mg (54%); colorless oil. 1H NMR (400 MHz, CDC13) δ 0.85 (t, J=7 Hz, 3 H), 1.19-1.28 (m, 4 H), 1.50-1.52 (m, 2 H), 1.85-1.86 (m, 2 H), 1.93-1.95 (m, 2 H), 2.69-2.72 (m, 4 H), 3.94 (s, 3 H), 4.17-4.21 (m, 2 H), 7.04 (t, J=8 Hz, 1 H), 7.51 (dd, J=8, 1 Hz, 1 H), 7.60 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) δ 13.93, 20.92, 22.41, 22.71, 23.02, 23.43, 28.90, 29.63, 44.51, 52.16, 110.29, 115.87, 117.54, 121.66, 123.53, 130.01, 132.56, 137.53, 168.78.
Example 74 - 9-pentyl-2,3A9-tetrahvdro-lH-carbazole-8-carboxylic acid Methyl 9-pentyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 73) (212 mg, 0.708 mmol) was hydrolyzed using KOH (20 mg, 3.70 mmol) in refluxing EtOH/H2O (10 ml : 1ml) for 3.5 h. Most of EtOH evaporated and 2 M HCl added and the mixture extracted with EtOAc dried and evaporated. Yield 196 mg (97%).
Η NMR (400 MHz, DMSO-d6) δ 0.80 (t, J=7 Hz, 3 H), 1.11-1.47 (m, 6 H), 1.79-1.89 (m, 4 H), 2.61-2.71 (m, 4 H), 4.17-4.21 (m, 2 H), 6.99 (t, J=8 Hz, 1 H), 7.39 (d, J=6 Hz, 1 H), 7.53 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 13.76, 20.44, 21.75, 21.89, 22.51, 22.87, 28.19, 29.17, 43.70, 109.23, 117.24, 117.31, 120.79, 122.55, 129.26, 131.70, 137.31, 169.41.
Example 75 - methyl 9-ethyl-2,3A9-tetrahvdro-lH-carbazole-8-carboxylate Powdered KOH (522 mg, 9.30 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-8-carboxylate (Example 28) (540 mg, 2.355 mmol) in DMSO (5 ml) and the yellow mixture was stirred for 5 min before ethyl iodide (470 μl, 5.83 mmol) was added and stirring continued for 10 min and the reaction quenced with sat. NH4C1 and extracted with Et O. The product was purified by flash chromatography using 2% and 5% EtOAc in hexanes. Yield 472 mg (78%); slightly yellow oil. 1H NMR (400 MHz, CDCI3) δ 1.18 (t, J=7 Hz, 3 H), 1.84-1.97 (m, 4 H), 2.71-2.73
(m, 4 H), 3.96 (s, 3 H), 4.26 (q, J=7 Hz, 2 H), 7.05 (t, J=8 Hz, 1 H), 7.54 (d, J=8 Hz, 1 H), 7.60 (d, J=8 Hz, 1 H). 13C NMR (100 MHz, CDCI3) δ 15.23, 20.90, 22.50, 22.99, 23.40, 39.34, 52.13, 110.51, 115.66, 117.58, 121.74, 123.72, 130.03, 132.55, 137.24, 168.86. MS: 258 (M+l). Example 76 - 9-ethyl-2,3 A9-tetrahvdro-lH-carbazole-8-carboxylic acid
Methyl 9-ethyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 75) (450 mg, 1.748 mmol) was hydrolyzed using KOH (0.80 g) in EtOH (20 ml) and H2O (2 ml). The mixture was refluxed for 3 h, most of solvent evaporated and 2 M HCl added. The white precipitate was filtered and washed with water and dried under vacuum. Yield 361 mg
(85%); white solid. Mp. 158 °C.
*H NMR (400 MHz, DMSO-d6) δ 1.08 (t, J=7 Hz, 3 H), 1.76-1.89 (m, 4 H), 2.61-2.72
(m, 4 H), 4.24 (q, J=7 Hz, 2 H), 7.00 (t, J=8 Hz, 1 H), 7.39 (m, 1 H), 7.53 (d, J=8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6) δ 15.07, 20.45, 21.66, 22.50, 22.85, 109.44, 117.19, 117.36, 120.75, 122.50, 129.31, 131.56, 137.06, 169.50. MS: 244 (M+l). Found: C, 73.56; H, 7.29;
N, 5.61. Calc. for Cι5H NO2: C, 74.05; H, 7.04; N, 5.76. 300512
Example 77 - 9-isopropyl-2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid Powdered KOH (0.5 g) was added to a solution of methyl 2,3,4,9-tetrahydro-lH- carbazole-8-carboxylate (Example 28) (500 mg, 2.181 mmol) in DMSO (5 ml) and the yellow mixture was stirred for 5 min before addition of isopropyl iodide (540 μl, 2.181 mmol) and stirring continued for 20 min before quenching with sat. NH4C1 and extraction with Et2O. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 57 mg (10%). !H NMR (400 MHz, CDC13) δ 1.49 (d, J=7 Hz, 6 H), 1.86-1.95 (m, 4 H), 2.72-2.75
(m, 2 H), 2.93-2.96 (m, 2 H), 3.96 (s, 3 H), 4.77-4.80 (m, 1 H), 7.05 (t, J=8 Hz, 1 H), 7.50 (dd, J=7, 1 Hz, 1 H), 7.56 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) δ 15.23, 20.90, 22.50, 22.99, 23.40, 39.34, 52.13, 110.51, 115.66, 117.58, 121.74, 123.72, 130.03, 132.55, 137.24, 168.86. MS: 272 (M+l). This material was hydrolyzed using KOH (0.14 g), EtOH (5 ml) and H2O (1 ml) and the mixture refluxed for 3 h. Most of solvent evaporated and 2 M HCl was added. The white precipitated was filtered, washed with water and dried under vacuum. Yield 51 mg (94%); white solid. Mp. 192 °C.
1H NMR (400 MHz, DMSO-d6) 1.40 (d, J=7 Hz, 6 H), 1.77-1.87 (m, 4 H), 2.63-2.65 (m, 2 H), 2.88-2.89 (m, 2 H), 4.86-4.91 (m, 1 H), 6.98 (t, J=8 Hz, 1 H), 7.29 (d, J=8 Hz, 1 H), 7.47 (d, J=8 Hz, 1 H). I3C NMR (100 MHz, DMSO-d6) 6 20.65, 21.75, 22.25, 23.37, 24.92, 48.39, 111.45, 117.48, 117.62, 120.22, 122.38, 128.65, 133.04, 136.93, 170.35. MS: 258 (M+l). Found: C, 69.36; H, 7.16; N, 4.88%. Calc. for Cι6Hι9NO2H2O: C, 69.83; H, 7.69; N, 5.09%.
5 Example 78 - 8-("methoxycarbonyl)-l,2,3,4-tetrahvdro-9H-carbazol-9-yl]acetic acid
Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (2 g, 8.7 mmol) was added to a suspension of KOH (1.46 g, 26.1 mmol) in DMSO (20 ml). The mixture was stirred for 4 minutes and poured onto a solution of benzyl-2-bromoacetate (2.06 ml, 13 mmol) in DMSO (40 ml) in a water bath (10 °C). The mixture was stirred for 3 minutes and o quenched with 2N HCl until pH = 2. The mixture was diluted with diethyl ether and washed with water (5x). After drying (MgSO4) and evaporation the crude product was taken up in DCM/hexane 1:1 and filtered through a short plug of silica. Evaporation gave 3 g of a colorless oil, (50% purity HPLC) used in the next step without further purification.
The crude product was dissolved in MeOH (60 ml) and Pd/C was added under an 5 atmosphere of nitrogen and the mixture was hydrogenated (1 atm) for 2 hours, the mixture was filtered and evaporated and the residue was suspended in DCM and filtered through a plug of silica (700 ml DCM). The product was eluated with 10 % MeOH in DCM. Yield 0.6 g (24%)
0 Example 79 - methyl 9-('2-chloro-2-oxoethyl -2,3,4,9-tetrahvdro-lH-carbazole-8- carboxylate
Oxalyl chloride (0.040 ml, 0.45 mmol) was added to a solution of [8- (methoxycarbonyl)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]acetic acid (Example 78) (0.1 g, 0.35 mmol) in DCM followed by one drop of DMF. After 10 minutes the mixture was 5 evaporated and dissolved in DCM (1 ml) and used immediately.
Example 80 - methyl 9-(2-morpholin-4-yl-2-oxoethylV2,3A9-tetrahvdro-lH- carbazole-8-carboxylate
Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (0.2 g, 0.87 0 mmol) was added to a suspension of KOH (0.25 g, 4.45 mmol) in DMSO (4 ml) and stirred 5 minutes before 4-(2-chloroacetyl)-morpholine (0.4 g, 2.44 mmol) was added. The mixture was stirred for 5 minutes and 2 N HCl was added. (pH=2) and the mixture was diluted with diethyl ether and washed with water (3x). After drying (MgSO4) and evaporation the crude product was purified by flash chromatography with DCM. Yield: 0.130 g (42%). White solid. 1H NMR (400 MHz, CDC13) δ 1.80-1.89 (m, 2 H) 1.90-1.97 (m, 2 H) 2.61 (t, J=6.02 Hz, 2 H) 2.71 (t, J=6.02 Hz, 2 H) 3.50-3.64 (m, 4 H) 3.66-3.83 (m, 4 H) 3.87 (s, 3 H) 5.21 (s, 2 H) 7.04 (t, J=7.65 Hz, 1 H) 7.63 (dd, J=7.65, 1.13 Hz, 1 H) 7.69 (dd, J=7.65, 1.13 Hz, 1 H). MS (70eV) m/z (%) 357 (M+,100).
Example 81 - 9-(2-morpholin-4-yl-2-oxoethyl)-2,3A9-tetrahydro-lH-carbazole-8- carboxylic acid
Methyl 9-(2-morpholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate (Example 80) (0.1 g, 0.3 mmol) and 2 N NaOH (0.5 ml) was dissolved in MeOH '(4 ml) and heated at 45 °C overnight. After evaporation the residue was diluted with water and washed with diethyl ether (2x). 2 N HCl was added dropwise and the white crystals were filtered off and washed with water (2x) and dried (vacum). Yield 0.045 g. (47%). White solid.
1H NMR (400 MHz, CDCI3) δ 0.76-1.84 (m, 2 H) 1.86-1.94 (m, 2 H) 2.57 (t, J=6.02 Hz, 2 H) 2.67 (t, J=6.02 Hz, 2 H) 3.47-3.59 (m, 4 H) 3.65 (br.s., 1 H) 3.61-3.79 (m, 4 H) 5.17 (s, 2 H) 7.00 (t, J=7.53 Hz, 1 H) 7.57 (dd, J=7.78, 1.00 Hz, 1 H) 7.68 (dd, J=7.65, 1.13 Hz, 1 H), MS (70eV) m/z (%) 341 (M\ 100)
Example 82 - 9-r2-(dimethylamino)-2-oxoethyl]-2,3 A9-tetrahydro-lH-carbazole-8- carboxylic acid
Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (0.2 g, 0.87 mmol) was added to a suspension of KOH (0.244 g, 4.35 mmol) in DMSO and stirred for 5 minutes before N-(2-chloroacetyl)-diethylamine (0.26 g, 1.74 mmol) was added. The reaction was stirred for 2 minutes before 1 N HCl was added dropwise to pH was adjusted to 3. The mixture was partitioned between water and diethyl ether, washed with water (3x), dried (MgSO4) and evaporated. The crude product was filtered through a short column of silica gel (DCM) and the product was eluted with 5% MeOH in DCM. After evaporation, the crude product was dissolved in MeOH (1 ml) and 3 drops of water along with 0.1 g KOH. The mixture was stirred for 2 days at 40 °C and evaporated, dissolved in water and washed with DCM, dried (MgSO ) and evaporated, recrystallization from DCM /hexane gave 0.025 g (10%) of title product. White solid.
1H NMR (400 MHz, CDC13) δ 1.81-2.02 (m, 4 H) 2.59-2.80 (m, 4 H) 2.97 (s, 3 H) 3.09 (s, 3 H) 5.15 (s, 2 H) 7.06 (t, J=7.65 Hz, 1 H) 7.27 (br. s., 1 H) 7.68 (d, J=7.53 Hz, 1 H) 7.79 (d, J=7.53 Hz, 1 H). MS (70eV) m/z (%) 299 (M\100)
Example 83 - 9-r2-(diethylaminoV2-oxoethyl"l-2,3 A9-tetrahydro-lH-carbazole-8- carboxylic acid Same experimental as for Example 82. Recrystallization from DCM/hexane. Yield
0.035 g. (12%). White solid.
1H NMR (400 MHz, CDC13) δ 1.11 (t, J=7.15 Hz, 3 H) 1.27 (t, J=7.15 Hz, 3 H) 1.80- 1.89 (m, 2 H) 1.90-2.00 (m, 2 H) 2.61 (t, J=6.02 Hz, 2 H) 2.71 (t, J=5.90 Hz, 2 H) 3.32-3.45 (m, 4 H) 5.18 (s, 2 H) 7.06 (t, J=7.65 Hz, 1 H) 7.67 (dd, J=7.65, 1.13 Hz, 1 H) 7.76 (dd, J=7.53, 1.25 Hz, 1 H) 11.19 (br. s., 1 H). MS (70eV) m/z (%) 327 (M-,100).
Example 84 - 9-(2-amino-2-oxoethylV2.3 A9-tetrahydro-lH-carbazole-8-carboxylic acid
Oxalyl chloride (0.040 ml, 0.45 mmol) was added to a solution of [8- (methoxycarbonyl)-l, 2,3, 4-tetrahydro-9H-carbazol-9-yl] acetic acid (Example 78) (0.1 g, 0.35 mmol) in DCM followed by one drop of DMF. After 10 minutes the mixture was evaporated and dissolved in DCM (1 ml) and splitted in 2 parts. 2 N NH3 (0.2 ml) was added and the reaction was stirred for lh and evaporated. The crude product hydrolyzed for 2 days in 0.2 N NaOH (1 ml) in MeOH (1 ml) at 50 °C. After evaporation, 1 N HCl was added and the white solid precipitate was collected and recrystallized from DCM/hexane. Yield 0.016 g (34%). White solid.
1HNMR (400 MHz, DMSO-d6) 6 1.74-1.87 (m, 4 H) 2.46-2.68 (m, 4 H) 5.00 (s, 2 H) 6.98 (t, J=7.40 Hz, 1 H) 7.14 (d, J=7.03 Hz, 1 H) 7.41-7.51 (m, 2 H) 7.91 (s, 1 H) 12.70 (br. s., 1 H). MS (70eN) m/z (%) 271 (M",100) Example 85 - 9-C2-oxo-2-pyrrolidin-l-ylethylV2.3A9-tetrahy-lro-lH-carbazole-8- carboxylic acid
Pyrrolidine (0.028 ml, 0.4 mmol) was added to the acid chloride methyl 9-(2-chloro- 2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 79) (0.175 mmol) in DCM and the mixture was stirred for 2 h and evaporated. The mixture was partitioned between water and DCM, washed with IN HCl and evaporated. The crude product was hydrolyzed for 2 days in 0.2 N NaOH (1 ml) in MeOH (1 ml) at 50 °C. After evaporation, 1 N HCl was added and the white solid precipitate was collected and recrystallized from DCM/hexane. Yield 0.018 g (32%). 1H NMR (400 MHz, CDC13) 6 1.85 (dt, J=13.30, 6.65 Hz, 4 H) 1.92-2.07 (m, 4 H)
2.64 (t, J=5.90 Hz, 2 H) 2.71 (t, J=5.65 Hz, 2 H) 3.48 (ddd, J=12.61, 6.78, 6.46 Hz, 4 H) 5.03 (s, 2 H) 7.05 (t, J=7.65 Hz, 1 H) 7.66 (d, J=7.78 Hz, 1 H) 7.75 (d, J=7.53 Hz, 1 H) 10.88 (br. s., 1 H). MS (70eN) m/z (%) 325 (M",100)
Example 86 - 9-[2-(,3-hvdroxypiperidin-l-yl)-2-oxoethyl]-2,3A9-tetrahydro-lH- carbazole-8-carboxylic acid
3-hydroxvpiperidine (0.071 g, 0.7 mmol) was added to a solution of methyl 9-(2- chloro-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 79) (0.35 mmol) in DCM (2 ml) and stirred overnight. The mixture was diluted with DCM and washed with 0.5 N HCl and water, dried (MgSO4) and evaporated. The crude was dissolved in
MeOH (4 ml) and a solution of 2N NaOH (0.5 ml) was added and the mixture was stirred at 45 °C for 7 hours. After evaporation the residue was diluted with water and washed with DCM. 2 N HCl was added dropwise to the alkaline phase and the white solid precipitate was collected and washed with water twice and dried. Yield 45 mg (36%). 1HNMR (400 MHz, DMSO-d6) δ 1.23-1.63 (m, 4 H) 1.73-1.96 (m, 4 H) 2.41-2.71
(m, 4 H) 2.91-3.14 (m, 2 H) 3.57-3.81 (m, 2 H) 4.00-4.17 (m, 1 H) 4.85-5.02 (m, 1 H) 5.06- 5.21 (m, 1 H) 5.25-5.43 (m, 1 H) 6.95-7.09 (m, 1 H) 7.47 (d, J=7.28 Hz, 1 H) 7.59 (d, J=7.28 Hz, 1 H) 12.74 (br. s., 1 H). MS (70eN) m/z (%) 355 (M",100).
Example 87 - 9-.2-r(2-hydroxyethyl)amino1-2-oxoethyl)-2.3,4.9-tetrahvdro-lH- carbazole-8-carboxylic acid Experimental: See Example 86. Yield 20 mg (18%).
1H NMR (400 MHz, DMSO-d6) δ 1.70-1.97 (m, 4 H) 2.52-2.74 (m, 4 H) 3.04-3.19 (m, 2 H) 3.23-3.49 (m, 3 H) 4.93 (s, 2 H) 6.98-7.11 (m, 1 H) 7.47 (d, J=7.28 Hz, 1 H) 7.57 (d, J=7.78 Hz, 1 H) 7.76 (d, J=5.02 Hz, 1 H) 12.79 (br. s., 1 H). MS (70eV) m/z (%) 315 (M" ,100).
Example 88 - methyl 9-benzyl-2,3 A9-tetrahvdro-lH-carbazole-7-carboxylate Powdered KOH (244 mg, 4.35 mmol) was added to a solution of methyl 2,3,4,9- tetrahydro-lH-carbazole-7-carboxylate (Example 30) (257 mg, 1.120 mmol) in DMSO (5 ml) and the yellow solution stirred for 3 min before addition of benzyl bromide (260 μl, 2.25 mmol) and stirring was continued for 5 min and mixture quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using hexanes/Et2O 9:1. Yield 219 mg (61%); white solid. Mp. 165 °C.
1HNMR (400 MHz, CDC13) 6 1.85-1.91 (m, 4 H), 2.62-2.63 (m, 2 H), 2.76-2.77 (m, 2 H), 3.88 (s, 3 H), 5.30 (s, 2 H), 6.97 (d, J=7 Hz, 2 H), 7.21-7.26 (m, 3 H), 7.49 (d, J=8 Hz, 1 H), 7.78 (dd, J=8, 2 Hz, 1 H), 7.99 (s, 1 H). I3C NMR (100 MHz, CDC13) δ 21.00, 22.35, 22.97, 46.28, 51.75, 110.68, 111.12, 117.25, 120.24, 122.30, 126.07, 127.35, 128.78, 130.98, 136.02, 137.72, 139.62, 168.43. MS: 320 (M+l).
' Example 89 - 9-benzyl-2,3 A9-tetrahvdro-lH-carbazole-7-carboxylic acid
Methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylate (Example 88) (141 mg, 0.441 mmol) and KOH (300 mg, 5.34 mmol) was refluxed in EtOH (10 ml) and H2O (1 ml) for 3 h. Mixture acidified with 2 N HCl and precipitate filtered and washed with H O and Et2O. Yield 37 mg (28%); white solid. Mp. 248 °C. lH NMR (400 MHz, DMSO-d6) δ 1.78-1.86 (m, 4 H), 2.67-2.70 (m, 4 H), 5.41 (s, 2
H), 6.99 (d, J=7 Hz, 2 H), 7.21-7.29 (m, 3 H), 7.45 (d, J=8 Hz, 1 H), 7.60 (dd, J=8, 1 Hz, 1 H), 7.95 (s, 1 H), 12.39 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 20.51, 21.71, 22.44, 22.50, 45.45, 109.43, 111.17, 116.93, 119.73, 122.46, 126.07, 127.07, 128.61, 130.21, 135.38, 138.25, 139.63, 168.33. MS: 306 (M+l). Example 90 - methyl 5-propyl-5.6.7.8.9.10-hexahvdrocvclohepta[b1indole-4- carboxylate
Powdered KOH (3.64 g, 64.87 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (3.16 g, 12.97 mmol) in DMSO (60 ml) and the yellow mixture stirred for 5 min before 1-iodopropane (2.53 ml, 25.94 mmol). Stirring was continued for 5 min before quenched with sat. NH4C1 and extraction with Et2O. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 2.13 g (56%); colorless oil.
1H NMR (400 MHz, CDC13) 6 0.82 (t, J=7 Hz, 3 H), 1.58-1.64 (m, 2 H), 1.77-1.81 (m, 4 H), 1.82-1.93 (m, 2 H), 2.82-2.89 (m, 4 H), 3.97 (s, 3 H), 4.18-4.22 (m, 2 H), 7.07 (t, J=8 Hz, 1 H), 7.48 (dd, J=7, 1 Hz, 1 H), 7.64 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) δ 11.08, 23.60, 23.93, 26.45, 26.83, 28.01, 31.48, 46.00, 52.22, 114.61, 115.89, 117.46, 121.33, 123.16, 129.98, 131.71, 140.98, 169.19. MS: 286 (M+l).
Example 91 - 5-propyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid
Methyl 5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 90) (135 mg, 0.473 mmol) was hydrolyzed using KOH (0.4 g) in EtOH (10 ml) and H2O (2 ml). The mixture was refluxed for 2 h before most of EtOH was evaporated, solution acidified using 2 M HCl, aqueous phase extracted with EtOAc, combined organic layers dried (MgSO4) and evaporated. Yield 108 mg (84%); white solid. Mp. 121-122 °C.
1H NMR (400 MHz, DMSO-d6) 6 0.71 (t, J=7 Hz, 3 H), 1.47-1.85 (m, 8 H), 2.74-2.77 (m, 2 H), 2.84-2.87 (m, 2 H), 4.19-4.22 (m, 2 H), 6.98 (t, J=8 Hz, 1 H), 7.31 (dd, J=7, 1 Hz, 1 H), 7.58 (dd, J=8, 1 Hz, 1 H), 13.01 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 10.82, 23.32, 23.44, 25.76, 26.54, 27.83, 31.03, 45.13, 113.70, 117.37, 117.57, 120.51, 122.08, 129.40, 130.80, 140.85, 169.94. MS: 272 (M+l).
Example 92 - 5-[2-ftrifluoromethyl)benzyl]-5,6 ,8,,9 0-hexahydrocyclo- hepta[b]indole-4-carboxylic acid
Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) in DMSO (not dry?) (5 ml). The yellow mixture was stirred for 5 min and 2-trifluoromethyl-benzyl bromide (844 mg, 3.35 mmol) was added and stirring continued for 10 min before quenching with sat. NH4C1 and extraction with Et2O. The product was purified by flash chromatography using 5% MeOH in DCM. Yield 224 mg (58%). This material was purified further by recryst. from Et2O. Yield 44 mg (5%). Mp. 201 °C. 1H NMR (400 MHz, DMSO-d6) 6 1.57-1.80 (m, 6 H), 2.62 (m, 2 H), 2.84-2.85 (m, 2
H), 5.86 (s, 2 H), 6.01 (d, J=7 Hz, 1 H), 7.08 (t, J=8 Hz, 1 H), 7.36-7.48 (m, 3 H), 7.73 (d, J=8 Hz, 2 H), 12.85 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 23.34, 25.60, 26.18, 27.74, 30.60, 44.72, 115.08, 117.13, 118.17, 121.51, 123.71, 125.15, 125.85, 125.90, 126.00, 127.19, 129.79, 132.32, 132.82, 137.82, 140.79, 169.10. Found: 387.1444 (M4). Calc. for C22H20F3NO2: 387.1446.
Example 93 - methyl 5-benzyl-5,6,7,8,9,10-hexahvdrocvcloheptarb1indole-4- carboxylate
Powdered KOH (0.23 g, 4.11 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (200 mg, 0.882 mmol) in dry DMSO (5 ml). After 5 min, benzyl bromide (147 μl, 1.233 mmol) was added and stirring continued for 10 min. Sat. NH4C1 was added and the mixture extracted with Et O. The product was purified by flash chromatography using 2% and 5% EtOAc in hexanes as eluents. Yield 222 mg (81%); colorless oil. 1H NMR (400 MHz, CDC13) 6 1.69-1.88 (m, 6 H), 2.76-2.79 (m, 2 H), 2.85-2.88 (m,
2 H), 3.60 (s, 3 H), 5.52 (s, 2 H), 6.82 (d, J=7 Hz, 2 H), 7.07 (t, J=8 Hz, 1 H), 7.16-7.23 (m, 3 H), 7.45 (dd, J=7, 1 Hz, 1 H), 7.67 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 623.97, 26.59, 26.74, 28.07, 31.27, 48.28, 51.89, 115.29, 116.16, 117.95, 121.60, 123.70, 125.74, 126.09, 126.74, 127.43, 127.87, 128.37, 130.29, 130.33, 132.71, 139.01, 141.45, 168.87. MS: 334 (M+l).
Example 94 - 5-benzyl-5.6.7.8,9 0-hexahydrocyclohepta[b]indole-4-carboxylic acid Methyl 5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 93) (211 mg, 0.632 mmol) was refluxed with KOH (0.40 g), EtOH (10 ml) and H2O (2 ml) for 3 h. Most of EtOH was evaporated and 2 N HCl added. The acidic solution was extracted with EtOAc and dried (MgSO4). The residue was purified by flash chromatography using 2% MeOH in DCM. Yield 104 mg (51%); white solid. Mp. 140-141 °C.
1H NMR (400 MHz, DMSO-d6) 6 1.60-1.80 (m, 6 H), 2.77-2.81 (m, 4 H), 5.67 (s, 2 H), 6.74 (d, J=7 Hz, 2 H), 7.03 (t, J=8 Hz, 1 H), 7.13-7.21 (m, 3 H), 7.39 (d, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 H), 12.86 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 23.41, 25.91, 26.39, 27.82, 30.80, 47.10, 114.61, 117.46, 117.79, 121.11, 123.19, 125.69, 126.69, 128.38, 129.88, 132.01, 139.18, 141.24, 169.44. MS: 320 (M+l).
Example 95 - methyl 5-(3-cyanobenzyl)-5,6 ,8.9.10-hexahydrocycloheptarb1indole- 4-carboxylate
Powdered KOH (1.59 g, 28.33 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (1.350 mg, 5.548 mmol) in dry DMSO (50 ml) the yellow mixture was stirred for 2 min before 3-cyanobenzyl bromide (1.85 g, 9.44 mmol) and stirring continued for 2 min before the mixture was poured into sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 5% and 10% EtOAc in hexanes as eluents. Yield: 1.410 g (71%); white solid. Mp.120 °C.
1H NMR (400 MHz, CDC13) 6 1.58-1.77 (m, 6 H), 2.60-2.63 (m, 2 H), 2.75-2.77 (m, 2 H), 3.56 (s, 3 H), 5.45 (s, 2 H), 6.94 (d, J=8 Hz, 1 H), 6.99 (t, J=8 Hz, 1 H), 7.06 (s, 1 H), 7.20 (t, J=8 Hz, 1 H), 7.35 (d, J=8 Hz, 1 H), 7.43 (dd, J=8, 1 Hz, 1 H), 7.59 (dd, J=8, 1 Hz, 1 H). MS: 359 (M+l). Found: C, 77.08; H, 6.20; 7.75. Calc. for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82.
Example 96 -5-[3-faminocarbonyDbenzyl]-5.6.7.8.9.10-hexahydrocyclo- hepta[b]indole-4-carboxylate Methyl 5-(3-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate
(Example 95) (1.788 g, 4.988 mmol) was hydrolyzed using KOH (2.80 g, 49.9 mmol), EtOH (100 ml) and H2O (20 ml). The mixture was refluxed for 3 h and acidified with 6 M HCl, precipitate filtered and washed with water. HPLC revealed two products. The collected material was refluxed in EtOH (20 ml) and filtered, and dried. Yield 1.271 g (70%); white solid (99% pure, HPLC). Mp. 271 °C. Η NMR (400 MHz, DMSO-d6) δ 1.62-1.82 (m, 6 H), 2.76-2.82 (m, 4 H), 5.68 (s, 2 H), 6.69 (d, J=8 Hz, 1 H), 7.03 (t, J=8 Hz, 1 H), 7.23-7.38 (m, 3 H), 7.47 (s, 1 H), 7.63-7.68 (m, 2 H), 7.87 (s, 1 H), 12.85 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 23.42, 25.91, 26.36, 27.79, 30.82, 47.16, 114.65,117.35, 117.85, 121.16, 123.19, 125.34, 125.57, 128.19, 128.24, 129.87, 131.94, 134.41, 139.46, 141.20, 167.71, 169.36. MS: 363 (M+l). Found: C, 72.48; H, 5.96; N, 7.47%. Calc. for C22H22N2O3y4H2O: C, 72.05; H, 6.18; N, 7.64%.
Example 97 - methyl 5-(4-cvano-butyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole- 4-carboxylate To a solution of methyl 5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate
(Example 34) (534 mg, 2.194 mmol) in dry DMSO (15 ml) was added powdered KOH (0.59 g, 10.5 mmol) at RT and the mixture stirred for 5 min before 5-bromovaleronitrile (384 μl, 3.298 mmol) was added and the mixture stirred for 15 min more before quenched with sat. NH4C1 and extracted with diethyl ether. The wanted product isolated by flash chromatography using 15% and 20% EtOAc in hexanes. Yield: 306 mg (43%); yellow oil. Recovered starting material: 70 mg (13%).
1H NMR (400 MHz, CDC13) 6 1.50-1.53 (m, 2 H), 1.72-1.91 (m, 8 H), 2.27 (t, J=7.2 Hz, 2 H), 2.79-2.87 (m, 4 H), 3.95 (s, 3 H) 4.29-4.33 (m, 2 H), 7.06 (t, J=7.7 Hz, 1 H), 7.53 (dd, J=7.4, 1.1 Hz, 1 H), 7.63 (dd, J=7.8, 1.3 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 16.96, 22.73, 23.92, 26.51, 26.86, 27.93, 29.60, 31.42, 43.73, 52.37, 115.26, 115.56, 117.80, 119.34, 121.86, 123.95, 130.16, 132.02, 140.69, 168.93. MS: 325 (M+l).
Example 98 - 5-(5-amino-5-oxopentylV5.6 .8.9,10-hexahvdrocycloheptarb]indole-4- carboxylic acid and Example 99 - 5-(4-cyanobutyl)-5, 6,7,8.9, 10-hexahydrocyclohepta[b]mdole-4- carboxylic acid
Methyl 5-(4-cyano-butyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 97) (150 mg, 0.463 mmol) was refluxed with EtOH (10 ml) and 2 M KOH (2 ml) for 2 h. Most of solvent evaporated, 6 M HCl (1 ml), solid material filtered and dissolved in MeOH and purified by prepatative HPLC (30 mm column, 30-60% MeCN). First eluated: 5- (5-amino-5-oxopentyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 98); 20 mg. MS: 329 (M+l). Second eluated: 5-(4-cyano-butyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 99); 5 mg. MS: 311 (M+l).
Example 100 - methyl 5-C3-methoxybenzvD-5,6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylate
Powdered KOH (0.86 g, 15.32 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (1.15 g, 4.73 mmol) in dry DMSO (30 ml) and the yellow mixture stirred for 5 min before 3-methoxybenzyl chloride (1.03 ml, 7.09 mmol) was added. The mixture was stirred for further 10 min before .quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 5% EtOAc in hexanes. Yield 834 mg (51%); colorless oil.
1H NMR (400 MHz, CDC13) 6 1.71-1.90 (m, 6 H), 2.77-2.80 (m, 2 H), 2.85-2.88 (m, 2 H), 3.65 (s, 3 H), 3.68 (s, 3 H), 5.50 (s, 2 H), 6.39-6.43 (m, 2 H), 6.71 (dd, J=8.2, 2.4 Hz, 1 H), 7.06-7.15 (m, 2 H), 7.48 (dd, J=7.4, 1.1 Hz, 1 H), 7.67 (m, 1 H). 13C NMR (100 MHz, CDCI3) δ 23.95, 26.56, 26.76, 28.08, 31.26, 48.17, 51.91, 55.04, 111.55, 111.97, 115.30, 116.10, 117.94, 118.08, 121.61, 123.74, 129.38, 130.36, 132.80, 140.76, 141.43, 159.70, 168.82. GC-MS: 100%, 363 (M+).
Example 101- 5-(3-methoxybenzyl)-5,6,7,8,9, 10-hexahvdrocyclohepta[blindole-4- carboxylic acid
Methyl 5-(3-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 100) (699 mg, 1.923 mmol) was refluxed with EtOH (15 ml) and 2 M KOH (3 ml) for 2.5 h. Solvent evaporated and 6 M HCl (1.5 ml) and water added. The mixture was extracted with EtOAc and dried (MgSO4). Yield 566 mg (84%); white solid. Mp. 94 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.63-1.82 (m, 6 H), 2.79-2.81 (m, 4 H), 3.61 (s, 3 H), 5.63 (s, 2 H) 6.26-6.28 (m, 2 H), 6.70 (dd, J=8.38, 1.8 Hz, 1 H), 7.03 (t, J=7.7 Hz, 1 H), 7.10 (t, J=8.0 Hz, 1 H), 7.37-7.39 (m, 1 H), 7.66 (dd, J=7.9, 1.1 Hz, 1 H), 12.88 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 23.39, 25.86, 26.43, 27.85, 30.78, 46.94, 54.80, 111.70, 111.73, 114.63, 117.42, 117.83, 117.85, 121.14, 123.20, 129.52, 129.88, 132.02, 140.80, 141.30, 159.26, 169.40. MS: 350 (M+l). Found: C, 74.85; H, 6.65; N, 3.79%. Calc. for C22H23NO3yH2O: C, 74.70; H, 6.70; N, 3.96%.
Example 102 - 5-C2-cyanobenzyl)-5, 6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylic acid
A stirred solution of Example 34 (200 mg, 0.82 mmol) in wet DMSO (5 mL) was treated with KOH powder (230 mg, 4.10 mmol). After 5 min the dark brown solution was treated with 2-cyanobenzyl bromide (322 mg, 1.64 mmol). Stirring continued for 10 min and then the reaction mixture was poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 30 mL), the combined organic layers dried (Na2SO4) and evaporated in vacuo. The residual solid was purified by flash column chromatography on silica gel eluting with DCM / methanol (20:1 v/v) to give 32 mg (11%) of a mint-colored solid: Mp 207.1-208.4 °C.
1H NMR (100 MHz, CDC13) δ 1.66-1.71 (m, 2H) 1.76-1.81 (m, 2H), 1.84-1.90 (m, 2H) 2.68-2.71 (m, 2H) 2.85-2.88 (m, 2H) 5.82 (s, 2H) 6.51 (d, J=7.53 Hz, IH) 7.14 (t, J=7.78 Hz, IH) 7.26-7.28 (m, IH) 7.34-7.38 (m, IH) 7.64 (dd, Jl=7.65, J2=1.13 Hz, IH) 7.75 (d, J=8.03 Hz, IH); MS (El ) m/z 345.2.
Example 103 - 5-[2-(aminocarbonyDbenzyl]-5,6,7,8,9,10-hexahvdrocvclo- hepta[b]indole-4-carboxylic acid
A stirred solution of Example 102 (75 mg, 0.22 mmol) in ethanol (5 mL) and water (1 mL) was treated with KOH powder (122 mg, 2.2 mmol) and refluxed for 2 h in a seal-capped tube. After cooling, the ethanol was evaporated and the residue was acidified with aqueous HCl (10%) until pH 3. The precipitate that formed was collected on a filter and recrystallized from acetonitrile (hot filtration!). This afforded 11 mg (14%>) of the title compound as a yellow solid: Mp 154-155 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.53 (m, 2H) 1.68-1.69 (m, 2H), 1.78-1.79 (m, 2H) 2.61-2.64 (m, 2H) 2.80-2.82 (m, 2H) 5.83 (s, 2H) 5.89 (d, J=7.03 Hz, IH) 7.04 (t, J=7.78 Hz, IH) 7.15-7.20 (m, 2H) 7.37 (d, J=7.03 Hz, IH) 7.47 (br s, NH) 7.51 (d, J=7.53 Hz, IH) 7.69 (d, J=6.53 Hz, IH) 7.87 (br s, NH); MS (El ) m/z 363.0. Example 104 - methyl 4-oxo-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxylate DDQ (9.91 g, 43.64 mmol) in THF (50 ml) was added dropwise to a solution of methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (5.05 g, 21.82 mmol) in
THF (200 ml) and H2O (30 ml) at 0°C. The mixture was stirred for 3 h before K2CO3 (23 g) was added and stirring continued at RT for 2 h. Water and DCM were added and the organic layer evaporated. The product was purified by flash chromatography using 20-50 % EtOAc in hexanes as eluents. Yield 4.25 g (80%); white solid. Mp. 173 °C.
1HNMR (400 MHz, CDC13) 62.24-2.28 (m, 2 H), 2.58-2.61 (m, 2 H), 3.02 (t, J=6
Hz, 2 H), 3.98 (s, 3 H), 7.27-7.29 (m, 1 H), 7.87 (d, J=8 Hz, 1 H), 8.42 (d, J=8 Hz, 1 H), 10.05 (s, 1 H). 13C NMR (100 MHz, CDC13) δ 23.41, 23.59, 38.06, 52.10, 112.45, 113.26,
121.91, 124.94, 125.77, 127.09, 135.77, 151.75, 167.71, 194.25. GC-MS: 243 (M4). Found:
C, 69.03; H, 5.57; N, 5.60. Calc. for Cι4Hι3NO3: C, 69.12; H, 5.39; N, 5.76%.
Example 105 - 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 104) (95 mg,
0.391 mmol) was hydrolyzed using 2 M LiOH (2 ml), MeOH, (2 ml) and THF (2 ml): The mixture was stirred at ambient temperature overnight and acidified by addition of 2 M HCl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) and evaporated. Yield 84 mg (93%); white solid. Mp. 335-336 °C. 1H NMR (400 MHz, DMSO-d6) 6 2.08-2.13 (m, 2 H), 2.42-2.44 (m, 2 H), 3.04 (t,
J=6.2 Hz, 2 H), 7.24 (t, J=7.7 Hz, 1 H), 7.77 (d, J=7.5 Hz, 1 H), 8.20 (d, J=7.5 Hz, 1 H), 11.73 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 22.91, 23.34, 37.86, 111.74, 114.14, 121.29, 124.69, 12.25, 125.87, 134.93, 15.14, 167.50, 193.36. MS: 230 (M+l). Found: C, 67.44; H, 5.03; N, 5.71%. Calc. for C^HnNOs '/s^O: C, 67.44; H, 4.90; N, 6.05%.
Example 106 - methyl 4-hydroxyimino-2,3 ,4,9-tetrahydro- lH-carbazole-8- carboxylate
Methyl 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 104) (2.30 g, 9.48 mmol) was refluxed with hydroxylamine hydrochloride (3.29 g, 47.4 mmol) and sodium acetate (3.89 g, 47.4 mmol) in EtOH (40 ml) and H2O (20 ml) for 2 h. TLC showed full conversion. Water (200 ml) was added and precipitate filtered and washed with water and dried under vacuum. Yield 2.13 g (87%). Mp.190 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.88-1.92 (m, 2 H), 2.67-2.68 (m, 2 H), 2.87-2.97 (m, 2 H), 3.93 (s, 3 H), 7.15 (t, J=8 Hz, 1 H), 7.73 (dd, J=8, 1 Hz, 1 H), 8.17 (d, J=8 Hz, 1 H), 10.39 (s, 1 H), 11.24 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 21.75, 22.34, 22.63, 51.89, 106.91, 112.25, 119.48, 123.56, 125.71, 126.55, 134.61, 143.31, 152.19, 166.47. MS: 259 (M+l). Found: C, 65.00; H, 5.70; N, 10.73%. Calc. for Cι4Hι4N2O3: C, 65.11; H, 5.46; N, 10.85%.
Example 107 - 4-hydroxyimino-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxylic acid
Methyl 4-hydroxyimino-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 106) (97 mg, 0.376 mmol) was refluxed with KOH (0.33 g, 5.88 mmol) in EtOH (5 ml) and H2O (1 ml) for 1.5 h. EtOH was evaporated and the solution made acidic using 2 M HCl. The precipitated material was washed with water and dried under vacuum. Yield 50 mg (54%); white solid. Mp. 206 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.87-1.90 (m, 2 H), 2.66-2.67 (m, 2 H), 2.86-2.89 (m, 2 H), 7.12 (t, J=8 Hz, 1 H), 7.70 (dd, J=8, 1 Hz, 1 H), 8.13 (d, J=8 Hz, 1 H), 10.35 (s, 1 H), 11.16 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 621.79, 22.40, 22.65, 106.76, 113.26, 119.39, 123.77, 125.57, 126.19, 135.08, 143.27, 152.33, 167.87. MS: 245 (M+l). Found: C, 61.69; H, 5.13; N, 10.89%. Calc. for Cι3Hι2N2O3: C, 61.68; H, 5.18; N, 11.07%.
Example 108 - 9-benzyl-4-benzyloxyimino-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid
Powdered KOH (0.15 g, 2.67 mmol) was added to a solution of methyl 4- hydroxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 105) (150 mg, 0.581 mmol) in DMSO (3 ml) and the mixture was stirred for 5 min before benzyl bromide (150 μl, 1.26 mmol) was added and stirring continued for 10 min and quenched with sat. NH4C1 and extracted with Et O. The product was purified by flash chromatography using hexanes/EtOAc 9:1 as eluent. Yield 63 mg; colorless oil. This material was hydrolyzed using KOH (0.12 g, 2.14 mmol) in refluxing EtOH (5 ml) and H2O (1 ml) for 2 h. Most EtOH was evaporated and the solution acidified using 2 M HCl. Precipitated compound was filtered and washed with water and dried under vacuum. Yield 45 mg (18% over two steps); white solid. Mp. 202 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.92-1.95 (m, 2 H), 2.73-2.82 (m, 4 H), 5.17 (s, 2 H), 5.65 (s, 2 H), 6.77 (d, J=7.0 Hz, 2 H), 7.13-7.46 (m, 10 H), 8.24 (d, J=7.0 Hz, 1 H), 13.02 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 21.53, 21.62, 22.80, 47.51, 75.07, 106.70, 118.18, 119.93, 124.41, 125.18, 125.95, 126.14, 127.05, 127.60, 128.16, 128.29, 128.59, 133.10, 137.86, 138.57, 145.55, 153.40, 168.84. MS: 425 (M+l).
Example 109 - methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate DDQ (2.77 g, 12.23 mmol) in THF (20 ml) was added dropwise to a solution of methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (1.95 g, 6.114 mmol) in THF (50 ml) and H2O (8 ml) at 0 °C and the mixture stirred for 3 h. K2CO3 (8 g) was added and mixture stirred for 2 h. Water and DCM were added. Aqueous layer was extracted with DCM, combined organic layers were dried (MgSO4). The product was purified by flash chromatography using hexanes/EtOAc 2:1. Yield 1.091 g (53%); white solid. Mp. 151 °C. -
1H NMR (400 MHz, CDC13) δ 2.12-2.19 (m, 2 H), 2.50-2.53 (m, 2 H), 2.80-2.83 (m, 2 H), 3.56 (s, 3 H), 5.52 (s, 2 H), 6.71 (dd, J=7, 2 Hz, 2 H), 7.11-7.18 (m, 4 H), 7.44 (dd, J=8,
1 Hz, 1 H), 8.46 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 22.58, 23.11, 37.71, 48.88, 52.23, 113.04, 117.37, 121.68, 125.52, 125.56, 125.73, 127.05, 127.39, 128.62,
133.40, 136.46, 153.70, 167.78, 194.16. MS: 334 (M+l).
Example 110 - 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 109) (98 mg, 0.294 mmol) was hydrolyzed using KOH (0.20 g), EtOH (5 ml) and water (1 ml). The mixture was refluxed for 2 h, most of EtOH evaporated, solution made acidic using
2 M HCl and solid material filtered, washed with water and dried under vacuum. Yield 81 mg (87%); white solid. Mp. 282 °C.
1H NMR (400 MHz, DMSO-d6) δ 2.14-2.17 (m, 2 H), 2.48-2.50 (m, 2 H), 2.98-3.01 (m, 2 H), 5.72 (s, 2 H), 6.83 (d, J=7 Hz, 2 H), 7.21-7.26 (m, 4 H), 7.48 (d, J=8 Hz, 1 H), 8.30 (d, J=8 Hz, 1 H), 13.17 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 22.08, 22.81, 37.46, 48.15, 112.01, 118.94, 121.48, 123.90, 124.96, 126.08, 126.64, 127.26, 128.68, 132.85, 137.07,154.77, 168.59, 193.42. Found: C, 76.25; H, 6.19; N, 4.53. Calc. for Cι8Hι7NO2y4H2O: C, 76.16; H, 6.21; N, 4.94%.
Example 111 - methyl 9-benzyl-4-("hvdroxyiminoV2.3 ,4,9-tetrahydro- lH-carbazole-
8-carboxylate
Methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 109) (1.074 g, 3.221 mmol) was refluxed with NH2-OHHCl (448 mg, 6.44 mmol) and NaOAc (528 mg, 6.44 mmol) in EtOH (40 ml) and H2O (20 ml) overnight. The mixture was extracted with DCM and the product purified by flash chromatography using hexanes/EtO Ac 4: 1 as eluent. Yield 798 mg (71 %); white solid.
1HNMR (400 MHz, CDC13) δ 2.05-2.98 (m, 2 H), 2.77-2.78 (m, 2 H), 2.92-2.93 (m, 2 H), 3.65 (s, 3 H), 5.56 (s, 2 H), 6.79 (m, 2 H), 7.21 (m, 4 H), 7.50 (dd, J=8, 1 Hz, 1 H), 7.99 (s, 1 H), 8.35 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 6 21.85, 22.30, 48.37, 52.15, 107.69, 116.83, 120.27, 124.90, 125.81, 125.96, 126.61, 127.14, 128.54, 133.69, 137.48, 144.93, 154.86, 168.26.
Example 112 - 9-benzyl-4-(Tιydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid Methyl 9-benzyl-5-hydroxyimino-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate
(Example 111) (100 mg, 0.287 mmol) was hydrolyzed using KOH (0.20 g), EtOH (5 ml) and water (1 ml). Most of EtOH evaporated and solution made acidic using 2 M HCl. The precipitate was filtered, washed with water and dried under vacuum. Yield 59 mg (61%); white solid. Mp. 221 °C. 1HNMR (400 MHz, DMSO-d6) 6 1.91-1.94 (m, 2 H), 2.68-2.70 (m, 2 H), 2.80-2.82
(m, 2 H), 5.65 (s, 1 H), 6.78 (d, J=7 Hz, 2 H), 7.11-7.23 (m, 4 H), 7.44 (dd, J=8, 1 Hz, 1 H), 8.25 (dd, J=8, 1 Hz, 1 H), 10.50 (s, 1 H), 12.99 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 21.58, 21.76, 22.13, 47.44, 107.73, 118.04, 119.60, 124.23, 125.09, 125.95, 126.33, 127.02, 128.57, 133.09, 138.05, 144.41, 152.20, 168.91. MS: 335 (M+l). Found: C, 69.25; H, 5.34; N, 7.62. Calc. for C2oHι8N2O3 3/4H2O: C, 69.08; H, 5.65; N, 8.06%. Example 113 - methyl 4-oxo-9-propyl-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxylate DDQ (3.68 g, 16.20 mmol) in THF (25 ml) was added dropwise to a solution of methyl 9-proρyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 71) (2.20 g, 8.10 mmol) in THF (70 ml) and water (10 ml) at 0 °C. The mixture was stirred at 0 °C for 3 h and K2CO3 (8 g) was added and mixture stirred at ambient temperature for 2 h. Water and DCM were added and aqueous layer extracted with DCM.The product was purified by flash chromatography using hexanes/EtOAc 2:1 and 1:1 as eluents. Yield 2.10 g (91%); white solid. Mp.90-91 °C.
Η NMR (400 MHz, CDC13) δ 0.82 (t, J=7 Hz, 3 H), 1.60-1.65 (m, 2 H), 2.24-2.29 (m, 2 H), 2.56-2.59 (m, 2 H), 2.94-2.97 (m, 2 H), 3.96 (s, 3 H), 4.27-4.31 (m, 2 H), 7.23-7.27 (m, 1 H), 7.61 (dd, J=8, 1 Hz, 1 H), 8.51 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, CDCI3) 6 10.94, 22.85, 22.90, 23.24, 37.82, 47.07, 52.60, 112.74, 116.97, 121.51, 125.52, 125.63, 127.16, 133.02, 153.25, 168.16, 194.08. MS: 286 (M+l). Found: C, 71.45; H, 6.73; N, 4.74%. Calc. for Cι7Hι9NO3: C, 71.56; H, 6.71; N, 4.91%.
Example 114 - 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 113) (131 mg, 0.459 mmol) was hydrolyzed using KOH (0.2 g), EtOH (5 ml) and water (1 ml). The mixture was refluxed for 2.5 h. Most of EtOH evaporated and the solution acidified using 2 M HCl. The precipitate was filtered and washed with water and dried under vacuum. Yield 85 mg (69%); white solid. Mp. 256 °C.
1H NMR (400 MHz, DMSO-d6) δ 0.76 (t, J=7 Hz, 3 H), 1.55-1.64 (m, 2 H), 2.12-2.17 (m, 2 H), 2.43-2.45 (d, J=6.78 Hz, 2 H), 3.02 (t, J=6 Hz, 2 H), 4.30 (t, J=8 Hz, 2 H), 7.23 (t, J=8 Hz, 1 H), 7.50 (d, J=7 Hz, 1 H), 8.25 (d, J=7 Hz, 1 H), 13.42 (s, 1 H). 13CNMR (100 MHz, DMSO-d6) δ 10.66, 21.99, 22.51, 22.84, 37.48, 46.31, 111.51, 118.94, 121.27, 123.54, 124.21, 126.43, 132.06, 154.33, 169.10, 193.21. MS: 272 (M+l). Found: C, 68.37; H, 6.28; N, 4.68%. Calc. for
Figure imgf000079_0001
C, 68.55, H, 6.47; N, 4.28%. , Example 115 - methyl 4-Chydroxyimino>9-propyl-2,3,4,9-tefrahvdro-lH-carbazole- 8-carboxylate
Methyl 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 113) (933 mg, 3.27 mmol), hydroxylamine hydrochloride (908 mg, 13.07 mmol) and sodium acetate (10.80 g, 13.07 mmol) was refluxed in EtOH (30 ml) and water (15 ml) for 4 h. Most of EtOH evaporated and water (20 ml) was added. Precipitate was filtered, washed with water and dried under vacuum. Yield 808 mg (82%); white solid. Mp. 164-165 °C.
1H NMR (400 MHz, DMSO-d6) 60.72 (t, J=7.40 Hz, 3 H), 1.47-1.52 (m, 2 H), 1.92- 1.95 (m, 2 H), 2.67-2.70 (m, 1 H), 2.83-2.86 (m, 2 H), 3.90 (s, 3 H), 4.12-4.16 (m, 2 H), 7.14 (t, J=8 Hz, 1 H), 7.43 (dd, J=8, 1 Hz, 1 H), 8.23 (dd, J=8, 1 Hz, 1 H), 10.45 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 10.70, 21.59, 21.70, 22.13, 22.50, 45.62, 52.58, 107.11, 116.50, 119.36, 123.56, 125.18, 126.09, 132.14, 144.23, 152.20, 168.09. MS: 301 (M+l). Found: C, 67.76; H, 6.70; N, 9.10%. Calc. Cι7H20N2O3: C, 68.01; H, 6.72; 9.33%.
Example 116 - methyl 10-oxo-5-propyl-5, 6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylate
DDQ (3.14 g, 13.83 mmol) in THF (25 ml) was added dropwise to a solution of methyl 5-propyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 90)
(1.973 g, 6.91 mmol) in THF (70 ml) and water (10 ml). The mixture was stiired for 3 h at 0 °C. K2CO3 (10 g) was added and stirring continued for 2 h. Water and DCM were added, and aqueous layer extracted with DCM. The product was purified by flash chromatography using hexanes/EtOAc 4:1 and 2:1 as eluents. Yield 1.33 g; yellow oil.
1H NMR (400 MHz, CDC13) 6 0.83 (t, J=7 Hz, 3 H), 1.60-1.65 (m, 2 H), 1.89-2.01
(m, 4 H), 2.77-2.80 (m, 2 H), 3.05-3.06 (m, 2 H), 3.95 (s, 3 H), 4.23-4.27 (m, 2 H), 7.22 (t, J=8 Hz, 1 H), 7.54 (dd, J=8, 1 Hz, 1 H), 8.64 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz,
CDCI3) δ 10.93, 21.65, 23.12, 24.80, 25.73, 43.01, 46.51, 52.55, 115.63, 116.65, 121.19,
125.23, 125.78, 128.71, 132.50, 149.82, 168.63, 198.00. MS: 300 (M+l). Example 117 - 10-oxo-5-propyl-5.6.7.8,9,10-hexahydrocyclohepta| >]indole-4- carboxylic acid
Methyl 10-oxo-5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 116) (141 mg, 0.472 mmol) was hydrolyzed using KOH (0.40 g), EtOH (10 ml) and H2O (2 ml). The mixture was refluxed for 2 h. Water (20 ml) added and the solution made acidic using 2 M HCl. Precipitate filtered, washed with water and dried under vacuum. Yield 64 mg (48%); white solid. Mp. 257 °C.
1H NMR (400 MHz, DMSO-d6) δ 0.79 (t, J=7 Hz, 3 H), 1.57-1.62 (m, 2 H), 1.80-1.95 (m, 4 H), 2.68-2.71 (m, 2 H), 3.14-3.18 (m, 2 H), 4.30-4.34 (m, 2 H), 7.19 (t, J=8 Hz, 1 H), 7.43 (dd, J=7, 1 Hz, 1 H), 8.42 (dd, J=8, 1 Hz, 1 H), 13.39 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6) 6 10.66, 21.20, 22.83, 24.33, 24.71, 42.51, 45.72, 114.44, 118.75, 120.89, 123.77, 123.83, 128.04, 131.48, 150.87, 169.57, 196.95. MS: 286 (M+l).
Example 118 - methyl 5-benzyl-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole- 4-carboxylate
To a solution of DDQ (1.86 g, 8.19 mmol) in dry THF (16 mL) was dropwise added methyl 5-benzyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 93) (1.37 g, 4.11 mmol) in 5 % aqueous THF (5 mL) over a 5-min period. The resulting darkblue solution slowly turned brown and was stirred for 2 more h. The reaction mixture was poured into diethyl ether (100 mL) and washed with water (100 mL). The organic phase was dried (Na2SO4) and filtered over a short plug of silica gel. Evaporation in vacuo gave a crude yellow solid that was purified by flash column chromatography using silica gel eluting with DCM. This gave the title compound as an ivory solid (0.54 g, 38%): Mp 142.2-142.4 °C. 1H NMR (400 MHz, CDC13) δ 1.91-1.96 (m, 4H) 2.82-2.85 (m, 2H) 3.00-3.03 (m, 2H) 3.62 (s, 3H) 5.63 (s, 2H) 6.79-6.82 (m, 2H) 7.20-7.27 (m, 4H) 7.52 (d, J=7.53 Hz, IH) 8.69 (d, J=8.03 Hz, IH); MS (EI+) m/z 348.2.
Example 119 - 5-benzyl- 10-oxo-5, 6,7,8, 9,10-hexahvdrocycloheptarb]indole-4- carboxylic acid To a solution of methyl 5-benzyl- 10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-
4-carboxylate (Example 118) (500 mg, 1.44 mmol) in ethanol (15 mL) and water (3 mL) was added KOH (400 mg, 7.20 mmol), and the resulting reaction mixture was refluxed for 1 h. The clear solution was allowed to cool to RT, and ethanol was removed on the rotavapor. Water (20 mL) was added and the aqueous layer was acidified with 10%ι HCl. The ivory- colored precipitate that formed was collected on a filter and air-dried (421 mg, 88 %). Part of this material (225 mg) was recrystallized from ethanol to give a white solid (172 mg): Mp = 255.3-255.4 °C.
1HNMR (400 MHz, DMSO-d6) δ 1.77-1.84 (m, 4H) 2.70-2.73 (m, 2H) 3.08-3.11 (m, 2H) 5.79 (s, 2H) 6.80 (d, J=7.03 Hz, 2H) 7.16-7.26 (m, 4H) 7.45 (d, J=7.53 Hz, IH) 8.47 (d, J=8.03 Hz, IH) 13.20 (br s, IH); MS (El4) m z 334.2.
Example 120 - 5-benzyl-10-(hydroxyiminoy5,6,7,8,9,10-hexahydrocyclo- heptarblindole-4-carboxylic acid
5-benzyl-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 119) (54 mg, 0.162 mmol) was refluxed with NH2OHHCl (56 mg, 0.81 mmol) and NaOAc (66 mg, 0.81 mmol) in EtOH (2 ml) and water (1 ml) in a Stemblock tube for 2.5 h. Two drops of 6 M HCl and water (5 ml) was added and the precipitated separated by centrifugation and washed with water and dried under high vaccum. Yield 10 mg (18%). NMR indicates -90% of one main isomer. MS: 349 (M+l).
Example 121 - methyl 5-(3-cyanobenzyP-10-oxo-5,6,7, 8,9.10- hexahydrocyclohepta[b]indole-4-carboxylate
DDQ (1.27 g, 5.5 mmol) in anhydrous THF (10 ml) was added dropwise to methyl 5-
(3-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 95)
(1.0 g, 2.8 mmol) in 5 % water in THF (20 ml). The mixture was stirred for 2 hours and additionally DDQ (0.25 g) was added. After 1 hour the mixture was evaporated into dryness and partitioned between water and DCM. The organic phase was dried (MgSO4) and evaporated and the residue was taken up in DCM and filtered through a short plug of silica.
Yield 0.2 g (19 %).
1H NMR (400 MHz, CDC13) δ 1.99-2.02 (m, 4 H) 2.81-2.88 (m, 2 H) 2.95-3.01 (m, 2 H) 3.68 (s, 3 H) 5.68 (s, 2 H) 6.99 (d, J=7.53 Hz, 1 H) 7.23-7.30 (m, 3 H) 7.35 (t, J=7.78 Hz,
1 H) 7.52 (d, J=8.03 Hz, 1 H) 7.60 (d, J=7.53 Hz, 1 H). MS (70eN) m/z (%) 373 (M+,100). Example 122 - 5-[3-faminocarbonyl benzyl]-10-oxo-5,6,7,8,9,10- hexahvdrocycloheptarblindole-4-carboxylic acid
Methyl 5-(3-cyanobenzyl)-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 121) (0.15 g, 0.40 mmol) was dissolved in 2N NaOH (1.2 ml) and EtOH (10 ml) and heated at 80 °C for 3.5 hours. The mixture was acidified with 1 N HCl, pH = 3 and evaporated to residue of 5 ml. The yellow solid precipitate was collected and washed with water/methanol 1:1 (2x) and dried. Yield 65 mg, (43 %).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.88 (m, 4 H) 2.70-2.75 (m, 2 H) 3.04- 3.12 (m, 2 H) 5.81 (s, 2 H) 6.81 (d, J=8.03 Hz, 1 H) 7.22 (t, J=7.53 Hz, 1 H) 7.30 (t, J=7.53 Hz, 1 H) 7.35 (s, 1 H) 7.46 (d, J=7.53 Hz, 2 H) 7.69 (d, J=8.03 Hz, 1 H) 7.92 (s, 1 H) 8.49 (d, J=8.03 Hz, 1 H). MS (70eV) nVz (%) 377 (M^IOO).
Example 123 - 9-benzyl-l-oxo-2.3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (0.10 g; 0.31 mmol) in pyridine (0.5 ml) was added dropwise to TFA-anhydride (0.5 ml) at 0°C and stirred at 25°C for 20 hours. Water was added carefully and the solid was filtered off and taken up in DCM. The organic phase was washed with water (2x), dried (MgSO ) and evaporated. Yield of intermediate 0.098 g. The intermediate was dissolved in ethanol (1 ml) and IN NaOH (1 ml) was added and the mixture was stirred at 20°C overnight. The mixture was evaporated and partitioned between water and DCM and acidified to pH 5 with IN HCl, extracted with DCM (2x) and the combined organic phases were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography 2.5 % MeOH in DCM to 5 % MeOH in DCM. Yield: 0.030 g (31%). Yellow solid.
1H NMR (400 MHz, CDC13) δ 2.20-2.33 (m, 2 H) 2.62-2.73 (m, 2 H) 3.08 (t, J=6.15 Hz, 2 H) 6.29 (s, 2 H) 6.69-6.78 (m, 2 H) 7.04-7.22 (m, 4 H) 7.89 (dd, J=7.65, 2.13 Hz, 2 H) 10.23 (br. s., 1 H), MS (70eV) m/z (%) 318 (M",100) Example 124 - 9-benzyl-l- trifluoroacetyl -2.3,4.9-tetrahydro-lH-carbazole-8- carboxylic acid
9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (Example 40) (0.050 g, 0.16 mmol) in pyridine (0.5 ml) was added dropwise to TFA-anhydride (0.5 ml) at RT and stirred 50°C overnight. The mixture was evaporated and partitioned between water and DCM. pH was adjusted to 3 with IN HCl and extracted twice with DCM. The combined organic phases was dried (MgSO4) and evaporated. The crude product was purified by preparative HPLC. Tautomeric ratio of 2:3. Yield: 0.009 g (14%); colorless oil.
1H NMR (400 MHz, CDC13) 6 1.71-2.09 (m, 2 H) 2.13-2.39 (m, 2 H) 2.69-2.86 (m, 1 H) 2.88-3.03 (m, 1 H) 4.27-4.40 (m, 1 H) 5.08 (d, J=17.32 Hz, 1 H) 5.73 (d, J=17.32 Hz, 1 H) 6.67 (dd, J=6.02, 2.76 Hz, 2 H) 7.09-7.20 (m, 4 H) 7.78 (dd, J=7.53, 2.51 Hz, 2 H) 11.39 (br. s., 1 H), MS (70eV) m/z (%) 400 (M",100).
Example 125 - methyl 5-(3-bromo-5-methoxybenzyl -5,6.7,8,9,10-hexahydro- cyclohepta[b]indole-4-carboxylate
Powdered KOH (0.32 g, 5.70 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (572 mg, 2.35 mmol) in dry DMSO (10 ml). After 2 min of stirring at ambient temperature l-bromo-3-(bromomethyl)-5- methoxybenzene (Example 1) (790 mg, 2.82 mmol) in DMSO (4 ml) was added and stirring continued for 5 min before the solution was poured into sat. NH4C1 (50 ml) and extracted with Et O (100 ml). The ether layer was evaporated and the product was purified by flash chromatography using 2% EtOAc in hexanes as eluents. Yield 692 mg (67%); colorless oil. 1H NMR (400 MHz, CDC13) 6 1.73-1.89 (m, 6 H), 2.75-2.78 (m, 2 H), 2.85-2.88 (m, 2 H), 3.63 (s, 3 H), 3.70 (s, 3 H), 5.46 (s, 2 H), 6.21 (s, 1 H), 6.72 (s, 1 H), 6.86 (s, 1 H), 7.08 (t, J=7.7 Hz, 1 H), 7.51 (d, J=7.5 Hz, 1 H), 7.67 (d, J=8.0 Hz, 1 H). 13C NMR (100 MHz,
CDCI3) δ 14.09, 22.62, 23.92, 26.55, 26.77, 28.03, 31.22, 31.55, 47.75, 52.03, 55.29, 110.87, 115.25, 115.59, 115.95, 118.12, 121.39, 121.83, 122.74, 124.05, 130.44, 132.79, 141.14, 142.54, 160.40, 168.66. GC-MS: 100%, 441/443 (M4). Example 126 - 5-f3-bromo-5-methoxybenzyl>5,6,7,8,9,10-hexahvdrocyclo- hepta[b]indole-4-carboxylic acid
Methyl 5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 125) (105 mg, 0.237 mmol) was refluxed in 2 M KOH (1 ml) and EtOH (5 ml) for 2.5 h. Most of solvent evaporated, 6 M HCl (1 ml) and water added. The mixture was extracted with EtOAc and dried (MgSO ). Yield 82 mg (82%); white solid. Mp.
183 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.64-1.84 (m, 6 H), 2.78-2.83 (m, 4 H), 3.64 (s, 3
H), 5.62 (s, 2 H), 6.22 (s, 1 H), 6.51 (s, 1 H), 6.95 (t, J=2.0 Hz, 1 H), 7.06 (t, J=7.7 Hz, 1 H), 7.41 (dd, J=7.4, 1.1 Hz, 1 H), 7.69 (dd, J=7.9, 1.1 Hz, 1 H), 12.91 (s, 1 H). 13CNMR (100
MHz, DMSO-d6) δ 23.35, 25.77, 26.44, 27.84, 30.77, 46.63, 55.38, 111.28, 114.57, 114.87,
117.28, 118.04, 120.65, 121.29, 122.16, 123.36, 129.84, 131.95, 141.14, 143.01, 160.15, .
169.30. MS: 428/430 (M+l). Found: C, 60.68; H, 5.86; N, 2.95%. Calc. for
C22H22BrNO3y2H2O: C, 60.45; H, 5.30; N, 3.21%.
Example 127 - methyl 5-f3-cyano-5-methoxybenzyl)-5,6,7,8,9,10-hexahvdro- cycloheptarblindole-4-carboxylate
Methyl 5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 125) (421 mg, 0.951 mmol) and CuCN (128 mg, 1.43 mmol) in DMF (10 ml) was heated at 160 °C in a sealed tube (stemblock tube) for 20 h. The mixture was filtered through a short plug of silica and washed with ether. The filtrate was evaporated and purified by flash chromatography using 5% - 20% EtOAc in hexanes. Yield 167 mg (45%); white solid; or powdered KOH (186 mg, 3.32 mmol) was added to a solution of methyl
5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (323 mg, 1.327 mmol) in DMSO (10 ml) and the mixture stirred for 5 min before 3-(bromomethyl)-5- methoxybenzonitrile (Example 3) (360 mg, 1.592 mmol) in DMSO (5 ml) was added and the mixture stirred for 5 min before quenched with sat. NH4C1 and extracted with Et2O. The product was purified by flash chromatography using 10-20% EtOAc in hexanes. Yield 244 mg; white solid. Mp. 148 °C. Η NMR (400 MHz, CDC13) δ 1.71-1.89 (m, 6 H), 2.71-2.74 (m, 2 H), 2.84-2.87 (m,
2 H), 3.70 (s, 6 H), 5.52 (s, 2 H), 6.57 (s, 1 H), 6.74 (s, 1 H), 6.95 (d, J=1.0 Hz, 1 H), 7.09 (t, J=7.7 Hz, 1 H), 7.53 (dd, J=7.4, 1.1 Hz, 1 H), 7.69 (dd, J=7.8, 1.3 Hz, 1 H). 13C NMR (100 MHz, CDC13) 623.90, 26.57, 26.77, 27.97, 31.15, 47.77, 52.08, 55.48, 113.18, 115.11, 115.72, 115.97, 117.01, 118.37, 118.64, 121.98, 122.22, 124.49, 130.54, 132.86, 140.88, 142.75, 159.84, 168.51. Found: 388.1782 (M ). Calc. for C24H24N2O3: 388.1787. Found; C, 74.12; H, 6.38; N, 7.07%. Calc. for C24H24N2O3: C, 74.21; H, 6.23; N, 7.21%.
Example 128 - 5-[3-aminocarbonylV5-methoxybenzyl]-5,6,7,8,9,10- hexahydrocvclohepta[b]indole-4-carboxylate
Methyl 5-(3-cyano-5-methoxybenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 127) (142 mg, 0.366 mmol) was refluxed with 2 M KOH (1 ml) and EtOH (5 ml) for 2.5 h. Most of solvent evaporated and water and 6 M HCl (0.5 ml) added. The precipitate filtered, washed with water. HPLC indicated 84% purity of the crude compound. The product was refluxed with EtOH, filtered and washed with EtOH. Yield 10 mg (7%); white solid. Mp. 287 °C. 1H NMR (400 MHz, DMSO-d6) 6 1.63-1.83 (m, 6 H), 2.77-2.82 (m, 4 H), 3.64 (s, 3
H), 5.64 (s, 2 H), 6.22 (s, 1 H), 7.01-7.05 (m, 2 H), 7.21 (s, 1 H), 7.31 (s, 1 H), 7.38 (m, 1 H), 7.67 (d, J=7.0 Hz, 1 H), 7.87 (s, 1 H), 12.87 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 23.41, 25.88, 26.41, 27.84, 30.81, 47.01, 55.11, 110.35, 114.52, 114.69, 117.40, 117.68, 117.90, 121.17, 123.22, 129.87, 131.96, 135.82, 140.94, 141.23, 159.10, 167.49, 169.36. Found: 392.1724 (M4). Calc. for C23H24N2O : 392.1736.
Example 129 - methyl 5-r("5-cvano-2-furyl methyl]-5,6,7,8,9,10-hexahydro- cvcloheptaFblindole-4-carboxylate
Powdered KOH (309 mg, 5.51 mmol) was added to a solution of methyl 5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (550 mg, 2.26 mmol) in dry DMSO (20 ml) and the mixture stirred for 5 min before a solution of 5-(bromomethyl)-2- furonitrile (311077001, prepared after Erwing et. al. J. Med. Chem. 1999, 42, 3557-3571; and Chan et al., supra) (505 mg, 2.71 mmol) in DMSO. After 10 min of additional stirring at ambient temperature, the mixture was poured into sat. NH4C1 (100 ml) and extracted with Et2O (200 ml). The ether layer was evaporated and the title compound purified by flash chromatography using 5-10% EtOAc in hexanes. Yield 483 mg (61%); white solid. Mp. 121- 122 °C.
1H NMR (400 MHz, CDC13) δ 1.78-1.91 (m, 6 H), 2.81-2.88 (m, 4 H), 3.89 (s, 3 H), 5.64 (s, 2 H), 5.89 (d, J=3.5 Hz, 1 H), 6.91 (d, J=3.5 Hz, 1 H), 7.10 (t, J=7.7 Hz, 1 H), 7.60 (d, J=6.8 Hz, 1 H), 7.66 (d, J=7.8 Hz, 1 H). 13C NMR (100 MHz, CDC13) δ 23.78, 26.45, 26.63, 27.82, 31.07, 41.80, 52.34, 108.45, 111.42, 115.55, 116.15, 118.57, 122.30, 122.93, 124.75, 125.26, 130.76, 132.72, 140.71, 157.91, 168.49. Found: 348.1475 (M ). Calc. for C2ιH20N2O3: 348.1474.
Example 130 - 5-fr(5-aminocarbonylV2-furyllmethyll-5.6,7.8,9.10- hexahvdrocyclohepta[b]indole-4-carboxylic acid
Methyl 5-[(5-cyano-2-furyl)methyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate (Example 129) (175 mg, 0.502 mmol) was hydrolyzed using 2 M KOH (2 ml) and EtOH (10 ml) at reflux. The reaction was monitored by HPLC and stopped after 2 h when HPLC indicated that all starting material was hydrolyzed and LC-MS indicated that the nitrile group was hydrolyzed to carboxamide (74%) and carboxylic acid (26%). Most of EtOH was evaporated and water (10 ml) and 6 M HCl (1 ml) was added. The precipitate filtered, washed with water. The crude material suspended in refluxing EtOH (3 ml), filtered and dried under vacuum. Yield 47 mg (26%); white solid. Mp. 236 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.85 (m, 6 H), 2.76-2.78 (m, 2 H), 2.95-2.98
(m, 2 H), 5.70 (s, 2 H), 5.97 (d, J=3.3 Hz, 1 H), 6.91 (d, J=3.3 Hz, 1 H), 7.04 (t, J=7.5 Hz, 1 H), 7.35 (s, 2 H), 7.44 (d, J=7.3 Hz, 1 H), 7.65 (d, J=7.5 Hz, 1 H), 13.19 (s, 1 H). 13C NMR (100 MHz, DMSO-dg) 6 23.28, 25.75, 26.29, 27.67, 30.73, 108.88, 114.30, 114.74, 117.36, 118.12, 121.30, 123.36, 130.09, 131.55, 141.05, 147.11, 153.86, 159.00, 169.71. Found: 352.1412. Calc. for C20H20N2O : 352.1423 (M4).
Example 131 - 5- 4,6-dimethoxy-pyrimidin-2-ylmethyl -5,6,7,8,9,10-hexahydro- cyclohepta b]indole-4-carboxylic acid
2-chloromethyl-4-6-dimethoxypyrimidine (0.94 g, 5.0 mmol) was added to a suspension of methyl 5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (0.6 g, 2.5 mmol), KOH (0.7 g, 12.4 mmol) and Kl (0.83 g, 5.0 mmol) in DMSO (9 ml) at 25 °C. The mixture was stirred for 2 hours and diluted with diethyl ether and pH was adjusted to 3 with IN HCl, washed with water (3x), dried (MgSO4) and evaporated. The crude product was suspended in DCM and filtered. The white solid was dissolved in 2N NaOH and filtered. 2N HCl was added to the filtrate and the white solid precipitate was collected. Yield 0.3 g (32 %).
Η NMR (400 MHz, CDC13) δ 1.68-1.82 (m, 4 H) 1.84-1.93 (m, 2 H) 2.79-2.86 (m, 2 H) 2.86-2.96 (m, 2 H) 3.67 (s, 6 H) 5.62 (s, 2 H) 5.79 (s, 1 H) 7.08 (t, J=7.65 Hz, 1 H) 7.68 (d, J=7.78 Hz, 1 H) 7.72 (dd, J=7.53, 1.00 Hz, 1 H). MS (70eV) m/z (%) 382 (M+,100).
Example 132 - 5-j[6-hydroxy-2-(methylthio pyrimidin-4-yllmethyl|-5,6,7,8.9.10- hexahvdrocyclohepta b]indole-4-carboxylic acid
Methyl 5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate (Example 34) (0.1 g, 0.41 mmol) and KOH (0.28 g, 4.92 mmol) in DMSO (1 ml) was added to a solution of the 6-chloromethyl-2-methylsulfanylpyrimidine-4-ol (0.156 g, 0.82 mmol) and Kl (0.166 g, 1.0 mmol) at 50 °C and stirred for 5 minutes. IN HCl was added to pH=3 and the mixture was diluted with diethyl ether and washed with water twice.'After evaporation the crude product was purified by flash chromatography with 5 % MeOH in DCM. Yield 0.011 g (7 %).
Η NMR (400 MHz, CDCI3) δ 1.70-1.98 (m, 6 H) 2.38 (s, 3 H) 2.77-2.92 (m, 4 H) 5.22 (s, 1 H) 5.51 (s, 2 H) 7.06 (d, J=7.53 Hz, 1 H) 7.52 (d, J=7.28 Hz, 1 H) 7.63 (d, J=7.78 Hz, 1 H). MS (70eV) m/z (%) 382 (M-, 100)
Example 133 - 5-[(4-hydroxy-6-methoxypyrimidin-2-yl')methyl]-5,6,7,8,9.10- hexahvdrocyclohepta["b]mdole-4-carboxylic acid
5-(4,6-dimethoxy-pyrimidin-2-ylmethyl)-5,6,7,8,9, 10-hexahydro- cyclohepta[b]indole-4-carboxylic acid (Example 131) (0.1 g, 0.26 mmol) was dissolved in 2N NaOH (2 ml) and heated in a sealed vial at 100 °C for 36 hours. The mixture was cooled and 2N HCl was added dropwise (2.1 ml) and The white solid precipitate was collected and washed with water (2x) and dried. Yield 51 mg (54 %).
1HNMR (400 MHz, DMSO-d6) δ 1.61-1.72 (m, 4 H) 1.77-1.87 (m, 2 H) 2.71-2.79 (m, 2 H) 2.81-2.87 (m, 2 H) 3.56 (s, 3 H) 5.36 (s, 1 H) 5.43 (s, 2 H) 6.98 (t, J=7.53 Hz, 1 H) 7.34 (d, J=7.28 Hz, 1 H) 7.51 (d, J=7.78 Hz, 1 H). MS (70eV) m/z (%) 368 (M^IOO). Example 134 - methyl 5- yridin-2-ylmethyl)-5,6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylate
KOH (245 mg, 4.37 mmol) and potassium iodide (288 mg, 1.73 mmol) were suspended in dry DMSO (10 mL). After 5 min, Example 35 (2.12 mg, 0.87 mmol) was added to give a yellow solution. After 5 min of stirring, 2-(chloromethyl)pyridine hydrochloride (450 mg, 2.74 mmol) was added. The resulting light brown solution was stirred for 5 min, and then poured in saturated aqueous NH4C1 (50 mL) giving a white suspension. The aqueous phase was extracted with diethyl ether (3 x 30 mL) and the combined organic phases were dried (Na2SO4), and evaporated in vacuo. The residual oil was purified by flash column chromatography on silica gel eluting with DCM / diethyl ether (9:1 v/v) affording 170 mg (57%) of a colorless oil.
1HNMR (400 MHz, CDC13) δ ppm 1.63-1.69 (m, 2H) 1.74-1.80 (m, 2H) 1.83-1.89 (m, 2H) 2.70-2.73 (m, 2H) 2.84-2.87 (m, 2H) 3.60 (s, 3H) 5.55 (s, 2H) 6.85 (d, J=7.78 Hz, IH) 7.08-7.14 (m, 2H) 7.49-7.53 (m, 2H) 7.68 (dd, Jl=7.91, J2=1.13 Hz, IH) 8.56 (d, J=4.02 Hz, IH); MS (EI+) m/z 335.2.
Example 135 - 5-(pyridin-2-ylmethylV5.6.7,8,9,10-hexahydrocyclohepta[b1indole-4- carboxylic acid A stirred solution of Example 134 (90 mg, 0.27 mmol) in ethanol (5 mL) and water (1 mL) was treated with KOH powder (150 mg, 2.70 mmol) and refluxed for 2 h in a seal- capped tube. After cooling, the ethanol was evaporated, water (2 mL) was added, and the clear solution was neutralized with aqueous HCl (10%). The precipitate that formed was collected on a filter, washed with water and dried in a vacuum oven at 40 °C. This afforded 80 mg (93%) of the title compound as an off-white solid: Mp °C.
1HNMR (400 MHz, DMSO-d6) δ 1.62-1.66 (m, 2H) 1.70-1.73 (m, 2H) 1.80-1.82 (m, 2H) 2.73-2.76 (m, 2H) 2.80-2.83 (m, 2H) 5.74 (s, 2H) 6.65 (d, J=7.78 Hz, IH) 7.06 (t, J=7.65 Hz, IH) 7.36-7.39 (m, IH) 7.43 (d, J=6.27 Hz, IH) 7.70 (dd, Jl=7.91, J2=1.13 Hz, IH) 7.83 (t, J=7.53 Hz, IH) 8.56 (d, J=4.52 Hz, IH); MS (El ) m/z 321.2. Example 136 - methyl 5-r(6-chloropyridin-3-vDmethyl]-5,6,7,8,9.10- hexahydrocycloheptarblindole-4-carboxylate
The preparation of the title compound was performed according to the synthesis described for Example 134, using KOH (490 mg, 8.75 mmol), potassium iodide (576 mg, 3.47 mmol), Example 35 (2.12 mg, 0.87 mmol) and 2-chloro-5-(chloromethyl)pyridine (860 mg, 5.30 mmol) in dry DMSO (20 mL). This procedure gave 0.4 g (61%) of a colorless oil that solidified on standing: Mp 116.6-116.7 °C.
1H NMR (400 MHz, CDC13) δ 1.68-1.80 (m, 4H) 1.85-1.90 (m, 2H) 2.73-2.75 (m, 2H) 2.83-2.85 (m, 2H) 3.73 (s, 3H) 5.55 (s, 2H) 6.99 (dd, Jl=8.28, J2=2.51 Hz, IH) 7.09 (t, J=7.65 Hz, IH) 7.14 (d, J=8.28 Hz, IH) 7.55 (dd, Jl=7.53, J2=1.00 Hz, IH) 7.68 (dd, Jl=7.78, J2=1.00 Hz, IH) 8.04 (d, J=2.26 Hz, IH); MS (El4) m/z 369.0.
Example 137 - 5-[r6-chloropyridin-3-yl')methyl]-5.6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylic acid The preparation of the title compound was performed according to the synthetis described for Example 135, using Example 136 (100 mg, 0.26 mmol) and KOH (145 mg, 2.60 mmol) in ethanol (5 mL) and water (1 mL). After workup the crude material was purified by flash column chromatography on silica gel eluting with DCM / methanol (9:1 v/v) giving 48 mg (52%) of a yellow solid. 1HNMR (400 MHz, CDC13) 6 1.73-1.83 (m, 4H) 1.87-1.93 (m, 2H) 2.79-2.81 (m,
2H) 2.85-2.88 (m, 2H) 5.68 (s, 2H) 6.95 (d, J=8.53 Hz, IH) 7.12 (t, J=7.53 Hz, IH) 7.15 (d, J=9.04 Hz, IH) 7.69-7.73 (m, 2H) 8.24 (br s, IH); MS (El4) m/z 355.2.
Example 138 - 5-[(2-cyanopyridin-4-yl methyl1-5,6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylic acid
To a stirred suspension of KOH powder (230 mg, 4.10 mmol) in DMSO (8 mL) was added Example 34 (200 mg, 0.82 mmol). After 5 min, Example 14 (242 mg, 1.23 mmol) was added resulting in a deep blue reaction mixture. Stirring continued for 10 more min and was then poured into water (50 mL) and acidified with aqueous HCl (10 mL).until pH 3. The aqueous phase was extracted with ethyl acetate (3 x 20 mL), the combined organic layers dried (Na SO4) and evaporated in vacuo leaving 0.5 g of a crude brown oil. Purifcation by flash column chromatography on silica gel eluting with a gradient of DCM to DCM / methanol (9:1 v/v) gave 78 mg (28%) of an off-white solid. An analytical sample was obtained by recrystallization from acetonitrile.
1H NMR (400 MHz, CDC13) δ 1.66-1.72 (m, 2H) 1.76-1.81 (m, 2H) 1.85-1.90 (m, 2H) 2.64-2.67 (m, 2H) 2.84-2.87 (m, 2H) 5.67 (s, 2H) 6.97 (dd, Jl=5.27, J2=1.76 Hz, IH) 7.12 (t, J=7.78 Hz, IH) 7.28 (s, IH) 7.70-7.73 (m, IH) 8.51 (d, J=6.02 Hz, IH); MS (El4) m/z 346.0.
Example 139 - 5-{[2- aminocarbonyDpyridin-4-yl1methyl>-5,6,7,8,9,10- hexahydrocyclohepta blindole-4-carboxylic acid
To a solution of Example 138 (70 mg, 0.20 mmol) in ethanol (2 mL) and water (0.5 mL) was added KOH (56 mg, 1.00 mmol). The resulting reaction mixture was refluxed in a seal-capped tube for 1 h. The ethanol was evaporated and water (2 mL) was added. The aqueous phase was acidified with HCl (10%) until pH 3. The solid that precipitated was collected on a filter and consisted of product and the di-carboxylic acid derivative (1 :2 H NMR, HPLC). The title compound was isolated through preparative RP-HPLC (5-20% acetonitrile in water, 0.1% AcOH) followed by freeze drying. This procedure gave 7 mg (10%) of an off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 1.57-1.63 (m, 2H) 1.67-1.73 (m, 2H) 1.80-1.85 (m, 2H) 2.70-2.72 (m, 2H) 2.81-2.84 (m, 2H) 5.74 (s, 2H) 6.89 (dd, Jl=5.02, J2=2.01 Hz, IH) 7.05 (t, J=7.78 Hz, IH) 7.39 (dd, Jl=7.53, J2=1.00 Hz, IH) 7.51 (d, J=1.00 Hz, IH) 7.60 (d, J=2.01 Hz, NH) 7.69 (dd, Jl=8.03, J2=1.00 Hz, IH) 8.06 (d, J=2.01 Hz, NH) 8.45 (d, J=5.52 Hz, IH); MS (EI+) m/z 364.2.
Example 140 - methyl 5-[(6-cvanopyridin-2-vDmethyll-5.6,7.8.9.10- hexahydrocyclohepta[b1indole-4-carboxylate
To a solution of Example 34 (550 mg, 2.26 mmol) in dry DMSO (20 mL) was added
KOH (310 mg, 5.52 mmol). After stirring for 5 min, Example 15 (535 mg, 2.71 mmol) in
DMSO (2 mL) was added dropwise over a 5-min period. The resulting solution was stirred for 10 min, and then poured in saturated aqueous NH4C1 (100 mL) giving a suspension. The aqueous phase was extracted with diethyl ether (2 x 100 mL) and the combined organic phases were dried (Na2SO4), and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica gel eluting with DCM to give 695 mg (86%) of a colorless oil that solidified on standing: Mp 86.3-86.4 °C.
1H MR (400 MHz, CDC13) δ 1.64-1.70 (m, 2 H) 1.74-1.80 (m, 2 H) 1.84-1.89 (m, 2 H) 2.66-2.69 (m, 2 H) 2.83-2.86 (m, 2 H) 3.71 (s, 3 H) 5.59 (s, 2 H) 6.86 (d, J=8.03 Hz, IH) 7.11 (t, J=7.78 Hz, IH) 7.55 (d, J=7.53 Hz, IH) 7.57 (dd, Jl=7.53, J2=1.00 Hz, IH) 7.64- 7.70 (m, 2H); MS (EI+) m/z 360.2.
Example 141 - 5- 1 [6-fammocarbonvDpyridin-2-yl]methyl| -5,6,7,8,9, 10- hexahvdrocyclohepta[b]indole-4-carboxylic acid
To a solution of Example 140 (200 mg, 0.56 mmol) in ethanol (5 mL) and water (1 mL) was added KOH (157 mg, 2.80 mmol). The resulting reaction mixture was refluxed in a seal-capped tube for 30 min. The ethanol was evaporated and water (2 mL) was added. The aqueous phase was acidified with HCl (10%) until pH 3. The solid that precipitated was collected on a filter and recrystallized from ethanol, affording 25 mg (12%) of the title compound as white crystals: Mp 259.1-259.2 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.59-1.71 (m, 4H) 1.79-1.84 (m, 2H) 2.78-2.83 (m, 4H) 5.76 (s, 2 H) 6.87 (dd, Jl=6.15, J2=2.64 Hz, IH) 7.04 (t, J=7.53 Hz, IH) 7.41 (dd, Jl=7.53, J2=1.00 Hz, IH) 7.63 (br s, 2NH) 7.67 (dd, Jl=7.91, J2=1.13 Hz, IH) 7.80-7.85 (m, 2H) 12.97 (br s, OH); MS (EI+) m/z 364.2.
Example 142 - methyl 5-(2-chloro-6-methoxypyridin-4-yl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate
To a solution of Example 34 (300 mg, 1.23 mmol) in dry DMSO (25 mL) was added KOH (173 mg, 3.08 mmol). After stirring for 5 min (clear yellow solution) 4-(bromomethyl)- 2-chloro-6-methoxypyridine (Example 19) (350 mg, 1.48 mmol) in DMSO (2 mL) was added dropwise over a 5-min period. The resulting darkbrown solution was stirred for 10 min, and then poured in saturated aqueous NH4C1 (50 mL) giving a suspension. The aqueous phase was extracted with diethyl ether (3 x 30 mL) and the combined organic phases were dried (MgSO ), and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica gel eluting with DCM/isohexane (1/1 v/v) to give 120 mg (24%) of a yellow oil.
1H NMR (400 MHz, CDC13) 6 1.56-1.74 (m, 2H) 1.76-1.82 (m, 2H) 1.86-1.91 (m, 2H) 2.69-2.72 (m, 2H) 2.84-2.86 (m, 2H) 3.73 (s, 3H) 3.85 (s, 3H) 5.48 (s, 2H) 6.03 (s, IH) 6.52 (s, IH) 7.07-7.11 (m, IH) 7.56 (d, J=7.53 Hz, IH) 7.68 (d, J=9.04 Hz, IH);
Example 143 - ("9-beιιzyl-2,3 A9-tefrahydro-lH-carbazol-8-vDmethanol DIBAH 20 % w in toluene (2.07 ml, 2.5 mmol) was added dropwise to a solution of methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 39) (0.2 g, 0.62 mmol) in toluene (2 ml) at 0°C and the mixture was stirred overnight at RT. Water was carefully added dropwise and pH was adjusted to 5 with IN HCl. The mixture was diluted with THF and filtered through a short plug of silica. The filtrate was evaporated and partitioned between water and DCM, and the organic phase was dried (MgSO4) and evaporated. Yield: 0.144 g (80 %). White solid mp 114.0-115.0 °C. 1H NMR (400 MHz, CDC13) δ 1.80-2.04 (m, 5 H) 2.63 (t, J=5.90 Hz, 2 H) 2.78 (t,
J=5.27 Hz, 2 H) 4.63 (d, J=5.77 Hz, 2 H) 5.62 (s, 2 H) 6.84 (d, J=7.03 Hz, 2 H) 6.95-7.10 (m, 2 H) 7.13-7.26 (m, 3 H) 7.53 (d, J=7.78 Hz, 1 H), MS (70eV) m/z (%) 292 (M+,100).
Example 144 - N-hvdroxy-5-r2-rtrifluoromethynbenzyll-5.6.7.8.9.10- hexahvdrocyclohepta[l3]indole-4-carboxamide
5-(2-trifluoromethyl-benzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid (Example 92) (0.17 g, 0.44 mmol) was dissolved in DCM (6 ml) and triethylamine (0.18 ml, 1.33 mmol), O-benzyl-hydroxylamine hydrochloride (0.14 g, 0.88 mmol) and EDCI (0.085g, 0.44 mmol) were added. After 5 minutes HOBT (0.059 g, 0.44 mmol) was added and the reaction was stirred overnight at 50°C. After cooling the mixture was diluted with water and acidified pH 3 with IN HCl. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in MeOH (5 ml) and Pd/C was added under N2 (g) and stirred for 2 hours in a balloon of H atmosphere. The mixture was filtered and evaporated. The crude product was purified by flash chromatography 1 % MeOH in DCM. Yield: 0.007 g (4 %). White solid mp 87.0-88.0 °C. 1H NMR (400 MHz, CDC13) δ ppm 1.44-1.70 (m, 3 H) 1.76-1.90 (m, 4 H) 2.60-2.68 (m, 2 H) 2.84-2.91 (m, 2 H) 5.66 (s, 2 H) 6.16 (d, J=7.28 Hz, 1 H) 7.04-7.10 (m, 2 H) 7.22- 7.34 (m, 2 H) 7.63-7.71 (m, 2 H) 8.12 (br. s., 1 H), MS (70eN) m/z (%) 403 (M+,100),
Example 145 - N-[5-benzyl-6-fmethylsulfonylV5.6,7,8,9,10-hexahydrocvclo- heptarblindol-4-yllmethanesulfonamide
Methansulfonylchloride (0.02 lg, 0.18 mmol) was added to a solution of 5-benzyl- 5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4-amine (Example 22) (0.054 g, 0.15 mmol) and triethylamine (0.026 ml, 0.18 mmol) in DCM (1 ml) and the reaction was stirred for 2 hours and diluted with water and DCM. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography 5 % EtOAc in hexane. Yield: 0.025 g (32 %). Grey solid.
1H NMR (400 MHz, CDC13) 6 1.38-1.52 (m, 2 H) 1.56-1.84 (m, 4 H) 2.32-2.46 (m, 1 H) 2.54-2.69 (m, 4 H) 2.70-2.88 (m, 2 H) 3.33 (s, 3 H) 5.51 (d, J=19.07 Hz, 1 H) 6.16-6.35 (m, 2 H) 7.02-7.09 (m, 2 H) 7.24-7.31 (m, 2 H) 7.58-7.68 (m, 2 H), MS (70eV) m/z (%) 515 (M+,100).
Example 146 - N-(5-r2-(trifluoromethyl benzyl]-5, 6,7,8,9, 10-hexahydrocyclo- heptarb1indol-4-yl)methanesulfonamide Methansulfonylchloride (0.021 g, 0.18 mmol) was added to a solution of 5-[2-
(trifluoromethyl)benzyl]-5, 6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-amine (Example 24) (0.084 g, 0.23 mmol) and triethylamine (0.026 ml, 0.18 mmol) in DCM (2 ml) and the reaction was stirred for 1 hour and diluted with water and DCM. After drying (MgSO4) and evaporation the crude product was purified by flash chromatography 10 % hexane in DCM to pure DCM. Yield: 0.035 g (45 %). White solid.
1H NMR (400 MHz, CDC13) δ 1.61-169 ( , 2 H) 1.73-1.93 (m, 4 H) 2.61-2.71 (m, 2 H) 2.81-2.88 (m, 2 H) 2.92 (s, 3 H) 5.99-6.13 (m, 3 H) 6.97 (d, J=7.53 Hz, 1 H) 7.08 (t, J=7.78 Hz, 1 H) 7.20-7.33 (m, 3 H) 7.56 (d, J=7.78 Hz, 1 H) 7.68 (d, J=6.78 Hz, 1 H), MS (70eV) m/z (%) 437 (M+,100) Example 147 - N- 5-f2-(trifluoromethyl benzyl]-5,6,7,8,9,10-hexahvdrocvclo- hepta[b]indol-4-vDbenzenesulfonamide
IN TBAF in THF (1.0 ml, 1 mmol) was added to N-{5-[2-(trifluoromethyl)benzyl]- 5,6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-yl}dibenzenesulfonamide (Example 25) (0.03 g, 0.05 mmol) at RT and stirred for 20 minutes. The mixture was evaporated and partitioned between water and DCM and acidified to pH 3 with IN HCl, extracted with DCM (2x) and the combined organic phases were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography 10 % hexane in DCM to 5 % hexane in DCM. Yield: 0.017 g (68 %). White solid mp 67.0-69.0 °C. 1H NMR (400 MHz, CDC13) δ 1.50-1.56 (m, 2 H) 1.58-1.67 (m, 2 H) 1.72-1.88 (m, 4
H) 2.58-2.66 (m, 2 H) 2.79-2.88 (m, 2 H) 5.95-6.03 (m, 3 H) 6.21 (d, J=7.53 Hz, 1 H) 6.81 (t, J=7.65 Hz, 1 H) 7.18-7.32 (m, 3 H) 7.38-7.51 (m, 2 H) 7.53-7.59 (m, 1 H) 7.60-7.74 (m, 2 H), MS (70eV) m/z (%) 499 (M+,100).
Example 148 - N-(5-benzyl-5.6.7,8,9,10-hexahvdrocyclohepta[b]indol-4-ylVl.l,l- trifluoromethanesulfonamide
A stirred solution of Example 22 (63 mg, 0.22 mmol) in DCM (5 mL) was cooled to 0 °C and triethylamine (38 μL, 0.24 mmol) was added followed by dropwise treatment of triflic anhydride (39 μL, 0.24 mmol). The resulting black solution was stirred for 3 h at RT, and then washed with aqueous HCl (5%, 5 mL). The acidic aqueous phase was extracted with DCM (2 x 5 mL) and the combined DCM layers were dried (Na2SO ) and evaporated to dryness. The solid residue was purified by flash column chromatography on silica gel eluting with n-hexane / diethyl ether (1:1 v/v) to give 62 mg (67%) of the title compound as off- white material. 1H MR (400 MHz, CDC13) δ 1.76-1.85 (m, 4H) 1.88-1.91 (m, 2H), 2.82-2.88 (m,
4H) 5.64 (s, 2H) 6.23 (br s, NH) 6.86 (d, J=6.53 Hz, 2H) 6.94 (d, J=7.53 Hz, IH) 7.03 (t, J=7.53 Hz, IH) 7.22-7.31 (m, 3H) 7.55 (d, J=6.53, IH); MS (El4) m/z 423.0; Anal. Calc. (found) for C2ιH2ιF3N2O2S: C 59.70 (60.3) H 5.01 (4.5) N 6.63 (6.6) S 7.59 (7.4). Example 149 - N-P-drifluoromethyDbenzyll-S.ό .S^ O-hexahvdrocvclo- hepta[b]indol-4-yl - 1,1,1 -trifluoromethanesulfonamide')
The preparation of the title compound was performed according to the synthetis described for Example 148, using Example 24 (54 mg, 151 μmol), triethylamine (26 μL, 166 μmol) and triflic anhydride (27 μL, 166 μmol). After the purification step the product was recrystallized from DCM / isohexanes to give 18 mg (24%) grayish crystals: Mp 166.8-166.9 °C.
1H NMR (400 MHz, CDC13) 6 1.63-1.69 (m, 2H) 1.77-1.89 (m, 4H), 2.64-2.66 (m, 2H) 2.85-2.88 (m, 2H) 5.91 (s, 2H) ) 6.09 (d, J=7.28 Hz, IH) 6.37 (br s, NH) 7.03 (d, J=6.53 Hz, IH) 7.09 (t, J=7.78 Hz, IH) 7.27-7.36 (m, 2H) 7.60 (d, J=8.03, IH) 7.72 (d, J=7.03, IH); MS (EI+) m/z 491.0.
Example 150 - 9-benzyl-N-hvdroxy-2,3,4,9-tetrahvdro-lH-carbazole-8-carboxamide A stirred solution of Example 26 (33 mg, 0.08 mmol) in methanol (3 mL) was hydrogenated over Pd/C (10%, spatula) under 1 atm of hydrogen. After 3 h the mixture was filter over Celite and evaporated in vacuo, affording 22 mg of a white solid, with HPLC purity of 86%. Purification by preparative RP-HPLC (5-95%) acetonitrile in water, 0.1 % AcOH) followed by freeze drying of pure fractions gave 3.5 mg of a white solid.
1H NMR (400 MHz, CDC13) 6 1.85-1.98 (m, 4H) ) 2.69 (t, J=6.02 Hz, 2H) 2.77 (t, J=6.02 Hz, 2H) 5.40 (s, 2H) 6.74-6.76 (m, 2H) 7.00-7.04 (m, 2H) 7.15-7.21 (m, 3H) 7.62 (dd, Jl=7.15, J2=1.88 Hz, IH) 7.72 (br s, H); MS (El4) m/z 321.
Example 151 - 4-benzyl-l,2,3,4-tetrahvdrocvclopentarb]indole-5-carboxylic acid 2-hydrazinobezoic acid hydrochloride (3.44 g, 18.23 mmol) and cyclopentanone (2.0 ml, 21.88 mmol) was refluxed in EtOH (30 ml) and cone. H2SO4 (3 ml) for 4 h. Cone. H2SO4 (2 ml) was added and the mixture refluxed for 30 min more. Water and Et O was added and organic phase washed with 1 M NaOH. The product was purified by flash chromatography. Yield 0.59 g (14%, -70% pure).
1H NMR (400 MHz, CDC13) δ 1.44 (t, J = 7 Hz, 3 H), 2.55 (m, 2 H), 2.82-2.92 (m, 4 H), 4.41 (q, J = 7 Hz, 2 H), 7.08 (t, J = 8 Hz, 1 H), 7.62 (d, J = 8 Hz, 1 H), 7.78 (d, J = 8 Hz,
1 H). The crude material was dissolved in DMSO (5 ml) and KOH (500 mg) was added and the mixture stirred for 5 min. Benzyl bromide (500 μl, 4.21 mmol) was added and the mixture stirred for 10 min before quenched with sat. NH4C1 and extracted with Et2O. The organic phase was dried (MgSO4) and the product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 509 mg (68% pure (GC)). The crude mixture was hydrolyzed using KOH (0.91 g) in refluxing EtOH (20 ml) and H2O (2 ml). After 1.5 h most of EtOH was evaporated and the solution acidified by addition of 2 M HCl. The precipitate was filtered washed with water and dried under vacuum. Yield 220 mg; white solid. Mp.213 °C.
1HNMR (400 MHz, DMSO-d6) 6 2.81-2.84 (m, 4 H), 3.29 (s, 2 H), 5.54 (s, 2 H), 6.82 (d, J=7 Hz, 2 H), 7.02 (t, J=8 Hz, 1 H), 7.15-7.22 (m, 3 H), 7.37 (d, J=7 Hz, 1 H), 7.55 (d, J=8 Hz, 1 H), 12.78 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 24.47, 25.37, 27.74, 49.89, 118.11, 118.33, 122.27, 122.88, 126.45, 126.77, 127.09, 128.58, 137.03, 138.73, 149.29, 168.84. MS: 292 (M+l). Found: C, 77.04; H, 5.63; N, 4.58%. Calc. for Cι9Hι7NO2y4H2O: C, 77.12; H, 5.96; N, 4.74%.
Example 152 - l-benzyl-2,3-dimethyl-lH-indole-7-carboxylic acid Powdered KOH (600 mg, 10.69 mmol) was added to solution of methyl 2,3-dimethyl- lH-indole-7-carboxylate (Example 32) (601 mg, 2.957 mmol) in DMSO (5 ml) and the bright yellow mixture was stirred for 5 min. and benzyl bromide (880 μl, 7.39 mmol) was added and stirring continues for 10 min before quenced with sat. NH4C1 and extracted with Et O. TLC and GC revealed a mixture of compounds. Some separation was obtained by flash chromatography using 5% Et2O in hexanes as eluent. The mixture (~50% pure) was hydrolyzed using KOH (0.5 g), THF (20 ml) and water (20 ml) which was refluxed for 2 h. Solvent evaporated, acidification using 2 M HCl and extraction with EtOAc. The product was purified by flash chromatography using 1-5% MeOH in DCM as eluent. Yield 244 mg (30%) over two steps); pale yellow solid. Mp. 177 °C.
1H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3 H), 2.28 (s, 3 H), 5.64 (s, 2 H), 6.69 (d, J=7 Hz, 2 H), 7.03 (t, J=8 Hz, 1 H), 7.13-7.21 (m, 3 H), 7.39 (dd, J=7, 1 Hz, 1 H), 7.65 (dd, J=8, 1 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) 6 8.77, 10.44, 47.37, 107.32, 117.18, 117.80, 121.62, 123.50, 125.72, 126.74, 128.48, 130.70, 132.56, 135.12, 138.97, 169.18. Found: C, 76.25; H, 6.19; N, 4.53%. Calc. for Cι8Hι7NO2y4H2O: C, 76.16; H, 6.21; N, 4.94%.
Example 153 - 2-acetyl-5-benzyl-2.3,4,5-tetrahydro-lH-pyrido[4.3-b]indole-6- carboxylic acid
2-bromophenylhydrazine hydrochloride (3.10 g, 13.87 mmol) and 1-acetyl-piperidin- 4-one (1.71 ml, 13.87 mmol) in EtOH (25 ml) was heated in a pressure tube at 110 °C for 6 h. Water added and the aqueous phase extracted with DCM. Yield 2.39 g. The crude material was dissolved in DMSO (50 ml) and powdered KOH (2.0 g) added. After 2 min, benzyl bromide (2.00 ml, 16.84 mmol) was added and the mixture stirred for 5 min and quenched with sat. NH4C1 and extracted with Et O. The product was purified by flash chromatography using 2% MeOH in DCM. Yield: 1.36 g (26% over two steps); brownish oil. MS: 383/385 (M+l). t-BuLi (1.20 ml, 2.00 mmol, 1.7 M in hexanes) was added to a solution of the material from above (403 mg, 1.051 mmol) in dry THF (10 ml) at -78 °C under N2. After stirring for 5 min the mixture was added CO2(s) and the cold bath removed. At room temp 2 M HCl was added and the mixture extracted with EtOAc. Yield 250 mg of a product that shows 49% purity on HPLC. A small amount of the material was purified by preparative HPLC. MS: 394 (M+l).
Example 154 - methyl 9-(3-nitrobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylate
Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (2.0 g, 8.7 mmol) was dissolved in DMF (40 ml) and NaH (0.4 g, 10 mmol, ~60 % in oil) was added.
After two minutes 3-nitrobenzyl bromide (2.6 g, 12 mmol) was slowly added and the reaction stirred at ambient temperature for 40 minutes. Water (80 ml) and ethyl acetate (80 ml) was added and the phases separated. The aqueous phase was extracted with ethyl acetate (80 ml) and diethyl eter (80 ml), the combined organic phases was washed with brine and evaporated.
The crude product was further purified using flash chromatography (5 % ethyl acetate, 95 % iso-hexane) to afford 1.2 g (38 % yield) of an yellow oil which was further used to produce Example 155 and 156. 1H NMR (400 MHz, DMSO-d6) 1.79 - 1.81 (m, 2H), 1.82 - 1.85 (m, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.0 Hz, 2H), 3.61 (s, 3H), 5.55 (s, 2H), 7.07 (t, J = 7.5 Hz, IH), 7. 13 (d, J = 7.6 Hz, IH), 7.38 (d, J = 7.38, IH), 7.52 (d, J = 8.1 Hz, IH), 7.67 (d, J = 7.5 Hz, IH), 7.70 (s, IH), 8.05 (d, J = 8.1 Hz, IH). (M + 1) = 365, found: 365 (CI).
Example 155 - 9-[3-(acetylamino)benzyl]-2,3,4,9-tetrahvdro-lH-carbazole-8- carboxylic acid
Methyl 9-(3 -nitrobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example 154) (360 mg, 0.99 mmol) was dissolved in methanol (20 ml) and 50 mg palladium on charcoal was added. After flushing with N2, hydrogen gas was added and the reaction was stirred for four hours. The reaction mixture was filtrered through celite and evaporated to afford 330 mg (100 %) of the aniline, which was dissolved in DCM (30 ml) and triethyl amine (1.2 eq.) was added. After cooling acetyl chloride (78 mg, 0.99 mmol) was slowly added and the mixture was stirred over night. Water was added and the phases separated. The organic phase was washed with water (20 ml), 1M HCl (20 ml), 1M NaOH (20 ml) and evaporated. The residual oil was dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1:1:1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) to afford 5 mg (2 % yield) of the title product as a white solid.
1H NMR (400 MHz, DMSO-d6) 1.77 - 1.80 (m, 2H), 1.81 - 1.84 (m, 2H), 1.92 (s, 3H), 2.56 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 5.51 (s, 2H), 6.34 (d, J = 7.5 Hz, IH), 6.91 - 6.99 (m, 2H), 7.02 (s, IH), 7.39 - 7.45 (m, 2H), 7.48 (d, J = 7.5 Hz, IH), 9.21 (bs, IH), 12.62 (s, IH). (M + 1) = 363, found: 363 (CI).
Example 156 - 9-(3-nitrobenzyl -2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
Methyl 9-(3 -nitrobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate (Example
154) (110 mg, 0.3 mmol) was dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1:1:1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) to afford 20 mg of the title product as yellow crystals, mp = 207.7 - 207.8 °C.
1H NMR (400 MHz, DMSO-d6) 1.78 - 1.80 (m, 2H), 1.84 - 1.87 (m, 2H), 2.63 (t, J = 6.5 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 5.69 (s, IH), 7.04 - 7.10 (m, 2H), 7.43 (d, J = 7.6 Hz, IH), 7.51 (tJ = 8.0 Hz, IH,), 7.65 (d, J = 7.5 Hz, IH), 7.72 (s, IH), 8.04 (d, J = 8.0 Hz, IH), 12.82 (bs, IH). (M + 1) = 351, found: 351 (CI).
Example 157 - 9-(2-chlorobenzylV2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (220 mg, 0.96 mmol)
(Example 28) was dissolved in DMF (20 ml) and NaH (48 mg, 1.2 mmol, -60 % in oil) was added. After two min, 2-chlorobenzyl bromide (250 mg, 1.22 mmol) was added slowly and the reaction stirred at ambient temperature for 20 minutes. Water (40 ml) and ethyl acetate (40 ml) was added and the phases separated. The aqueous phase was extracted with ethyl acetate (40 ml) and diethyl eter (40 ml), the combined organic phases was washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) and dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1 : 1 : 1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) to afford the title product. Yield 14 mg (4 %); colorless oil.
1HNMR (400 MHz, CDC13) 1.18 - 1.26 (m, IH), 1.45 - 1.56 (m, IH), 1.83 - 1.86 (m, IH), 2.04 - 2.14 (m, IH), 2.35 - 2.38 (m, IH), 2.62 - 2.66 (m, IH), 2.88 - 2.97 (m, IH), 3.01 - 3.04 (m, IH), 3.41 (dd, J = 4.1, 8.2 Hz, 2H), 6.58 (d, J = 6.5 Hz, IH), 6.94 (t, J = 7.5 Hz, IH), 7.05 (t, J = 7.5 Hz, IH), 7.20 - 7.25 (m, 3H), 8.01 (dd, J = 3.0, 6.0 Hz, IH), 13.38 (bs, IH). 13C NMR (100 MHz, CDC13) 23.7, 31.8, 33.1, 37.4, 40.1, 61.8, 122.6, 128.2, 129.0, 129.8, 131.1, 132.2, 132.3, 132.7, 136.1, 136.6, 145.9, 155.6, 168.7, 194.3. (M + 1) = 340, found: 340 (CI). Example 158 - 9-C3-bromobenzyl -2.3A9-tetrahvdro-lH-carbazole-8-carboxylic acid Methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (Example 28) (220 mg, 0.96 mmol) was dissolved in DMF (20 ml) and NaH (48 mg, 1.2 mmol, -60 % in oil) was added. After two min, 3-bromobenzyl chloride (250 mg, 1.22 mmol) was added slowly and the reaction stirred at ambient temperature for 20 minutes. Water (40 ml) and ethyl acetate (40 ml) was added and the phases separated. The aqueous phase was extracted with ethyl acetate (40 ml) and diethyl eter (40 ml), the combined organic phases was washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) and dissolved in THF/ methanol / LiOH (2 M) (20 ml, 1 : 1 : 1) and stirred over night. After washing with ethyl acetate, the aqueous phase was acidified (pH 2) using cone. HCl and extracted twice with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude product was further purified using flash chromatography (5 % methanol, 95 % DCM) to afford the title product. Yield 170 mg (44 %); white crystals. Mp = 158.0 - 158.1 °C. 1H NMR (400 MHz, CDC13) 1.86 - 1.90 (m, 2H), 1.91 - 1.96 (m, 2H), 2.63 (t, J = 6.1
Hz, 2H), 2.76 (t, J = 5.6 Hz, 2H), 5.56 (s, 2H), 6.60 (d, J = 8.0 Hz, IH), 6.99 (dd, J = 7.5, 8.0 Hz, IH), 7.05 (s, IH), 7.12 (dd, J = 7.5, 8.1 Hz, IH), 7.25 - 7.28 (m, IH), 7.72 (dd, J = 1.0, 8.0 Hz, IH), 7.75 (dd, J = 1.0, 7.5 Hz, IH). 13C NMR (100 MHz, CDCI3) 21.9, 23.6, 23.8, 24.3, 49.0, 112.4, 119.2, 123.6, 124.3, 125.5, 126.7, 130.1, 131.0, 131.1, 131.5, 134.5, 139.2, 142.4, 173.4. (M + 1) = 385, found: 385 (CI).
Example 159 - methyl 5,6,7,8,9,10-hexahydrocyclohepta b]indole-3-carboxylate 3-hydrazinobenzoic acid (9 g, 59 mmol), cycloheptanone (8 g, 71 mmol) and cone. HCl (5 ml, 60 mmol) in acetic acid (200 ml) was refluxed for 3 h. Solvent evaporated and the residue partioned between water and EtOAc. The organic layer was extracted with 2 M
NaOH and the combined aqueous layers acidified using 6 M HCl and exctracted with EtOAc. The organic layers were dried (MgSO4) and evaporated. The residue was dissolved in MeOH (200 ml) and cone. H2SO4 was added. The mixture was refluxed for 3 h before diethyl ether and water was added. The organic layer was washed with water, sat. NaHCO3 and brine. The product was isolated by flash chromatography using 20% EtOAc in hexanes. Yield: 2.00 g. Mp. 183°C. 1H NMR (400 MHz, DMSO-d6) δ 1.73 (m, 6 H) 2.79 (m, 4 H) 3.81 (s, 3 H) 7.44 (d, J=8.28 Hz, 1 H) 7.55 (dd, J=8.28, 1.51 Hz, 1 H) 7.87 (s, 1 H) 11.13 (s, IH). 13C NMR (100 MHz, DMSO-d6)d 24.18, 26.91, 28.42, 28.69, 31.41, 51.59, 112.36, 112.97, 116.75, 118.97, 120.41, 132.06, 133.24, 142.82, 167.41.
Examples 160-199 were prepared in the following manner:
The starting material (120 mg) was dissolved in DMSO and KOH (5 equivalents) was added. After 5 min, the electrophile (1.2 eq.) was added and the reaction was stirred at ambient temperature for 15 min. The reaction was quenched with sat. NH4C1 and extracted twice with ethyl acetate. After evaporation of the solvent, the crude mixture was dissolved in THF: MeOH: LiOH (2M, 20 mL) 1:1:1 and stirred over night. The reaction mixture was acidified and extracted twice with ethyl acetate. The combined organic phases were evaporated and the crude product purified by preparative HPLC giving the title compounds.
Example 160 - 5-(2-fluorobeι-zyl)-5,6,7,8,9,10-hexahvdrocvclohepta[b]indole-4- carboxylic acid
Example 34 was reacted with 2-fluorobenzylbromide. Yield: 20 mg (12%). 1H NMR (400 MHz, DMSO-d6) 1.60 - 1.65 (m, 2H), 1.69 - 1.72 (m, 2H), 1.80 - 1.84 (m, 2H), 2.74 - 2.77 (m, 2H), 2.80 - 2.83 (m, 2H), 5.74 (s, 2H), 6.13 (dd, IH, J = 8.0, 9.0 Hz), 6.95 (dd, IH, J = 7.1, 8.1 Hz), 7.03 (dd, J = 7.5, 7.5 Hz), 7.12 - 7.22 (m, 2H), 7.36 (d, IH, J = 7.5 Hz), 7.65 (d, IH, J = 8.0 Hz). MS: 338 (M+l).
Example 161 - 5- 3-fluorobenzylV5,6,7,8,9,10-hexahydrocycloheptar lindole-4- carboxylic acid
Example 34 was reacted with 3-fluorobenzylbromide. Yield: 20 mg (12%). 1H NMR (400 MHz, DMSO-d6) 1.60 - 1.62 (m, 2H), 1.68 - 1.70 (m, 2H), 1.80 - 1.82 (m, 2H), 2.76 - 2.82 (m, 4H), 5.67 (s, 2H), 6.50 - 6.54 (m, 2H), 6.95 - 7.00 (m, IH), 7.03 (dd, IH, J = 7.5, 7.5 Hz), 7.22 - 7.26 (m, IH), 7.37 (d, IH, J = 7.0 Hz), 7.67 (d, IH, J = 8.0 Hz). MS: 338 (M+l). Example 162 - 5-(4-fluorobenzylV5,6,7,8,9,10-hexahvdrocyclohepta[b]indole-4- carboxylic acid
Example 34 was reacted with 4-fluorobenzylbromide. Yield: 20 mg (12%).
1HNMR (400 MHz, DMSO-d6) 1.57 - 1.73 (m, 4H), 1.77 - 1.86 (m, 2H), 2.73 - 2.85 (m, 4H), 5.63 (s, 2H), 6.74 - 6.77 (m, 2H), 7.00 - 7.05 (m, 3H), 7.35 (d, IH, J = 7.5 Hz), 7.64 (d, 2H, J = 7.6 Hz). MS: 338 (M+l).
Example 163 - 5-(2,4-difluorobenzyl -5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid Example 34 was reacted with 2,4-difluorobenzylbromide. Yield: 20 mg (11%).
1H NMR (400 MHz, DMSO-d6) 1.60 - 1.66 (m, 2H), 1.67 - 1.73 (m, 2H), 1.80 -
1.85 (m, 2H), 2.75 - 2.78 (m, 2H), 2.80 - 2.82 (m, 2H), 5.67 (s, 2H), 6.15 - 6.21 (m, IH),
6.86 (dt, IH, J = 2.0, 8.1 Hz), 7.04 (dd, IH, J = 7.5, 7.5 Hz), 7.17 - 7.23 (m, IH), 7.38 (dd, IH, J - 1.0, 7.6 Hz), 7.67 (dd, IH, J = 1.0, 8.0 Hz). MS: 356 (M+l).
Example 164 - 5-(2,5-difluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid
Example 34 was reacted with 2,5-difluorobenzylbromide. Yield: 10 mg (6%). 1H NMR (400 MHz, DMSO-d6) 1.59 - 1.66 (m, 2H), 1.67 - 1.71 (m, 2H), 1.80 - 1.84 (m, 2H), 2.75 - 2.78 (m, 2H), 2.81 - 2.83 (m, 2H), 5.70 (s, 2H), 5.84 - 5.88 (m, IH), 7.03 - 7.10 (m, 2H), 7.20 - 7.26 (m, IH), 7.39 (d, IH, J = 7.5 Hz), 7.68 (d, IH, J = 8.1 Hz). MS: 356 (M+l).
Example 165 - 5-|"3-(trifluoromethyl)benzyl-5,6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxylic acid
Example 34 was reacted with 3-(trifluoromethyl)benzylbromide. Yield: 10 mg (5%). 1H NMR (400 MHz, DMSO-d6) 1.58 - 1.61 (m, 2H), 1.67 - 1.70 (m, 2H), 1.80 - 1.83 (m, 2H), 2.74 - 2.77 (m, 2H), 2.80 - 2.82 (m, 2H), 5.73 (s, 2H), 6.95 (d, IH, J = 8.0 Hz), 7.04 (dd, IH, J = 8.0, 8,0 Hz), 7.16 (s, IH), 7.39 (d, IH, J = 7.5 Hz), 7.43 - 7.54 (m, 2H), 7.68 (d, IH, J = 7.6 Hz). MS: 388 (M+l). Example 166 - S- -ftrifluoromethvDbenzyl-S.ό .δ^.lO-hexahvdrocyclo- hepta[b]indole-4-carboxylic acid
Example 34 was reacted with 4-(trifluoromethyl)benzylbromide. Yield: 10 mg (5%).
1H NMR (400 MHz, DMSO-d6) 1.59 - 1.65 (m, 2H), 1.67 - 1.74 (m, 2H), 1.78 - 1.85 (m, 2H), 2.73 - 2.76 (m, 2H), 2.80 - 2.83 (m, 2H), 5.75 (s, 2H), 6.93 (d, 2H, J = 8.1
Hz), 7.04 (dd, IH, J = 7.0, 7.5 Hz), 7.38 (d, IH, J = 7.0 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.68 (d, IH, J = 7.5 Hz). MS: 388 (M+l).
Example 167 — 9-(2,6-difluorobenzyl)-2,3,4,9-tetrahydiO-lH-carbazole-7-carboxylic acid
Example 30 was reacted with 2,6-difluorobenzylbromide. Yield: 130 mg (73%). Mp. 282-284°C.
1H NMR (400 MHz, DMSO-d6) 1.75 - 1.77 (m, 2H), 1.83 - 1.86 (m, 2H), 2.61 - 2.64 (m, 2H), 2.72 - 2.75 (m, 2H), 5.41 (s, 2H), 7.08 - 7.13 (m, 2H), 7.38 - 7.45 ( , 2H), 7.58 (d, IH, J = 8.0 Hz), 8.06 (s, IH). MS: 356 (M+l).
Example 168 - 9-(2-fluorobenzyl -2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid Example 30 was reacted with 2-fluorobenzylbromide. Yield: 3 mg (2%). MS: 324 (M+l).
Example 169 - 9-(3-fluorobenzyl)-2,3,4,9-tetrahvdro-lH-carbazole-7-carboxylic acid Example 30 was reacted with 3-fluorobenzylbromide. Yield: 3 mg (2%). !H NMR (400 MHz, CDC13) 1.85 - 1.95 (m, 4H), 2.63 (t, 2H, J = 6.1 Hz), 2,76 (t, 2H, J = 5,0 Hz), 5.30 (s, 2H), 6.63 (d, IH, J = 9.0 Hz), 6.76 (d, IH, J = 8.5 Hz), 6.91 - 6.93 (m, IH), 7.21 - 7.24 (m, IH), 7.52 (d, IH, J = 8.5 Hz), 7.84 (dd, IH, J = 1.5, 8.0 Hz), 8.0 (d, IH, J = 8.0 Hz). MS: 324 (M+l).
Example 170 - 9-(4-fluorobenzyl)-2,3,4,9-tetrahvdro-lH-carbazole-7-carboxylic acid Example 30 was reacted with 4-fluorobenzylbromide. Yield: 3 mg (2%). MS: 324 (M+l). Example 171 - 9-(2.5-difluorobenzyl)-2.3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid
Example 30 was reacted with 2,5-difluorobenzylbromide. Yield: 100 mg (59%). Mp. 234°C. 1H NMR (400 MHz, DMSO-d6) 1.75 - 1.85 (m, 4H), 2.65 - 2.73 (m, 4H), 5.46 (s,
2H), 6.36 - 6.41 (m, IH), 7.13 - 7.18 (m, IH), 7.27 - 7.33 (m, IH), 7.47 (d, IH, J = 8.5), 7.62 (dd, IH, J = 1.0, 8.1 Hz), 7.99 (s, IH), 12.45 (bs, IH). MS: 342 (M+l).
Example 172 - 9-(2,3-difluorobenzyl)-2,3 ,4,9-tefrahydro-lH-carbazole-7-carboxylic acid
Example 30 was reacted with 2,3-difluorobenzylbromide. Yield: 2 mg (1%). Η NMR (400 MHz, DMSO-d6) 1.90 - 1.96 (m, 4H), 2.68 (t, 2H, J = 5.0 Hz), 2.79 (t, 2H, J = 5.6 Hz), 5.40 (s, 2H), 6.28 - 6.31 (m, IH), 6.88 - 6.93 (m, IH), 7.04 - 7.11 (m, IH), 7.56 (d, IH, J = 8.5 Hz), 7.88 (d, IH, J = 8.5 Hz), 8.06 (s, IH). MS: 342 (M+l).
Example 173 - 9-f2,4-difluorobenzyl)-2,3 ,4,9-tefrahvdro-lH-carbazole-7-carboxylic acid
Example 30 was reacted with 2,4-difluorobenzylbromide. Yield: 2 mg (1%). 1H NMR (400 MHz, DMSO-d6) 1.80 - 1.92 (m, 4H), 2.64 (t, 2H, J = 5.0 Hz), 2.76 (t, 2H, J = 6.0 Hz), 5.30 (s, 2H), 6.45 - 6.51 (m, IH), 6.65 - 6.70 (m, IH), 6.81 - 6.87 (m, IH), 7.52 (d, IH, J = 8.1 Hz), 7.84 (d, IH, J = 8.1 Hz), 8.02 (s, IH). MS: 342 (M+l).
Example 174 - 9-r2-("trifluoromethyl)benzyll-2,3,4,9-tetrahvdro-lH-carbazole-7- carboxylic acid Example 30 was reacted with 2-(trifluoromethyl)benzylbromide. Yield: 10 mg (7%).
1H NMR (400 MHz, DMSO-d6) 1.77 - 1.85 (m, 4H), 2.59 (t, 2H, J = 4.3 Hz), 2.71 (t, 2H, J = 5.0 Hz), 5,56 (s, 2H), 6.25 (d, IH, J = 6.5 Hz), 7.45 - 7.48 ( , 2H), 7.51 (d, IH, J = 8.2 Hz), 7.63 (d, IH, J = 8.0 Hz), 7.79 - 7.81 (m, IH), 7.83 (s, IH). MS: 373 (M+l). Example 175 - 9-[4-(trifluoromethy benzvn-2,3,4.9-tetrahvdro-lH-carbazole-7- carboxylic acid
Example 30 was reacted with 4-(trifluoromethyl)benzylbromide. Yield: 10 mg (7%).
1H NMR (400 MHz, DMSO-d6) 1.78 - 1.86 (m, 4H), 2.64 - 2.70 (m, 4H), 5.54 (s, 2H), 7.15 (d, 2H, J = 8.1 Hz), 7.47 (d, IH, J = 8.3 Hz), 7.62 (d, IH, J = 8.2 Hz), 7.67 (d, 2H, J = 8.1 Hz), 7.95 (s, IH). M+l 373.
Example 176 - 5-(2,3-difluorobenzylV5.6,7.8,9.10-hexahvdrocvclohepta[blindole-4- carboxylic acid Example 34 was reacted with 2,3-difluorobenzylbromide. Yield: 10 mg (6%). lR NMR (400 MHz, DMSO-d6) 1.65 - 1.72 (m, 4H), 1.82 - 1.84 (m, 2H), 2.77 - 2.83 (m, 4H), 5.75 (s, 2H), 5.95 - 5.98 (m, IH), 6.94 - 6.99 (m, IH), 7.04 (dd, IH, J = 7.5, 7.8 Hz), 7.20 - 7.27 (m, IH), 7.39 (d, IH, J = 7.4 Hz), 7.69 (d, IH, J = 7.8 Hz). M+l 356.
Example 177 - 9-(2,6-difluorobenzyl -2,3.4,9-tetrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 2,6-difluorobenzylbromide. Yield: 11 mg (7%>). 1H NMR (400 MHz, DMSO-d6) 1.70 - 1.77 (m, 2H), 1.81 - 1.85 (m, 2H), 2.60 - 2.65 (m, 4H), 5.79 (s, 2H), 6.92 - 7.02 (m, 3H), 7.28 - 7.34 (m, IH), 7.46 (d, IH, J = 7.5 Hz), 7.55 (d, IH, J = 7.7 Hz). M+l 342.
Example 178 - 9-f2,5-difluorobenzyl)-2,3,4,9-tefrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 2,5-difluorobenzylbromide. Yield: 40 mg (27%). Η NMR (400 MHz, DMSO-d6) 1.65 - 1.68 (m, 2H), 1.70 - 1.74 (m, 2H), 2.49 (t,
2H, J = 6.1 Hz), 2.55 (t, 2H, J = 5.3 Hz), 5.51 (s, 2H), 5.65 - 5.69 (m, IH), 6.91 - 6.96 (m, 2H), 7.06 - 7.12 (m, IH), 7.30 (d, IH, J = 6.8 Hz), 7.51 (d, IH, J = 7.0 Hz). M+l 342.
Example 179 - 9-(3-methylbenzyl)-2.3.4.9-tetrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 3-methylbenzylbromide. Yield: 50 mg (31%). 1H NMR (400 MHz, DMSO-d6) 1.74 - 1.88 (m, 4H), 2.17 (s, 3H), 2.64 - 2.68 (m, 4H), 5.54 (s, 2H), 6.40 (d, IH, J = 7.5 Hz), 6.72 (s, IH), 6.95 (d, IH, J = 7.5 Hz), 7.00 - 7.06 (m, 2H), 7.40 (d, 2H, J = 7.5 Hz), 7.60 (d, IH, J = 7.5 Hz). M+l 320.
Example 180 - 5-π-fluorobenzylV5,6,7,8,9,10-hexahvdrocvcloheptaπ3]indole-3- carboxylic acid
Example 159 was reacted with 3-fluorobenzylbromide. Yield: 50 mg (30%).
1H NMR (400 MHz, DMSO-d6) 1.62 - 1.68 (m, 4H), 1.81 - 1.85 (m, 2H), 2.79 -
2.83 (m, 4H), 5.54 (s, 2H), 6.70 (d, IH, J = 8.2 Hz), 6.74 (d, IH, J = 8.3 Hz), 7.02 - 7.06 (m, IH), 7.28 - 7.34 (m, IH), 7.51 (d, IH, J = 8.6 Hz), 7.52 (d, IH, J = 8.2 Hz), 7.97 (s, IH),
12.45 (bs, IH). M+l 338.
Example 181 - 5-(4-fluorobenzylV5,6,7,8,9,10-hexahvdrocyclohepta[b]indole-3- carboxylic acid Example 159 was reacted with 4-fluorobenzylbromide. Yield: 50 mg (30%).
1H NMR (400 MHz, DMSO-d6) 1.63 - 1.69 (m, 4H), 1.79 - 1.83 (m, 2H), 2.79 -
2.84 (m, 4H), 5.50 (s, 2H), 6.55 - 6.99 (m, 2H), 7.09 - 7.14 (m, 2H), 7.51 (d, IH, J = 8.2 Hz), 7.61 (dd, IH, J = 1.2, 8.3 Hz), 7.98 (d, IH, J = 1.2 Hz), 12.43 (bs, IH). M+l 338.
Example 182 - 9-[3-(-rifluoromethoxy)benzyl]-2,3,4,9-tetrahvdro-lH-carbazole-8- carboxylic acid
Example 28 was reacted with 3-(trifluoromethoxy)benzylbromide. Yield: 20 mg (10%).
1H NMR (400 MHz, DMSO-d6) 1.78 - 1.80 (m, 2H), 1.82 - 1.86 (m, 2H), 2.60 (t, 2H, J = 5.8 Hz), 2.68 (t, 2H, J = 5.3 Hz), 5.63 (s, 2H), 6.68 - 6.70 (m, 2H), 7.03 - 7.06 (m, IH), 7.15 (d, IH, J = 7.3 Hz), 7.31 - 7.35 (m, IH), 7.43 (d, IH, J = 7.6 Hz), 7.63 (d, IH, J = 7.8 Hz), 12.82 (bs, IH). M+l 389.
Example 183 - 5-(2-fluorobenzylV5,6,7,8,9,10-hexahvdrocyclohepta[b]indole-3- carboxylic acid
Example 159 was reacted with 2-fluorobenzylbromide. Yield: 10 mg (6%). ΗNMR (400 MHz, DMSO-d6) 1.63 - 1.68 (m, 4H), 1.81 - 1.85 (m, 2H), 2.81 - 2.84 (m, 4H), 5.54 (s, 2H), 6.45 - 6.49 (m, IH), 7.02 - 7.06 (m, IH), 7.20 - 7.31 (m, 2H), 7.51 (d, IH, J = 8.5 Hz), 7.61 (d, IH, J = 8.3 Hz), 7.97 (s, IH), 12.44 (bs, IH). M+l 338.
Example 184 - 9-r3-fluoro-5-(trifluoromethvDbenzyl1-2,3 A9-tefrahydro-lH- carbazole-8-carboxylic acid
Example 28 was reacted with 3-fluoro-5-(trifluoromethyl)benzylbromide. Yield: 20 mg (10%).
1H NMR (400 MHz, DMSO-d6) 1.77 - 1.80 (m, 2H), 1.83 - 1.87 (m, 2H), 2.60 (t, 2H, J = 5.8 Hz), 2.69 (t, 2H, J = 5.5 Hz), 5.66 (s, 2H), 6.72 (d, IH, J = 9.3 Hz), 7.05 - 7.09 (m, 2H), 7.45 (d, IH, J = 7.5 Hz), 7.50 (d, IH, J = 8.8 Hz), 7.65 (d, IH, J = 7.8 Hz), 12.86 (bs, IH). M+l 392.
Example 185 - 9-r2-fluoro-6-('trifluoromethvnbenzyl1-2,3,4.9-tetrahvdro-lH- carbazole-8-carboxylic acid
Example 28 was reacted with 2-fluoro-6-(trifluoromethyl)benzylbromide. Yield: 20 mg (10%).
1H NMR (400 MHz, DMSO-d6) 1.69 - 1.74 (m, 4H), 2.34 (t, 2H, J = 5.3 Hz), 2.61 (t, 2H, J = 5.2 Hz), 5.90 (s, 2H), 7.02 - 7.05 (m, IH), 7.33 - 7.38 (m, IH), 7.50 - 7.54 (m, 2H), 7.57 - 7.63 (m, 2H), 12.85 (bs, IH). M+l 392.
Example 186 - 9-.2-methylbenzyl)-2,3A9-tetrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 2-methylbenzylbromide. Yield: 20 mg (13%). 1H NMR (400 MHz, DMSO-d6) 1.79 - 1.85 (m, 4H), 2.32 (s, 3H), 2.57 (t, 2H, J = 5.8
Hz), 2.71 (t, 2H, J = 5.3 Hz), 5.58 (s, 2H), 5.64 (d, IH, J = 7.8 Hz), 6.83 - 6.87 (m, IH), 7.00 - 7.05 (m, 2H), 7.13 (d, IH, J = 5.5 Hz), 7.39 (d, IH, J = 7.3 Hz), 7.64 (d, IH, J = 7.8 Hz), 12.66 (bs, IH). M+l 320. Example 187 - 9-(2,5-dichlorobenzyl -2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 2,5-dichlorobenzylbromide. Yield: 20 mg (11%).
Η NMR (400 MHz, DMSO-d6) 1.78 - 1.85 (m, 4H), 2.55 (t, 2H, J = 6.1 Hz), 2.70 (t, 2H, J = 5.3 Hz), 5.62 (s, 2H), 5.87 (d, IH, J = 2.5 Hz), 7.07 - 7.11 (m, IH), 7.30 (dd, IH, J = 2.5, 8.5 Hz), 7.46 - 7.50 (m, 2H), 7.68 (d, IH, J = 7.5 Hz), 12.84 (bs, IH). M+l 375.
Example 188 - 9-(3,4-difluorobenzyl -2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid Example 28 was reacted with 3,4-difluorobenzylbromide. Yield: 20 mg (12%).
!H NMR (400 MHz, DMSO-d6) 1.77 - 1.81 (m, 4H), 1.84 - 1.88 (m, 4H), 5.55 (s, 2H), 6.47 (s, IH), 6.79 - 6.84 (m, IH), 7.05 (dd, IH, J = 7.5, 7.6 Hz), 7.23 - 7.30 (m, IH), 7.41 (d, IH, J = 7.5 Hz), 7.63 (d, IH, J = 7.7 Hz), 12.84 (bs, IH). M+l 342.
Example 189 - 9-(2,3-difluorobenzyl -3-methyl-2,3.4,9-tetrahydro-lH-carbazole-8- carboxylic acid
Example 38 was reacted with 2,3-difluorobenzylbromide. Yield: 10 mg (7%). 1H NMR (400 MHz, DMSO-d6) 1.09 (d, 3H, J = 6.5 Hz), 1.47 - 1.55 (m, IH), 1.89 - 1.98 (m, 2H), 2.23 - 2.29 (m, IH), 2.61 - 2.74 (m, 2H), 2.81 - 2.86 (m, IH), 5.71 (s, 2H), 5.86 - 5.89 (m, IH), 6.91 - 6.97 (m, IH), 7.05 (dd, IH, J = 7.5, 7.7 Hz), 7.20 - 7.26 (m, IH), 7.43 (d, IH, J = 7.5 Hz), 7.63 (d, IH, J = 7.6 Hz), 12.81 (bs, IH). M+l 356.
Example 190 - 9-(2-fluoro-3-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid Example 28 was reacted with 2-fluoro-3-methylbenzylbromide. Yield: 10 mg (6%).
1H NMR (400 MHz, DMSO-d6) 1.77 - 1.85 (m, 4H), 2.20 (s, 3H), 2.61 (t, 2H, J = 5.7 Hz), 2.68 (t, 2H, J = 5.5 Hz), 5.66 (s, 2H), 5.83 - 5.86 (m, IH), 6.78 - 6.82 (m, IH), 7.02 - 7.09 ( , 2H), 7.42 (d, IH, J = 7.0 Hz), 7.63 (d, IH, J = 7.3 Hz), 12.77 (bs, IH). M+l 338. Example 191 - 9-(2,5-dimethoxybenzylV2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid
Example 28 was reacted with 2,5-dimethoxybenzylbromide. Yield: 12 mg (7%). M+l 366.
Example 192 - 9-(2-bromo-5"fluorobenzyl)-2.3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid
Example 28 was reacted with 2-fluoro-5-fluorobenzylbromide. Yield: 1.1 mg (0.5%). M+l 403.
Example 193 - 9-(3-phenoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid
Example 28 was reacted with 3-phenoxybenzylbromide. Yield: 1.9 mg (1%). M+l 398.
Example 194 - 9-.2-fluorobenzyl)-3-methyl-2.3 A9-tefrahydro-lH-carbazole-8- carboxylic acid
Example 38 was reacted with 2-fluorobenzylbromide. Yield: 2 mg (1%). M+l 338.
Example 195 - 9-(3-fluorobenzyl)-3-methyl-2,3,4,9-tetrahvdro-lH-carbazole-8- carboxylic acid
Example 38 was reacted with 3-fluorobenzylbromide. Yield: 10 mg (5%). M+l 338.
Example 196 - 9-.4-fluorobenzyl>3-methyl-2,3 A9-tefrahydro-lH-carbazole-8- carboxylic acid
Example 38 was reacted with 4-fluorobenzylbromide. Yield: 1 mg (0.5%). M+l 338.
Example 197 - 9-(2,4-difluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid Example 38 was reacted with 2,4-difluorobenzylbromide. Yield: 0.6 mg (0.3%). M+l
356. Example 198 - 5-(3-methylbenzylV5.6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid
Example 34 was reacted with 3-methyϊbenzylbromide. Yield: 0.4 mg (0.2%). M+l 334.
Example 199 - 5-(4-methylbenzyl)-5.6,7,8,9,10-hexahydrocyclohepta["b]indole-4- carboxylic acid
Example 34 was reacted with 4-methylbenzylbromide. Yield: 2 mg (1%). M+l 334.
PREPARATION OF PHARMACEUTICAL COMPOSITIONS
EXAMPLE 200: Preparation of tablets
Ingredients mg/tablet
1. Active compound 10.0
2. Cellulose, microcrystalline 57.0
3. Calcium hydrogen phosphate 15.0
4. Sodium starch glycolate 5.0
5. Silicon dioxide, colloidal 0.25
6. Magnesium stearate 0.75
The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
SPA assay for inhibitors
Inhibitor assays were performed in 96-well format. The reactions contained 100 nM (0.53 μCi) of a [3H] labelled compound (Biovitrum, Chemical Process Development), 50 nM human FABP-4(His)8 (Biovitrum, Target Expression and Purification), 50 μg YSi copper his- tag SPA beads (Amersham #RPNQ 0096) and serial dilutions of inhibitor. The assay buffer 11 :
was PBS pH 7.4 and the final reaction volume was 100 μL. 20 μL diluted inhibitor (<5%> DMSO), 10 μL of a 5 μg/μL YSi copper his-tag SPA beads stock, 10 μL lμM [3H] labelled compound (1.93 TBq(53 Ci)/mmol), diluted from a ethanol stock giving 0.44% ethanol in reaction, and 30 μL 167 nM human FABP-4(His)8 / well was added in enumerated order into isoplates (Corning #3604). Liquid handling instruments used were Tecan (genesis RSPl 50) and Quadra 96 (Tomtec). The inhibitors were initially dissolved in DMSO (10 mM). Final DMSO concentration in assay was <1%. The incubation time was 60 min at RT on shaker (1080 rpm). The reaction was left for 30 min for the beads to settle and measured in a Trilux 1450 microbeta counter (Wallac). Mean of triplicate was used for EC50 and Ki determinations using Excel Fit. The Ki values obtained were typically ranging from 10 nM and 100 μM.
The following Ki values have been determined:
Figure imgf000112_0001
Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations which would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

Claims
1. A compound of the formula (I)
Figure imgf000113_0001
wherein one of R°and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NH-SO2-Cι-C6-alkyl, or -NHSO2Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5- naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene, and the other of R° and R1 is -H or-CH-;
R2= -H;
R3= -H, -CO-Ci-Cβ-alkyl, -SO2-Cι-C6-alkyl, -CH(Rn)(CH2)mZ, wherein R11 = -H or Ci-Ce-alkyl, m= 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR12R13, wherein R12 and R13 are each independently -H, Cι-C6-alkyl or Ci-Cδ-hydroxyalkyl or R12 and R13 form with the nitrogen to which they are both attached together a heterocycle selected from pyrrolidinyl, morpholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R is a group of the formula (II): CH9
I 2
wherein
Ar is as defined above;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or-OPh; n = 0, 1 or 2;
R and R are each independently -H, or are absent, or R and R5 taken together are =NOH, or=NO-CH2-Ph; R6 = -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom not substituted by oxo, -CH or a phenyl group;
X = -CH, N or is absent;
Y is CH2 or is absent;
7 X
R and R are each independently -H, -COCF3, -SO2-Cι-C6-alkyl or are absent; or pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
2. A compound according to claim 1, wherein A and B are each a carbon atom not substituted by oxo; X is -CH orN;
Y is absent; which compound has the formula (III)
Figure imgf000115_0001
wherein R°, R1, R2, R3, R4, R5, R6, R7, R8, X, and n are as defined in claim 1.
3. A compound according to claim 1, wherein A and B are each a -CH or a phenyl group; X is absent; n = 0; R6 is absent;
Y is absent; which compound has the formula (IN)
Figure imgf000115_0002
wherein R°, R1, R2, R3, R4, R5, R7, R8, A, and B are as defined in claim 1.
4. The compound according to any one of claims 1-3, wherein one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R1 is -H or -CH3; R2= -H;
R3= -H, -CH(Rn)(CH2)mZ, wherein R11 = H or methyl, m= 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or-CONR12R13, wherein R and R are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, morpholinyl and 3-hydroxypiperidinyl; or R3 is a group of the formula (II), wherein
Ar is selected from phenyl, furan, pyridine, and pyrimidine; 5 R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2,
-NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; n= 0, 1 or 2;
R and R5 are each independently -H, or are absent, or R and R5 taken together are o =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom not substituted by oxo, -CH or a phenyl group;
X = CH, N or is absent;
Y is CH2 or is absent; 5 R and R are each independently -H, -COCF3, methanesulfonyl or are absent.
5. The compound according to any one of claims 1 to 4 selected from the group consisting of:
• 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
• methyl 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, 0 • methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-(4-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-(4-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 5 • 9-(4-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-(4-cyanobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate,
• 9-[4-(aminocarbonyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 9-(3-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 9-(3-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 0 • methyl 9-(4-methoxybenzyl)-2,3 ,4,9-tetrahydro- lH-carbazole-8-carboxylate,
• 9-(4-methoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(2-methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate,
9-(2-methoxybenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-(2-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(4-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-(4-(trifluoromethyl)benzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 9-(3-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, • 9-(3-(trifluoromethyl)benzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(2,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, • 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(4-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-(3-cyanobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(3-carboxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, [8-(methoxycarbonyl)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]acetic acid, • methyl 9-(2-chloro-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, methyl 9-(2-morpholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-(2-morpholin-4-yl-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(dimethylamino)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[2-(diethylamino)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • 9-(2-amino-2-oxoethyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
9-(2-oxo-2-pyrrolidin- 1 -ylethyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-[2-(3-hydroxypiperidin-l-yl)-2-oxoethyl]-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid, • 9- {2-[(2-hydroxyethyl)amino]-2-oxoethyl} -2,3,4,9-tetrahydro- lH-carbazole-8-carboxylic acid, methyl 9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylate,
9-benzyl-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, methyl 5-propyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate,
5-proρyl-5,6,7,8,9, 10-hexahydrocycloheρta[b]indole-4-carboxylic acid,
5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocycloheρta[b]indole-4-carboxylic acid, methyl 5-benzyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate,
5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, • 5-[3-(aminocarbonyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, methyl 5-(4-cyanobutyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate, 5-(5-amino-5-oxopentyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(4-cyanobutyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-methoxybenzyl)-5,6,7,8,9, 10-hexahydrocycloheρta[b]indole-4-carboxylate, • 5-(3-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2-cyanobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-[2-(aminocarbonyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-benzyl-4-benzyloxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • methyl 9-benzyl-4-(hydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-benzyl-4-(hydroxyimino)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 5-benzyl- 10-(hydroxyimino)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-benzyl-l-(trifluoroacetyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • methyl 5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-(3-bromo-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyano-5-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate, 5-[3-(aminocarbonyl)-5-methoxybenzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate, methyl 5-[(5-cyano-2-furyl)methyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-{[(5-aminocarbonyl)-2-furyl]methyl}-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
5-(4,6-dimethoxy-pyrimidin-2-ylmethyl)-5,6,7,8,9,10-hexahydro-cyclohepta[b]indole-4- carboxylic acid,
5- { [6-hydroxy-2-(methylthio)pyrimidin-4-yl]methyl} -5,6,7, 8,9, 10- hexahydrocyclohepta[b]indole-4-carboxylic acid,
5-[(4-hydroxy-6-methoxypyrimidin-2-yl)methyl]-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(pyridin-2-ylmethyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate
5-(pyridin-2-ylmethyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-[(6-chloropyridin-3-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-[(6-chloropyridin-3-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
5-[(2-cyanopyridin-4-yl)methyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
5- { [2-(aminocarbonyl)pyridin-4-yl]methyl} -5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylic acid, methyl 5-[(6-cyanopyridin-2-yl)methyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate,
5- { [6-(aminocarbonyl)pyridin-2-yl]methyl} -5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylic acid, methyl 5-(2-chloro-6-methoxypyridin-4-yl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-
4-carboxylate,
(9-benzyl-2,3,4,9-tetrahydro-lH-carbazol-8-yl)methanol, N-hydroxy-5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxamide,
N-[5-benzyl-6-(methylsulfonyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4- yl]methanesulfonamide,
N-(5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4- yl)methanesulfonamide,
N-(5-[2-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-4- yl)benzenesulfonamide,
9-benzyl-N-hydroxy-2,3,4,9-tetrahydro-lH-carbazole-8-carboxamide, 4-benzyl- 1 ,2,3,4-tetrahydrocyclopenta[b]indole-5-carboxylic acid, l-benzyl-2,3-dimethyl-lH-indole-7-carboxylic acid,
2-acetyl-5-benzyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole-6-carboxylic acid, methyl 9-(3-nitrobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, 9-[3-(acetylamino)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-nitrobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-bromobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-3-carboxylate, 5-(2-fluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(4-fluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2,4-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2,5-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-[3-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
5-[4-(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid,
9-(2,6-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2-fluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-7-carboxylic acid, 9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(4-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2,5-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic cid, 9-(2,3-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-(2,4-difluorobenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-7-carboxylic acid, 9-[2-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 9-[4-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, 5-(2,3-difluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-(2,6-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,5-difluorobenzyl)-2,3,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(3-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 5-(3-fluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 5-(4-fluorobenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 9- [3 -(trifluoromethoxy)benzyl] -2, 3 ,4,9-tetrahydro- 1 H-carbazole-8 -carboxylic acid, 5-(2-fluorobenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-3-carboxylic acid, 9-[3-fluoro-5-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
9-[2-fluoro-6-(trifluoromethyl)benzyl]-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
9-(2-methylbenzyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(2,5-dichlorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3,4-difluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,3-difluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2-fluoro-3-methylbenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,5-dimethoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2-bromo-5-fluorobenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(3-phenoxybenzyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2-fluorobenzyl)-3 -methyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(3 -fluorobenzyl)-3 -methyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 9-(4-fluorobenzyl)-3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-(2,4-difluorobenzyl)-3 -methyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, 5-(3-methylbenzyl)-5, 6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, and • 5-(4-methylbenzyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid.
6. A method for making a compound according to any one of claims 1 to 5, comprising reacting a compound according to any of Examples 1-26 with one or more chemical reagents,
5 in one or more steps, to provide the compound.
7. A compound of the formula (I)
Figure imgf000122_0001
wherein o one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, -NHSO2CF3,
-NH-SO2-Cι-C6-alkyl, tetrazole or -NHSO2Ar, wherein Ar is selected from phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, 5 isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H- 1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene, and the other of R° and R1 is -H or -CH3; 0 R2= -H or -CH3, provided that if one of R° and R1 is -CH3, then R2 is -H;
R3= -H, -CO-Ci-Cβ-alkyl, -SO2-Cι-C6-alkyl, -CH(Rn)(CH2)mZ, wherein Rn = -H or Ci-Cβ-alkyl, m= 0, 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or-CONR12R13, wherein R12 and R13 are each independently -H, Ci-Cδ-alkyl or Cι-C6-hydroxyalkyl or
1 1
R and R form with the nitrogen to which they are both attached together a heterocycle selected from pyrrolidinyl, morpholinyl and piperidinyl, wherein the piperidinyl is optionally substituted with one or more hydroxy groups; or R3 is a group of the formula (II):
Figure imgf000123_0001
wherein
Ar is as defined above;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)-Cι-C6-alkyl, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; n = 0, 1 or 2;
R4 and R5 are each independently -H, or are absent, or R4 and R5 taken together are =O, =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent; A and B are each a carbon atom, -CH or a phenyl group; X = -CH, N or is absent;
Y is CH2 or is absent;
R7 and R8 are each independently -H, -COCF3, -SO2-Cι-C6-alkyl or are absent, or R7 and R8 taken together are =O; or pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof; for use in therapy.
8. A compound according to claim 7, wherein A and B are each a carbon atom; X is -CH orN;
Y is absent; which compound has the formula (III)
Figure imgf000124_0001
wherein R°, R1, R2, R3, R4, R5, R6, R7, R8, X, and n are as defined in claim 7.
9. A compound according to claim 7, wherein A and B are each a -CH or a phenyl group; X is absent; n = 0; R is absent;
Y is absent; which compound has the formula (IN)
Figure imgf000124_0002
wherein R°, R1, R2, R3, R4, R5, R7, R8, A, and B are as defined in claim 7.
10. The compound according to any one of claims 7 to 9, wherein one of R° and R1 is -COOH, -COOMe, -CH2OH, -CONHOH, trifluoromethanesulfonylamino, methanesulfonylamino or phenylsulfonylamino; and the other of R° and R1 is -H or -CH3;
R2= -H or -CH3, provided that if one of R° and R1 is -CH3, then R2 is -H;
R3= -H, -CH(Rn)(CH2)mZ, wherein R11 = H or methyl, m= 0, 1, 2, 3 or 4, Z = -H, -CN, -COOH, -COC1 or -CONR 1l2-RT. 13 wherein R12 and R13 are each independently -H, methyl, ethyl or 1 -hydroxyethyl or
1 1 ^
R and R form together with the nitrogen to which they are both attached a heterocycle selected from pyrrolidinyl, morpholinyl and 3-hydroxypiperidinyl; or R3 is a group of the formula (II), wherein
Ar is selected from phenyl, furan, pyridine, and pyrimidine;
R9 and R10 are each independently -H, -CH3, -OCH3, -F, -Br, -CI, -CF3, -CO2H, -NO2, -NH2, -NHC(O)CH3, -CN, -CONH2, -OH, -SCH3, -SO2CH3, -SO2CF3, -OCF3, -SCF3, or -OPh; n= 0, 1 or 2;
R and R are each independently -H, or are absent, or R and R5 taken together are =O, =NOH, or =NO-CH2-Ph;
R6 = -H, -CH3, -COCH3 or is absent;
A and B are each a carbon atom, -CH or a phenyl group; X = CH, N or is absent;
Y is CH2 or is absent;
R7 and R are each independently -H, -COCF3, methanesulfonyl or are absent, or R7 and R8 taken together are =O.
11. The compound according to any one of claims 7 to 10, which is selected from the compounds according to claim 5 and also the following compounds:
• 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
• methyl 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• 2,3,4,9-tetrahydro-lH-carbazole-7-carboxylic acid, • methyl 2,3,4,9-tetrahydro-lH-carbazole-7-carboxylate,
• 2, 3 -dimethyl- lH-indole-7-carboxylic acid,
• methyl 2,3 -dimethyl- lH-indole-7-carboxylate,
• 2,3-diphenyl-lH-indole-7-carboxylic acid,
• 6-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, • methyl 6-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
• methyl 3-methyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, methyl 9-butyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-butyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-pentyl-2,3 ,4,9-tetrahydro- 1 H-carbazole- 8-carboxylate,
9-pentyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-ethyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-ethyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
9-isopropyl-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylic acid, methyl 4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
4-oxo-2,3, 4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 4-hydroxyimino-2,3 ,4,9-tetrahydro- 1 H-carbazole-8-carboxylate,
4-hydroxyimino-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
9-benzyl-4-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate,
4-oxo-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, methyl 4-(hydroxyimino)-9-propyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate, methyl 10-oxo-5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylate,
10-oxo-5-propyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-benzyl-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate,
5-benzyl- 10-oxo-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, methyl 5-(3-cyanobenzyl)-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylate,
5-[3-(aminocarbonyl)benzyl]-10-oxo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid,
9-benzyl-l-oxo-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid,
N-(5-benzyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-yl)- 1,1,1- trifluoromethanesulfonamide, • N-[2-(trifluoromethyl)benzyl]-5,6,7,8,9, 10-hexahydrocyclohepta[b]indol-4-yl)-l , 1,1- trifluoromethanesulfonamide, and
• 9-(2-chlorobenzyl)-2,3,4,9-tetrahydro- lH-carbazole-8-carboxylic acid.
12. The compound according to any one of claims 7 to 11 for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
13. The compound according to claim 12, wherein the disorders are selected from type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
14. A pharmaceutical composition comprising a compound according to any one of claims 7 to 11 as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
15. A pharmaceutical composition for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
16. The pharmaceutical composition according to claim 15, wherein the disorders are selected from type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
17. The pharmaceutical composition according to any one of claims 14 to 16, further comprising an additional therapeutically active agent.
18. A method for the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 7 to 11.
19. A method according to claim 18, wherein the subject is a human.
20. The method according to any one of claims 18 to 19, wherein the disorders are selected from type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
21. A method for inhibiting FABP-4, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 7 to 11.
22. A method according to claim 21, wherein the subject is a human.
23. Use of a compound according to any one of claims 7 to 11 for the manufacture of a medicament for use in the prophylaxis or treatment of disorders acting on the fatty acid binding protein FABP-4.
24. The use according to claim 23, wherein the disorders are selected from type 2 diabetes, hyperglycemia, hyperlipidemia, hyperinsulinemia, obesity, atherosclerosis, other chronic anti-inflammatory and autoimmune/inflammatory diseases, and chronic heart disease.
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